Complicated Intra-Abdominal Infections, cIAIs
Conditions
Keywords
cIAIs in hospitalized adults
Brief summary
Determine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized adults with cIAI
Detailed description
A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults.
Interventions
DRUGATM-AVI
Cohort 1: (Creatinine clearance \> 50 mL/min)6500mg ATM/1777mg AVI on day 1 followed by total daily dose of 6000mg ATM/1640mg AVI Cohorts 2 and 3: (Creatinine clearance \> 50 mL/min) As above, or: 6500 mg ATM/2167 mg on Day 1 followed by a total daily dose of 6000 mg ATM/2000 m AVI (Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1162 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/820 mg AVI, or: 4250 mg ATM/1417 mg AVI on Day 1 followed by total daily dose 3000 mg ATM/1000 mg AVI
DRUGMetronidazole
Metronidazole 500mg infused over 1 hour every 8 hours
Sponsors
Innovative Medicines Initiative
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent 2. Male or female from 18 to 90 years 3. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met 4. Diagnosis of cIAI EITHER: Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry 5. Patients who failed prior antibacterial treatment for their current cIAI can be enrolled but must: * Have a known or suspected pathogen causing cIAI that is resistant to the prior therapy * Require surgical intervention. 6. Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug
Exclusion criteria
1. Involvement in the planning and/or conduct of the study 2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigational study containing AVI 3. Patient has participated or intends to participate in any other clinical study that involves the administration of a study drug during the course of the study, or during the 30 days prior to study start. 4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs 5. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery within 24 hours of diagnosis primary etiology is not likely to be infectious 6. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation 7. Staged abdominal repair (STAR), open abdomen technique or where infection source control is not likely to be achieved; unlikely to solely respond to antimicrobial therapy 8. Infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole 9. Rapidly progressive or terminal illness 10. Systemic antibacterial agents received within the 72- hour period prior to study entry, unless: 1. A new infection and no more than 24 hours of prior antibiotic treatment received within the 72 hour period prior to study entry or 2. Patient is considered to have failed the previous treatment 11. Concurrent infection that may interfere with the evaluation of clinical cure for the study therapy 12. requirement for effective concomitant systemic antibacterials or antifungals 13. Creatinine clearance ≤30 ml/min or requirement for renal replacement therapy 14. Acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure 15. Hepatic disease as indicated by AST or ALT \>3 × ULN. Patients with AST and/or ALT \>3 × ULN and \< 5 × ULN are eligible if acute, not accompanied by a total bilirubin ≥ 2xULN and documented by the investigator as being directly related to cIAI. 16. Patient has a total bilirubin \>3 × ULN, unless isolated hyperbilirubinemia is directly related to cIAI or due to known Gilbert's disease 17. ALP \>3 × ULN. Patients with values \>3 × ULN and \<5 x ULN are eligible if acute and directly related to the infectious process being treated. 18. Immunocompromising illness 19. Active Clostridium difficile associated diarrhoea 20. Any other condition that may confound the results of the study or pose additional risks 21. Do not resuscitate order 22. Absolute neutrophil count \<1000/μL 23. Hematocrit \<25% or hemoglobin \<8 gm/dL. 24. Platelet count \<75,000/μL. 25. Currently receiving probenecid. 26. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control. 27. Unlikely to comply with protocol, 28. Currently receiving anti-convulsant therapy to prevent recurrence of a past history of seizures. 29. Prior liver, pancreas or small-bowel transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | From first dose of study drug up to the LFU visit (up to maximum of 38 days) | Physical examinations included an assessment of abdomen, cardiovascular, general appearance, head, eyes, ears, nose, lymph nodes, skin, musculoskeletal, neurological, respiratory systems and other (edemas). Clinically significant abnormality in physical examination was based on investigator's assessment. LFU visit occured within 20 to 24 days after last infusion. |
| Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug up to the LFU visit (up to maximum of 38 days) | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAEs was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or was an important medical event which may jeopardise the participants or require medical intervention to prevent one of the above outcomes. Treatment-emergent were events between first infusion of study drug and up to late follow-up (LFU) visit (20 to 24 days after last infusion). AEs included both non-serious AEs and SAEs. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Baseline up to EOT (up to a maximum of 15 days) | Criteria for ECG abnormalities: QT value: greater than or equal to (\>=) 450 milliseconds (msec), \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT: \>=30 msec, \>=60 msec. Decrease from baseline in QT: \>=30 msec, \>=60 msec. QTcB value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT interval using Bazett's correction (QTcB) value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcB: \>=30 msec, \>=60 msec. QT interval using Fridericia's correction (QTcF) value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QTcF value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcF value: \>=30 msec, \>=60 msec. EOT (end of treatment) visit occurred within 24 hours after last infusion. |
