Complicated Intra-abdominal Infection
Conditions
Keywords
cIAI
Brief summary
This is a Phase 3, multicenter, prospective, randomized, double-blind, double dummy study of CXA-201 Intravenous (IV) infusions (1500mg q8h) and metronidazole (500mg q8h) versus meropenem (1000mg q8h)for the treatment of adults with Complicated Intraabdominal Infections (cIAI).
Detailed description
Approximately, 500 subjects will be enrolled into this study, randomized 1:1 to receive CXA-201 and metronidazole or comparator (meropenem). Subject participation will require a minimum commitment of 38 days and a maximum of 45 days. An End of Treatment (EOT) visit will occur within 24 hours following the last dose of study drug administration/drug discontinuation. A Test of Cure (TOC)/Safety visit will be conducted 26 to 30 days following the first dose of study drug administration. A Last Follow-up (LFU) visit will be conducted 38 to 45 days after the first dose of study drug.
Interventions
DRUGCXA-201 and metronidazole
CXA-201 IV infusion (1500mg q8h) and metronidazole IV infusion (500mg q 8h) for 4-14 days
DRUGMeropenem
Meropenem IV infusion (1000mg q8h) for 4-14 days
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnoses of cIAI. * Subject requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of (before or after) the first dose of study drug.
Exclusion criteria
* Simple appendicitis; acute suppurative cholangitis; infected necrotizing pancreatitis; pancreatic abscess; or pelvic infections. * Complicated intraabdominal infection managed by staged abdominal repair (STAR), open abdomen technique including temporary closure of the abdomen, or any situation where infection source control is not likely to be achieved. * Use of systemic antibiotic therapy for IAI for more than 24 hours prior to the first dose of study drug, unless there is a documented treatment failure with such therapy. * Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity \[e.g., daptomycin, vancomycin, linezolid\] are allowed). * Severe impairment of renal function (estimated CrCl \< 30 mL/min), or requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (\< 20 mL/h urine output over 24 hours). * The presence of hepatic disease at baseline. * Considered unlikely to survive the 4 to 5 week study period. * Any rapidly-progressing disease or immediately life-threatening illness (including respiratory failure and septic shock). * Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibacterial (a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment), including cephalosporins, carbapenems, penicillins, or ß-lactamase inhibitors, or metronidazole, or nitroimidazole derivatives. * Women who are pregnant or nursing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Subjects With Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Intent to Treat (MITT) Population | TOC; 26-30 days after start of study drug administration | Clinical cure is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Subjects With Microbiological Outcome of Success at the TOC Visit in the Microbiologically Evaluable (ME) Population | TOC; 26-30 days after start of study drug administration | Success is eradication (absence of the baseline pathogen in a specimen appropriately obtained from the original site of infection) or presumed eradication (absence of material to culture in a subject who was assessed as a clinical cure) for each baseline pathogen |
| The Percentage of Subjects With Clinical Response at End of Therapy (EOT) Visit in the MITT Population | EOT; Within 24 hours of last study drug administration | Clinical response is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection. |
| The Percentage of Subjects With Clinical Response at End of Therapy in the ME Population | EOT; Within 24 hours of last study drug administration | Clinical response is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection. |
| The Percentage of Subjects With Clinical Response at Long Term Follow-Up (LFU) in the MITT Population | LFU; 38 to 45 days after first study drug administration | Clinical response is clinical cure at TOC and no signs and symptoms recur or worsen since the TOC visit. |
| The Percentage of Subjects With Clinical Response at LFU Visit in the ME Population | LFU; 38 to 45 days after first study drug administration | Clinical response is clinical cure at TOC and no signs and symptoms recur or worsen since the TOC visit |
Countries
Argentina, Bulgaria, Chile, Croatia, Estonia, Germany, Hungary, Israel, Latvia, Lithuania, Moldova, Poland, Serbia, South Korea, United States
Participant flow
Pre-assignment details
Two identical P3 protocols were initiated (NCT01445678 and NCT01445665) subsequently, Cubist and FDA agreed that integrated data from the 2 protocols could be analyzed and reported in a single Clinical Study Report. A total of 993 subjects were randomized to both arms, 493 to NCT5678 and 500 to NCT5665. Of these, 485 and 494 received treatment.
