Complicated Intra-abdominal Infections, Complicated Appendicitis
Conditions
Brief summary
This is a Phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics (PK) of eravacycline compared with meropenem in the treatment of complicated intra-abdominal infections (cIAIs).
Interventions
Sponsors
Tetraphase Pharmaceuticals, Inc
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
* Male or female participant hospitalized for cIAI * At least 18 years of age * Evidence of a systemic inflammatory response * Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area * Able to provide informed consent * If male: must agree to use an effective barrier method of contraception during the study and for 14 days following the last dose if sexually active with a female of childbearing potential * If female, not pregnant or nursing or, if of childbearing potential: either will commit to use at least two medically accepted, effective methods of birth control (for example, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring) during study drug dosing and for 14 days following last study drug dose or practicing sexual abstinence
Exclusion criteria
* Unlikely to survive the 6-8 week study period * Creatinine clearance of ≤50 milliliter (mL)/minute * Presence or possible signs of significant hepatic disease * Immunocompromised condition, including known human immunodeficiency virus (HIV) positivity, transplant recipients, and hematological malignancy * History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics, or to any of the excipients contained in the study drug formulations * Participation in any investigational drug or device study within 30 days prior to study entry * Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (for example, severe cerebral arteriosclerosis, epilepsy) * Antibiotic-related exclusions: 1. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of \>24-hours during the 72-hours preceding randomization \[however, participants with documented cIAI (that is, known baseline pathogen) who have received at least 72-hours of antibiotic therapy and are considered treatment failures may be enrolled. Treatment failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra-abdominal abscess after ≥72-hours of antibiotic therapy\], or 2. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, or 3. Need for concomitant systemic antimicrobial agents effective in cIAI other than study drug * Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion, or any other resuscitative measures and drug/fluid therapy at time of consent * Known or suspected inflammatory bowel disease or associated visceral abscess * The anticipated need for systemic antibiotics for a duration of more than 14 days * Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy, or antineoplastic therapy within the previous 3 months or that is anticipated to begin prior to the Test-of-Cure (TOC) visit * Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | TOC visit: 25-31 days after first dose of study drug | Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | TOC visit: 25-31 days after first dose of study drug | Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI. |
| Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population | TOC visit: 25-31 days after first dose of study drug | Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. |
Countries
Bulgaria, Czechia, Estonia, Georgia, Hungary, Latvia, Lithuania, Romania, Russia, Ukraine, United States
Participant flow
Recruitment details
Subjects with a diagnosis of complicated intra-abdominal infection (cIAI) requiring surgery were recruited into this study. Subjects were recruited in 65 centers worldwide. The first subject enrolled on 13 October 2016 and the last subject completed on 19 May 2017.
Participants by arm
| Arm | Count |
|---|---|
| Eravacycline Eravacycline 1.0 mg/kg q12h | 250 |
| Meropenem Meropenem 1 g q8h | 249 |
| Total | 499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Subject Non Compliance | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Meropenem | Eravacycline | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 75 Participants | 70 Participants | 145 Participants |
| Age, Categorical Between 18 and 65 years | 174 Participants | 180 Participants | 354 Participants |
| Age, Continuous | 52.8 years STANDARD_DEVIATION 18.24 | 52.1 years STANDARD_DEVIATION 17.69 | 52.4 years STANDARD_DEVIATION 17.931 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 238 Participants | 239 Participants | 477 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 7 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 249 Participants | 249 Participants | 498 Participants |
| Region of Enrollment Bulgaria | 41 participants | 52 participants | 93 participants |
| Region of Enrollment Czechia | 16 participants | 13 participants | 29 participants |
| Region of Enrollment Estonia | 11 participants | 20 participants | 31 participants |
| Region of Enrollment Georgia | 16 participants | 8 participants | 24 participants |
| Region of Enrollment Hungary | 20 participants | 10 participants | 30 participants |
| Region of Enrollment Latvia | 33 participants | 34 participants | 67 participants |
| Region of Enrollment Lithuania | 18 participants | 22 participants | 40 participants |
| Region of Enrollment Romania | 34 participants | 23 participants | 57 participants |
| Region of Enrollment Russia | 13 participants | 21 participants | 34 participants |
| Region of Enrollment Ukraine | 43 participants | 39 participants | 82 participants |
| Region of Enrollment United States | 4 participants | 8 participants | 12 participants |
| Sex: Female, Male Female | 120 Participants | 111 Participants | 231 Participants |
| Sex: Female, Male Male | 129 Participants | 139 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 250 | 1 / 249 |
| other Total, other adverse events | 29 / 250 | 8 / 249 |
| serious Total, serious adverse events | 15 / 250 | 16 / 249 |
Outcome results
Primary
Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population
Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.
Time frame: TOC visit: 25-31 days after first dose of study drug
Population: Microbiological Intent-to-Treat Population: all randomized subjects who have at least one baseline bacterial pathogen that causes cIAI and against which the investigational drug has in vitro antibacterial activity.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Clinical Cure | 177 Participants |
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Clinical Failure | 7 Participants |
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Indeterminate/missing | 11 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Clinical Cure | 187 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Clinical Failure | 7 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Indeterminate/missing | 11 Participants |
Secondary
Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population
Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI. Indeterminate/missing was defined as an outcome that was neither a clinical cure nor clinical failure, if the investigator did not complete an assessment, if a study visit was not conducted, or if the subject died for a cause unrelated to cIAI.
Time frame: TOC visit: 25-31 days after first dose of study drug
Population: Modified Intent-to-Treat Population: all randomized subjects who receive any amount of study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Clinical Cure | 231 Participants |
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Clinical Failure | 7 Participants |
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Indeterminate/missing | 12 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Clinical Cure | 228 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Clinical Failure | 9 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the All-Treated (MITT) Population | Indeterminate/missing | 12 Participants |
Secondary
Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population
Clinical cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no additional antibacterial therapy, surgical, or radiological intervention was required. Clinical failure was defined as death related to complicated intra-abdominal infection (cIAI), persistence of clinical symptoms of cIAI, unplanned surgical or percutaneous drainage procedures for complication or recurrence of cIAI, post-surgical wound infections requiring systemic antibiotics, or initiation of rescue antibacterial drug therapy for treatment of cIAI.
Time frame: TOC visit: 25-31 days after first dose of study drug
Population: Clinically Evaluable: all randomized subjects who meet key inclusion/exclusion criteria and follow other important components of the trial
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population | Clinical Cure | 218 Participants |
| Eravacycline | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population | Clinical Failure | 7 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population | Clinical Cure | 222 Participants |
| Meropenem | Number of Participants With a Favorable Clinical Response at the Test-of-Cure (TOC) Visit in the Clinically Evaluable (CE) Population | Clinical Failure | 9 Participants |