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Baseline up to LFU visit (up to maximum of 38 days) | Criteria for abnormality: Hemoglobin, hematocrit, erythrocytes less than(\<) 0.7\*lower limit of normal \[LLN\] and (&) greater than (\>) 30 percent (%) below baseline \[BB\]; \>1.3\*upper limit of normal \[ULN\] & \>30% above baseline \[AB\], leukocytes \<0.65\*LLN & \>60% BB; \>1.6\* ULN & \>100% AB; platelets \<0.65\*LLN & \>50% BB; \>1.5\*ULN & \>100% AB; neutrophils \<0.65\*LLN & \>75% BB; \>1.6\*ULN & \>100% AB, lymphocytes \<0.25\*LLN & \>75%BB; \>1.5\*ULN & \>100% AB, basophils, eosinophils, monocytes\>4.0\*ULN & \>300% AB. LFU visit occurred within 20 to 24 days after last infusion. |
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Baseline up to LFU visit (up to maximum of 38 days) | Criteria for abnormality: aspartate aminotransferase, alanine aminotransferase \>3.0\*ULN & \>100% AB, alkaline phosphatase \<0.5 \*LLN & \>80% BB&; \>3.0\*ULN & \>100% AB; bilirubin \>1.5\*ULN & \>100% AB; direct bilirubin \>2.0\*ULN & \>150% AB; protein \<0.5\*LLN & \>50%BB; \>1.5\*ULN & \>50% AB, albumin \<0.5\*LLN & \>50% BB; \>1.5\*ULN & \>50% AB, urea nitrogen \<0.2\* LLN & \>100% BB; \>3.0\*ULN & \>200% AB, creatinine \>2.0\*ULN & \>100% AB, sodium \<0.85\*LLN & \>10% BB;\>1.1\*ULN &\>10% AB; potassium \<0.8\*LLN &\>20% BB; \>1.2\*ULN &\>20% AB, chloride \<0.8\*LLN &\>20% BB;\>1.2\*ULN & \>20% AB, calcium \<0.7\*LLN & \>30% BB; \>1.3\*ULN & \>30% AB, phosphate \<0.5\*LLN & \>50% BB; \>3.0\*ULN & \>200% AB, bicarbonate \<0.7\*LLN & \>40% BB; \>1.3\*ULN & \>40% AB, glucose \<0.6\*LLN & \>40% BB, \>3.0\*ULN & \>200% AB. LFU visit occurred within 20 to 24 days after last infusion. |
| Number of Participants With Clinically Significant Vital Signs | From first dose of study drug up to LFU visit (up to maximum of 38 days) | Vital sign parameters included: Supine systolic blood pressure (millimeters of mercury \[mmHg\]), Supine diastolic blood pressure (mmHg), Heart rate (beats per minute), Respiratory rate (breaths per minute) and body temperature (degree celsius). Criteria for clinical significance in vital signs was based on investigator's assessment. LFU visit occurred within 20 to 24 days after last infusion. |
| Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr | Predose (0 hr) on Day 1 | All participants were to have sparse pharmacokinetics (PK) sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above lower limit of quantification (LLOQ). LLOQ for ATM was 0.1 microgram per milliliter (mcg/ml). |
| Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr | 0.42 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr | 3.25 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr | 5 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr | Predose (0 hr) on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 nanogram per milliliter (ng/ml). |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr | 0.42 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr | 3.25 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr | 5 hr Post dose on Day 1 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr | Predose (0 hr) on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr | 2.75 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr | 5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr | Predose (0 hr) on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr | 2.75 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr | 5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr | Predose (0 hr) on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr | 0.5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr | 1 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr | 2 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr | 3 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr | 3.25 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr | 3.5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr | 3.75 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr | 4 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr | 5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr | 6 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr | Predose (0 hr) on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr | 0.5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | — |
| Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | — |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr | 1 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr | 2 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr | 3 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr | 3.25 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr | 3.5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr | 3.75 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr | 4 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr | 5 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr | 6 hr Post dose on Day 4 | All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml. |
| Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | — |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration. |
| Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | — |
| Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | Plasma elimination half-life was defined as time measured for the plasma concentration of ATM and AVI to decrease by one half of its initial concentration. |
| Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | Apparent volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
| Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 | Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population | Test of Cure Visit (up to a maximum of 28 days) | Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days) | AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days) | AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days) | AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose. |
| Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days) | AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose. |
| Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population | Test of Cure Visit (up to a maximum of 28 days) | Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose. |
Countries
France, Germany, Spain
Participant flow
Pre-assignment details
The study was conducted at 11 centers in 3 countries from 19-May-2016 to 26-Oct-2017.