Participants by arm
| Arm | Count |
|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI CXA-201 and metronidazole: CXA-201 IV infusion (1500mg q8h) and metronidazole IV infusion (500mg q 8h) for 4-14 days | 482 |
| Meropenem as Treatment for cIAI Meropenem: Meropenem IV infusion (1000mg q8h) for 4-14 days | 497 |
| Total | 979 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 8 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 8 | 5 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 5 |
Baseline characteristics
| Characteristic | CXA-201 and Metronidazole as Treatment for cIAI | Meropenem as Treatment for cIAI | Total |
|---|---|---|---|
| Age, Continuous | 50.6 years STANDARD_DEVIATION 17.94 | 50.5 years STANDARD_DEVIATION 16.85 | 50.5 years STANDARD_DEVIATION 17.38 |
| Sex: Female, Male Female | 206 Participants | 195 Participants | 401 Participants |
| Sex: Female, Male Male | 276 Participants | 302 Participants | 578 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 159 / 482 | 138 / 497 |
| serious Total, serious adverse events | 39 / 482 | 36 / 497 |
Outcome results
Primary
The Percentage of Subjects With Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Intent to Treat (MITT) Population
Clinical cure is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection.
Time frame: TOC; 26-30 days after start of study drug administration
Population: MITT: Randomized patients, with baseline pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Intent to Treat (MITT) Population | 83.0 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Intent to Treat (MITT) Population | 87.3 percentage of subjects |
95% CI: [-8.91, 0.54]
Secondary
The Percentage of Subjects With Clinical Response at End of Therapy (EOT) Visit in the MITT Population
Clinical response is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection.
Time frame: EOT; Within 24 hours of last study drug administration
Population: MITT: Microbiological Intent-to-Treat: Randomized patients, with baseline pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Clinical Response at End of Therapy (EOT) Visit in the MITT Population | 89.2 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Clinical Response at End of Therapy (EOT) Visit in the MITT Population | 92.3 percentage of subjects |
95% CI: [-7.23, 0.89]
Secondary
The Percentage of Subjects With Clinical Response at End of Therapy in the ME Population
Clinical response is complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure was required for the index infection.
Time frame: EOT; Within 24 hours of last study drug administration
Population: Microbiologically evaluable: Treated patients, complied with protocol, with pathogens susceptible to study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Clinical Response at End of Therapy in the ME Population | 97.1 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Clinical Response at End of Therapy in the ME Population | 97.5 percentage of subjects |
95% CI: [-3.4, 2.33]
Secondary
The Percentage of Subjects With Clinical Response at LFU Visit in the ME Population
Clinical response is clinical cure at TOC and no signs and symptoms recur or worsen since the TOC visit
Time frame: LFU; 38 to 45 days after first study drug administration
Population: Microbiologically evaluable: Treated patients, complied with protocol, with pathogens susceptible to study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Clinical Response at LFU Visit in the ME Population | 100 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Clinical Response at LFU Visit in the ME Population | 99.3 percentage of subjects |
95% CI: [-0.88, 2.37]
Secondary
The Percentage of Subjects With Clinical Response at Long Term Follow-Up (LFU) in the MITT Population
Clinical response is clinical cure at TOC and no signs and symptoms recur or worsen since the TOC visit.
Time frame: LFU; 38 to 45 days after first study drug administration
Population: MITT: Randomized patients, with baseline pathogen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Clinical Response at Long Term Follow-Up (LFU) in the MITT Population | 82.5 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Clinical Response at Long Term Follow-Up (LFU) in the MITT Population | 86.6 percentage of subjects |
95% CI: [-9.09, 0.94]
Secondary
The Percentage of Subjects With Microbiological Outcome of Success at the TOC Visit in the Microbiologically Evaluable (ME) Population
Success is eradication (absence of the baseline pathogen in a specimen appropriately obtained from the original site of infection) or presumed eradication (absence of material to culture in a subject who was assessed as a clinical cure) for each baseline pathogen
Time frame: TOC; 26-30 days after start of study drug administration
Population: Microbiologically evaluable: Treated patients, complied with protocol, with pathogens susceptible to study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CXA-201 and Metronidazole as Treatment for cIAI | The Percentage of Subjects With Microbiological Outcome of Success at the TOC Visit in the Microbiologically Evaluable (ME) Population | 94.2 percentage of subjects |
| Meropenem as Treatment for cIAI | The Percentage of Subjects With Microbiological Outcome of Success at the TOC Visit in the Microbiologically Evaluable (ME) Population | 94.7 percentage of subjects |
95% CI: [-4.52, 2.59]