Participants by arm
| Arm | Count |
|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort Participants with normal renal function or mild renal impairment (CrCl \> 50 mL/min), received IV infusion of 500 mg ATM plus 137 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 410 mg AVI, over a 3 hour period every 6 hours, for a minimum of 5 days and up to maximum of 14 days. Participants also received 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion for a minimum of 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator. | 16 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort Participants received ATM-AVI IV infusion in following manner (1. normal renal function or mild renal impairment \[CrCl \>50mL/min\] : 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by maintenance infusions of 1500 mg ATM plus 500 mg AVI, over a 3 hour period every 6 hours; 2. moderate renal impairment \[CrCl 31-50 ml/min\]: 500 mg ATM plus 167 mg AVI over 30 minutes as loading dose, followed by IV extended loading infusion of 1500 mg ATM plus 500 mg AVI over 3 hour, followed by maintenance infusions of 750 mg ATM plus 250 mg AVI, over 3 hour period every 6 hours) along with 1 hour IV infusion of 500 mg metronidazole, every 8 hrs after first ATM-AVI maintenance infusion. All treatments were administered for minimum 5 days and up to maximum of 14 days. All study therapies could be discontinued (after at least 5 full days of IV therapy) at the discretion of the investigator. | 18 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Enrolled but not treated | 1 | 5 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | ATM-AVI+ Metronidazole:Low AVI Dose Cohort | ATM-AVI + Metronidazole: High AVI Dose Cohort | Total |
|---|---|---|---|
| Age, Continuous | 49.00 years STANDARD_DEVIATION 12.47 | 53.06 years STANDARD_DEVIATION 14.25 | 51.15 years STANDARD_DEVIATION 13.4 |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 17 Participants | 30 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 12 Participants | 14 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 1 / 18 |
| other Total, other adverse events | 10 / 16 | 10 / 18 |
| serious Total, serious adverse events | 4 / 16 | 5 / 18 |
Outcome results
Primary
Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Clearance of a drug was measure of the rate at which a drug was metabolized or eliminated by normal biological processes.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 6.4 liter/hour | Geometric Coefficient of Variation 35.4 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 10.1 liter/hour | Geometric Coefficient of Variation 42.6 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 6.4 liter/hour | Geometric Coefficient of Variation 35.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Apparent Clearance (CL) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 10.5 liter/hour | Geometric Coefficient of Variation 41.4 |
Primary
Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Apparent volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 20.3 liter | Geometric Coefficient of Variation 16.9 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 26.0 liter | Geometric Coefficient of Variation 22 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 19.6 liter | Geometric Coefficient of Variation 31.8 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Apparent Volume of Distribution at Steady State (Vss) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 23.7 liter | Geometric Coefficient of Variation 29.7 |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4
AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4 | 40437.0 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 74 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Avibactam (AVI): Intensive Sampling at Day 4 | 47477.5 hour*nanogram per milliliter (hr*ng/mL) | Geometric Coefficient of Variation 79.2 |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4
AUC(0-6) was defined as the area under the plasma concentration-time curve from time zero up to the six hours postdose.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4 | 235.2 hour*microgram/milliliter (hr*mcg/mL) | Geometric Coefficient of Variation 60.6 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours (AUC[0-6]) for Aztreonam (ATM): Intensive Sampling at Day 4 | 234.7 hour*microgram/milliliter (hr*mcg/mL) | Geometric Coefficient of Variation 54.6 |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4
AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4 | 40539.5 hr*ng/mL | Standard Deviation 73.8 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Avibactam (AVI): Intensive Sampling at Day 4 | 47422.2 hr*ng/mL | Standard Deviation 79.3 |
Primary
Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4
AUC(0-last) was defined as the area under the plasma concentration-time curve from time zero up to the time of the last measurable concentration.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4 | 235.9 hr*mcg/mL | Geometric Coefficient of Variation 60.4 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to the Last Measured Concentration (AUC[0-last]) for Aztreonam (ATM): Intensive Sampling at Day 4 | 234.3 hr*mcg/mL | Geometric Coefficient of Variation 54.7 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4 | 11552.4 ng/mL | Geometric Coefficient of Variation 164.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Maximum Observed Plasma Concentration (Cmax) of Avibactam (AVI): Intensive Sampling at Day 4 | 12116.2 ng/mL | Geometric Coefficient of Variation 61.2 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4 | 62.5 mcg/mL | Geometric Coefficient of Variation 146.9 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Maximum Observed Plasma Concentration (Cmax) of Aztreonam (ATM): Intensive Sampling at Day 4 | 55.4 mcg/mL | Geometric Coefficient of Variation 42.6 |
Primary
Number of Participants With Clinically Significant Vital Signs
Vital sign parameters included: Supine systolic blood pressure (millimeters of mercury \[mmHg\]), Supine diastolic blood pressure (mmHg), Heart rate (beats per minute), Respiratory rate (breaths per minute) and body temperature (degree celsius). Criteria for clinical significance in vital signs was based on investigator's assessment. LFU visit occurred within 20 to 24 days after last infusion.
Time frame: From first dose of study drug up to LFU visit (up to maximum of 38 days)
Population: The safety analysis included all enrolled participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Supine diastolic blood pressure | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Respiratory rate | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Heart rate | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Temperature | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Supine systolic blood pressure | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Temperature | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Supine systolic blood pressure | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Supine diastolic blood pressure | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Heart rate | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinically Significant Vital Signs | Respiratory rate | 1 Participants |
Primary
Number of Participants With Clinical Significant Physical Examination Findings : MITT Population
Physical examinations included an assessment of abdomen, cardiovascular, general appearance, head, eyes, ears, nose, lymph nodes, skin, musculoskeletal, neurological, respiratory systems and other (edemas). Clinically significant abnormality in physical examination was based on investigator's assessment. LFU visit occured within 20 to 24 days after last infusion.
Time frame: From first dose of study drug up to the LFU visit (up to maximum of 38 days)
Population: The MITT population included all enrolled participants who received any amount of study drug. Here, 'number analysed' = Participants evaluable for this outcome measure at specified categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | General appearance | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Musculoskeletal system | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Cardiovascular | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Neurological system | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Other | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Head, Eyes, Ears, Nose | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Respiratory system | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Abdomen | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Skin | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Lymph nodes | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Skin | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Abdomen | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Cardiovascular | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | General appearance | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Head, Eyes, Ears, Nose | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Lymph nodes | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Musculoskeletal system | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Other | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Respiratory system | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Clinical Significant Physical Examination Findings : MITT Population | Neurological system | 0 Participants |
Primary
Number of Participants With Electrocardiogram (ECG) Abnormalities
Criteria for ECG abnormalities: QT value: greater than or equal to (\>=) 450 milliseconds (msec), \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT: \>=30 msec, \>=60 msec. Decrease from baseline in QT: \>=30 msec, \>=60 msec. QTcB value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QT interval using Bazett's correction (QTcB) value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcB: \>=30 msec, \>=60 msec. QT interval using Fridericia's correction (QTcF) value: \>=450 msec, \>=480 msec, \>=500 msec, \>=500 and increase from baseline \>=60 msec. Increase from baseline in QTcF value: \>=30 msec, \>=60 msec. Decrease from baseline in QTcF value: \>=30 msec, \>=60 msec. EOT (end of treatment) visit occurred within 24 hours after last infusion.
Time frame: Baseline up to EOT (up to a maximum of 15 days)
Population: The safety analysis included all enrolled participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QT >=30 | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=480 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=500 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=500 and increase from baseline >=60 | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QT >=30 | 6 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QT>=60 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=450 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QT>=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=450 | 5 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=480 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=500 | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=500 and increase from baseline >=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcB >=30 | 3 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcB >=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcB >=30 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcB >=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=450 | 4 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=480 | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=500 | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=500 and increase from baseline >=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcF >=30 | 3 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcF >=60 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcF >=30 | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcF >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcF >=30 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=450 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcB >=30 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=480 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=500 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=500 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcB >=60 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QT value >=500 and increase from baseline >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcF >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QT >=30 | 4 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcB >=30 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QT>=60 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=500 and increase from baseline >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QT >=30 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcB >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QT>=60 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Decrease in QTcF >=60 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=450 | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=450 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=480 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | Increase in QTcF >=30 | 2 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=500 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcF value >=480 | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Electrocardiogram (ECG) Abnormalities | QTcB value >=500 and increase from baseline >=60 | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres
Criteria for abnormality: aspartate aminotransferase, alanine aminotransferase \>3.0\*ULN & \>100% AB, alkaline phosphatase \<0.5 \*LLN & \>80% BB&; \>3.0\*ULN & \>100% AB; bilirubin \>1.5\*ULN & \>100% AB; direct bilirubin \>2.0\*ULN & \>150% AB; protein \<0.5\*LLN & \>50%BB; \>1.5\*ULN & \>50% AB, albumin \<0.5\*LLN & \>50% BB; \>1.5\*ULN & \>50% AB, urea nitrogen \<0.2\* LLN & \>100% BB; \>3.0\*ULN & \>200% AB, creatinine \>2.0\*ULN & \>100% AB, sodium \<0.85\*LLN & \>10% BB;\>1.1\*ULN &\>10% AB; potassium \<0.8\*LLN &\>20% BB; \>1.2\*ULN &\>20% AB, chloride \<0.8\*LLN &\>20% BB;\>1.2\*ULN & \>20% AB, calcium \<0.7\*LLN & \>30% BB; \>1.3\*ULN & \>30% AB, phosphate \<0.5\*LLN & \>50% BB; \>3.0\*ULN & \>200% AB, bicarbonate \<0.7\*LLN & \>40% BB; \>1.3\*ULN & \>40% AB, glucose \<0.6\*LLN & \>40% BB, \>3.0\*ULN & \>200% AB. LFU visit occurred within 20 to 24 days after last infusion.
Time frame: Baseline up to LFU visit (up to maximum of 38 days)
Population: The safety analysis included all enrolled participants who received any amount of study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Protein: >1.5*ULN&>50% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Sodium: >1.1*ULN&>10%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bilirubin: >1.5*ULN&>100%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Potassium: <0.8*LLN&>20%BB | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Albumin: <0.5*LLN&>50%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Potassium: >1.2*ULN&>20%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alanine aminotransferase:>3.0x ULN | 2 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Chloride: <0.8*LLN&>20%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Albumin: >1.5*ULN&>50%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Chloride: >1.2*ULN&>20%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Direct Bilirubin : >2.0*ULN&>150% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Calcium: <0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Urea nitrogen: <0.2* LLN&>100%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Calcium: >1.3*ULN&>30%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alkaline phosphatase:>3.0*ULN&>100%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Phosphate: <0.5*LLN&>50% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Urea nitrogen: >3.0*ULN&>200%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Phosphate: >3.0*ULN&>200% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Protein: <0.5*LLN &>50%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bicarbonate: <0.7*LLN&>40% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Creatinine: >2.0*ULN&>100%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bicarbonate: >1.3*ULN&>40%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alkaline phosphatase: <0.5 *LLN&>80% BB& | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Glucose: <0.6*LLN&>40% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Sodium: < 0.85*LLN&>10%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Glucose: >3.0*ULN&>200%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Aspartate aminotransferase: >3.0*ULN&>100% AB | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Glucose: >3.0*ULN&>200%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Aspartate aminotransferase: >3.0*ULN&>100% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alanine aminotransferase:>3.0x ULN | 2 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alkaline phosphatase: <0.5 *LLN&>80% BB& | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Alkaline phosphatase:>3.0*ULN&>100%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bilirubin: >1.5*ULN&>100%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Direct Bilirubin : >2.0*ULN&>150% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Protein: <0.5*LLN &>50%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Protein: >1.5*ULN&>50% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Albumin: <0.5*LLN&>50%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Albumin: >1.5*ULN&>50%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Urea nitrogen: <0.2* LLN&>100%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Urea nitrogen: >3.0*ULN&>200%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Creatinine: >2.0*ULN&>100%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Sodium: < 0.85*LLN&>10%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Sodium: >1.1*ULN&>10%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Potassium: <0.8*LLN&>20%BB | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Potassium: >1.2*ULN&>20%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Chloride: <0.8*LLN&>20%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Chloride: >1.2*ULN&>20%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Calcium: <0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Calcium: >1.3*ULN&>30%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Phosphate: <0.5*LLN&>50% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Phosphate: >3.0*ULN&>200% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bicarbonate: <0.7*LLN&>40% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Bicarbonate: >1.3*ULN&>40%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Clinical Chemistry Paramteres | Glucose: <0.6*LLN&>40% BB | 0 Participants |
Primary
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters
Criteria for abnormality: Hemoglobin, hematocrit, erythrocytes less than(\<) 0.7\*lower limit of normal \[LLN\] and (&) greater than (\>) 30 percent (%) below baseline \[BB\]; \>1.3\*upper limit of normal \[ULN\] & \>30% above baseline \[AB\], leukocytes \<0.65\*LLN & \>60% BB; \>1.6\* ULN & \>100% AB; platelets \<0.65\*LLN & \>50% BB; \>1.5\*ULN & \>100% AB; neutrophils \<0.65\*LLN & \>75% BB; \>1.6\*ULN & \>100% AB, lymphocytes \<0.25\*LLN & \>75%BB; \>1.5\*ULN & \>100% AB, basophils, eosinophils, monocytes\>4.0\*ULN & \>300% AB. LFU visit occurred within 20 to 24 days after last infusion.
Time frame: Baseline up to LFU visit (up to maximum of 38 days)
Population: The safety analysis included all enrolled participants who received any amount of study drug. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Platelets: >1.5*ULN&>100% AB | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Neutrophils:<0.65*LLN&>75% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Neutrophils: >1.6*ULN & >100% AB | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Lymphocytes: <0.25*LLN&>75%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Lymphocytes: >1.5*ULN&>100%AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Basophils: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Eosinophils: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Monocytes: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hemoglobin: <0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hemoglobin: >1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hematocrit: <0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hematocrit:>1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Erythrocytes:<0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Erythrocytes: >1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Leukocytes: <0.65*LLN&>60%BB | 0 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Leukocytes:>1.6* ULN&>100%AB | 1 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Platelets: <0.65*LLN&>50%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Erythrocytes: >1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Platelets: >1.5*ULN&>100% AB | 5 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hemoglobin: >1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Neutrophils:<0.65*LLN&>75% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Lymphocytes: >1.5*ULN&>100%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Neutrophils: >1.6*ULN & >100% AB | 1 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hematocrit: <0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Lymphocytes: <0.25*LLN&>75%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Leukocytes: <0.65*LLN&>60%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hematocrit:>1.3*ULN&>30% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Basophils: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Platelets: <0.65*LLN&>50%BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Eosinophils: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Erythrocytes:<0.7*LLN&>30% BB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Monocytes: >4.0*ULN&>300% AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Leukocytes:>1.6* ULN&>100%AB | 0 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Potentially Clinically Significant Laboratory Abnormalities in Hematology Parameters | Hemoglobin: <0.7*LLN&>30% BB | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAEs was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; or was an important medical event which may jeopardise the participants or require medical intervention to prevent one of the above outcomes. Treatment-emergent were events between first infusion of study drug and up to late follow-up (LFU) visit (20 to 24 days after last infusion). AEs included both non-serious AEs and SAEs.
Time frame: From first dose of study drug up to the LFU visit (up to maximum of 38 days)
Population: The safety analysis included all enrolled participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 11 Participants |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 12 Participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 Participants |
Primary
Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 0.5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr | 37.6 mcg/mL | Geometric Coefficient of Variation 194 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0.5 hr | 33.8 mcg/mL | Geometric Coefficient of Variation 46 |
Primary
Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: Predose (0 hr) on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr | 18.3 mcg/mL | Geometric Coefficient of Variation 71.2 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration Aztreonam (ATM): Intensive Sampling at Day 4, 0 hr | 20.3 mcg/mL | Geometric Coefficient of Variation 88.5 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 0.5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr | 6374.4 ng/mL | Geometric Coefficient of Variation 215.4 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0.5 hr | 7140.3 ng/mL | Geometric Coefficient of Variation 69.3 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: Predose (0 hr) on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr | 2516.2 ng/mL | Geometric Coefficient of Variation 85.6 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 0 hr | 3184.3 ng/mL | Geometric Coefficient of Variation 137.5 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 1 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr | 7369.8 ng/mL | Geometric Coefficient of Variation 59.2 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 1 hr | 9435.7 ng/mL | Geometric Coefficient of Variation 64.4 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 2 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr | 8885.4 ng/mL | Geometric Coefficient of Variation 48.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 2 hr | 11668.0 ng/mL | Geometric Coefficient of Variation 59.5 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 3.25 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr | 8009.9 ng/mL | Geometric Coefficient of Variation 38.7 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.25 hr | 9631.5 ng/mL | Geometric Coefficient of Variation 66 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 3.5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr | 7095.8 ng/mL | Geometric Coefficient of Variation 43.9 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.5 hr | 8545.4 ng/mL | Geometric Coefficient of Variation 83.8 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 3.75 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr | 6340.3 ng/mL | Geometric Coefficient of Variation 50.3 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3.75 hr | 7227.1 ng/mL | Geometric Coefficient of Variation 88.4 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 3 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr | 9820.4 ng/mL | Geometric Coefficient of Variation 100.1 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 3 hr | 11903.2 ng/mL | Geometric Coefficient of Variation 62.6 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 4 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr | 5258.7 ng/mL | Geometric Coefficient of Variation 49.9 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 4 hr | 6727.6 ng/mL | Geometric Coefficient of Variation 94.2 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr | 3300.0 ng/mL | Geometric Coefficient of Variation 59.7 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 5 hr | 4300.3 ng/mL | Geometric Coefficient of Variation 120.9 |
Primary
Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 6 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr | 3275.7 ng/mL | Geometric Coefficient of Variation 205.4 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Intensive Sampling at Day 4, 6 hr | 2879.2 ng/mL | Geometric Coefficient of Variation 140.1 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 0.42 hr Post dose on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr | 7852.6 ng/mL | Geometric Coefficient of Variation 279.2 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0.42 hr | 9801.5 ng/mL | Geometric Coefficient of Variation 61.8 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 nanogram per milliliter (ng/ml).
Time frame: Predose (0 hr) on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 0 hr | 24.9 nanogram per milliliter (ng/mL) |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 3.25 hr Post dose on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr | 9976.5 ng/mL | Geometric Coefficient of Variation 25.8 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 3.25 hr | 12982.7 ng/mL | Geometric Coefficient of Variation 49.7 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 5 hr Post dose on Day 1
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr | 4086.6 ng/mL | Geometric Coefficient of Variation 35.3 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 1, 5 hr | 5549.0 ng/mL | Geometric Coefficient of Variation 76.6 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: Predose (0 hr) on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 0 hr | 4048.8 ng/mL | Geometric Coefficient of Variation 24.3 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 2.75 hr Post dose on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 2.75 hr | 9073.6 ng/mL | Geometric Coefficient of Variation 24.2 |
Primary
Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for AVI was 10 ng/ml.
Time frame: 5 hr Post dose on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Avibactam (AVI): Sparse Sampling at Day 4, 5 hr | 2745.7 ng/mL | Geometric Coefficient of Variation 40.5 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 1 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr | 41.2 mcg/mL | Geometric Coefficient of Variation 53.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 1 hr | 43.0 mcg/mL | Geometric Coefficient of Variation 44.7 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 2 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr | 49.6 mcg/mL | Geometric Coefficient of Variation 42.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 2 hr | 53.6 mcg/mL | Geometric Coefficient of Variation 44.7 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 3.25 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr | 45.8 mcg/mL | Geometric Coefficient of Variation 36.7 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.25 hr | 47.3 mcg/mL | Geometric Coefficient of Variation 49.8 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 3.5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr | 42.9 mcg/mL | Geometric Coefficient of Variation 37.9 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.5 hr | 43.2 mcg/mL | Geometric Coefficient of Variation 52.1 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 3.75 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr | 39.5 mcg/mL | Geometric Coefficient of Variation 41.8 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3.75 hr | 38.5 mcg/mL | Geometric Coefficient of Variation 57.6 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 3 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr | 53.6 mcg/mL | Geometric Coefficient of Variation 72 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 3 hr | 54.7 mcg/mL | Geometric Coefficient of Variation 42.1 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 4 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr | 34.2 mcg/mL | Geometric Coefficient of Variation 44.2 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 4 hr | 36.6 mcg/mL | Geometric Coefficient of Variation 63.3 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 5 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr | 23.8 mcg/mL | Geometric Coefficient of Variation 56.1 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 5 hr | 26.4 mcg/mL | Geometric Coefficient of Variation 76.8 |
Primary
Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 6 hr Post dose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr | 22.2 mcg/mL | Geometric Coefficient of Variation 149.8 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Intensive Sampling at Day 4, 6 hr | 19.0 mcg/mL | Geometric Coefficient of Variation 97.1 |
Primary
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 0.42 hr Post dose on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr | 39.0 mcg/mL | Geometric Coefficient of Variation 262 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0.42 hr | 39.4 mcg/mL | Geometric Coefficient of Variation 58.1 |
Primary
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr
All participants were to have sparse pharmacokinetics (PK) sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above lower limit of quantification (LLOQ). LLOQ for ATM was 0.1 microgram per milliliter (mcg/ml).
Time frame: Predose (0 hr) on Day 1
Population: PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 1, 0 hr | 0.1 microgram per milliliter (mcg/mL) |
Primary
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: Predose (0 hr) on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 0 hr | 19.7 mcg/mL | Geometric Coefficient of Variation 29 |
Primary
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 2.75 hr Post dose on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 2.75 hr | 46.4 mcg/mL | Geometric Coefficient of Variation 19.5 |
Primary
Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 5 hr Post dose on Day 4
Population: PK population: all participants who had at least 1 plasma concentration data available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ. Intensive rather than sparse sampling was conducted for all participants in low AVI dose cohort(Cohort 1)on Day4 and hence sparse data not reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentration of Aztreonam (ATM): Sparse Sampling at Day 4, 5 hr | 16.5 mcg/mL | Geometric Coefficient of Variation 37.3 |
Primary
Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 3.25 hr Post dose on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr | 55.7 mcg/mL | Geometric Coefficient of Variation 16 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 3.25 hr | 58.5 mcg/mL | Geometric Coefficient of Variation 36.3 |
Primary
Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr
All participants were to have sparse PK sampling on Day 1; the first sequentially enrolled 25 participants in study were to have intensive PK sampling on Day 4 while the remaining participants were to have sparse sampling on Day 4. Data was summarized only for observations above LLOQ. LLOQ for ATM was 0.1 mcg/ml.
Time frame: 5 hr Post dose on Day 1
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies participants who had observations above LLOQ.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr | 28.8 mcg/mL | Geometric Coefficient of Variation 23.9 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Concentrations of Aztreonam (ATM): Sparse Sampling at Day 1, 5 hr | 31.5 mcg/mL | Geometric Coefficient of Variation 50.8 |
Primary
Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Plasma elimination half-life was defined as time measured for the plasma concentration of ATM and AVI to decrease by one half of its initial concentration.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 2.3 hours | Standard Deviation 1.06 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 1.8 hours | Standard Deviation 0.59 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 2.8 hours | Standard Deviation 2.05 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Plasma Elimination Half-life (t1/2) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 2.2 hours | Standard Deviation 1.85 |
Primary
Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 6.0 hours |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 6.0 hours |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 6.0 hours |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Time of Last Measured Concentration (Tlast) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 6.0 hours |
Primary
Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 2.9 hours |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 2.9 hours |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 2.4 hours |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Time of Observed Maximum Concentration (Tmax) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 2.8 hours |
Primary
Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4
Apparent volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4
Population: The PK population included all participants who had at least 1 plasma concentration data assessment available for ATM-AVI. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 21.4 liter | Standard Deviation 15.3 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 28.2 liter | Standard Deviation 20.4 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | ATM | 21.6 liter | Standard Deviation 24.1 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Volume of Distribution (Vz) of Aztreonam (ATM) and Avibactam (AVI): Intensive Sampling at Day 4 | AVI | 27.4 liter | Standard Deviation 20.6 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
Population: The MITT population included all enrolled participants who received any amount of study drug. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified categories. AUC0-6 was assessed on Day 4 and presented in this OM, only for those participants who had clinical cure or failure at TOC visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Cure | 38003.8 hr*ng/mL | Geometric Coefficient of Variation 45.7 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Failure | 49730.0 hr*ng/mL | Geometric Coefficient of Variation 100.1 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Cure | 40314.0 hr*ng/mL | Geometric Coefficient of Variation 36.1 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Failure | 34633.7 hr*ng/mL | Geometric Coefficient of Variation 10.2 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
Population: mMITTpopulation set was used in this analysis. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified categories. AUC0-6 was assessed on Day 4 and presented in this OM, only for those participants who had clinical cure or failure at TOC visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Cure | 42401.9 hr*ng/mL | Geometric Coefficient of Variation 41.9 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Failure | 75509.9 hr*ng/mL | Geometric Coefficient of Variation 84.3 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Avibactam (AVI) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Cure | 60302.1 hr*ng/mL | — |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population)
AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
Population: The MITT population included all enrolled participants who received any amount of study drug. Here, 'Number analyzed' = Participants evaluable for this outcome measure at specified categories. AUC0-6 was assessed on Day 4 and presented in this OM, only for those participants who had clinical cure or failure at TOC visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Cure | 226.0 hr*mcg/mL | Geometric Coefficient of Variation 43 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Failure | 268.9 hr*mcg/mL | Geometric Coefficient of Variation 88.3 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Cure | 218.7 hr*mcg/mL | Geometric Coefficient of Variation 28.5 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (MITT Population) | Clinical Failure | 169.8 hr*mcg/mL | Geometric Coefficient of Variation 14.9 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population)
AUC(0-6): area under the plasma concentration-time curve from time 0 upto the 6hrs. Clinical cure;complete resolution or significant improvement of signs and symptoms of the index infection(cIAI)such as no further antimicrobial therapy, drainage, or surgical intervention necessary and does not meet any of failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. Data of AUC(0-6) based on intensive sampling at Day4, is reported in this outcome separately and only for those participants who had clinical response of cure and failure at TOC Visit. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Plasma samples collection for AUC0-6 at: predose, 0.5 1, 2, 3, 3.25, 3.5, 3.75, 4, 5 and 6 hour postdose on Day 4 assessed for participants with cure and failure at Test of Cure Visit (up to a maximum of 28 days)
Population: mMITTpopulation set was used in this analysis. Here, 'Number analyzed' = participants evaluable for this outcome measure at specified categories. AUC0-6 was assessed on Day 4 and presented in this OM, only for those participants who had clinical cure or failure at TOC visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Cure | 245.3 hr*mcg/mL | Geometric Coefficient of Variation 41.4 |
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Failure | 378.0 hr*mcg/mL | Geometric Coefficient of Variation 77 |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Area Under the Plasma Concentration Time Curve From Time Zero up to 6 Hours [AUC(0-6)] of Aztreonam (ATM) for Participants With Clinical Cure and Failure at TOC Visit: Intensive Sampling at Day 4 (mMITT Population) | Clinical Cure | 292.7 hr*mcg/mL | — |
Secondary
Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population
Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Test of Cure Visit (up to a maximum of 28 days)
Population: The MITT population included all enrolled participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population | 62.5 percentage of participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Percentage of Participants With Clinical Cure at Test of Cure (TOC) Visit: MITT Population | 55.6 percentage of participants |
Secondary
Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population
Clinical cure is defined as complete resolution or significant improvement of signs and symptoms of the index infection (cIAI) such as no further antimicrobial therapy, drainage, or surgical intervention is necessary and does not meet any of the failure criteria. Failure: death related to intra-abdominal infection; received treatment with additional antibiotics for ongoing symptoms of cIAI; previously met criteria for failure; persisting or recurrent infection within the abdomen; post-surgical wound infections included an open wound with signs of local infection such as purulent exudates, erythema, or warmth that requires additional antibiotics and/or non-routine wound care. TOC visit occurred up to a maximum of 28 days after first dose.
Time frame: Test of Cure Visit (up to a maximum of 28 days)
Population: The mMITT population included all enrolled participants who had any amount of study drug and had a diagnosis of cIAI (that is,met inclusion criterion ) and an intraabdominal pathogen at baseline. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ATM-AVI+ Metronidazole:Low AVI Dose Cohort | Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population | 66.7 percentage of participants |
| ATM-AVI + Metronidazole: High AVI Dose Cohort | Percentage of Participants With Clinical Cure at TOC Visit: Microbiologically Modified Intent-to-Treat (mMITT) Population | 54.5 percentage of participants |