Complicated Intra-abdominal Infections
Conditions
Brief summary
This is a Phase 3, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics of eravacycline compared with ertapenem in the treatment of adult complicated intra-abdominal infections (cIAI).
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
1. Male or female participant hospitalized for cIAI 2. At least 18 years of age (and not over 65 years of age for participant in India) 3. Evidence of a systemic inflammatory response 4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area 5. Able to provide informed consent 6. If male: must agree to use an effective barrier method of contraception during the study and for 90 days following the last dose if sexually active with a female of childbearing potential 7. 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 90 days following last study drug dose or practicing sexual abstinence
Exclusion criteria
1. Unlikely to survive the 6-8 week study period 2. Renal failure 3. Presence or possible signs of hepatic disease 4. Immunocompromised condition, including known human immunodeficiency virus (HIV) positivity (requiring anti-retroviral therapy or with CD4 count \<300), acquired immune deficiency syndrome (AIDS), organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (for example, \>40 mg prednisone or equivalent per day for greater than 2 weeks) 5. History of hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics or to excipients contained in the study drug formulations 6. Participation in any investigational drug or device study within 30 days prior to study entry 7. Known or suspected current Central Nervous System disorder that may predispose to seizures or lower seizure threshold 8. Previously received eravacycline in a clinical trial 9. Antibiotic-related exclusions: 1. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of \>24 hours during the 72-hour preceding enrollment (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 ertapenem or any other carbapenem, or tigecycline for the current infection or 3. Need for concomitant systemic antimicrobial agents other than study drug 10. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent 11. Known or suspected inflammatory bowel disease or associated visceral abscess 12. The anticipated need for systemic antibiotics for a duration of more than 14 days 13. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | TOC visit: 25-31 days after the first dose of study drug | Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the End-of-Treatment (EOT) visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | TOC visit: 25-31 days after first dose | Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented. |
| Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | TOC visit: 25-31 days after first dose | Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented. |
Countries
Argentina, Bulgaria, Czechia, Estonia, France, Germany, Latvia, Lithuania, Romania, Russia, South Africa, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eravacycline, 1.0 mg/kg q12h Eravacycline was administered IV at a dose of 1.0 mg/kg q12h for a minimum of 4 days and a maximum of 14 days. | 270 |
| Ertapenem, 1.0 g q24h Ertapenem was administered IV at a dose of 1.0 g q24h for a minimum of 4 days and a maximum of 14 days. | 271 |
| Total | 541 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Enterococcus Resistant | 0 | 1 |
| Overall Study | Inadvertently Not Scheduled | 1 | 0 |
| Overall Study | Lost to Follow-up | 15 | 3 |
| Overall Study | Noncompliance | 2 | 3 |
| Overall Study | Randomized but was a Screen Failure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | Total | Eravacycline, 1.0 mg/kg q12h | Ertapenem, 1.0 g q24h |
|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 16.49 | 54.8 years STANDARD_DEVIATION 16.92 | 54.8 years STANDARD_DEVIATION 16.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 8 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 523 Participants | 261 Participants | 262 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 4 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other Race | 9 participants | 4 participants | 5 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 523 participants | 263 participants | 260 participants |
| Region of Enrollment Bulgaria | 89 participants | 45 participants | 44 participants |
| Region of Enrollment Czech Republic | 31 participants | 14 participants | 17 participants |
| Region of Enrollment Estonia | 66 participants | 32 participants | 34 participants |
| Region of Enrollment Germany | 4 participants | 2 participants | 2 participants |
| Region of Enrollment Latvia | 48 participants | 25 participants | 23 participants |
| Region of Enrollment Lithuania | 52 participants | 26 participants | 26 participants |
| Region of Enrollment Romania | 84 participants | 42 participants | 42 participants |
| Region of Enrollment Russian Federation | 52 participants | 28 participants | 24 participants |
| Region of Enrollment South Africa | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Ukraine | 76 participants | 38 participants | 38 participants |
| Region of Enrollment United States | 38 participants | 18 participants | 20 participants |
| Sex: Female, Male Female | 222 Participants | 114 Participants | 108 Participants |
| Sex: Female, Male Male | 319 Participants | 156 Participants | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 270 | 28 / 268 |
| serious Total, serious adverse events | 17 / 270 | 16 / 268 |
Outcome results
Primary
Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population
Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the End-of-Treatment (EOT) visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time frame: TOC visit: 25-31 days after the first dose of study drug
Population: All randomized participants who had baseline bacterial pathogens that cause cIAI and against at least one of which the investigational drug has in vitro antibacterial activity (micro-ITT population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Cure | 191 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Failure | 19 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Indeterminate | 10 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Cure | 198 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Failure | 11 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms at the Test-of-cure (TOC) Visit in the Microbiological Intent-to-treat (Micro-ITT) Population | Indeterminate | 17 participants |
Secondary
Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit
Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time frame: TOC visit: 25-31 days after first dose
Population: All randomized participants who had no major protocol deviations (CE population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Cure | 222 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Failure | 17 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Indeterminate | 0 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Cure | 225 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Failure | 13 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Clinically Evaluable (CE) Population at the TOC Visit | Indeterminate | 0 participants |
Secondary
Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit
Clinical response was classified as cure (complete resolution or significant improvement of signs and symptoms of the index infection), failure (death related to complicated intra-abdominal infection \[cIAI\], unplanned surgical procedures or percutaneous drainage procedures, persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (outcome was neither cure nor failure, or assessment was not available). Participants who were failures at the EOT visit (within 24 hours of last dose) were considered failures at the TOC visit. The number of participants with a clinical response classification of cure, failure, or indeterminate is presented.
Time frame: TOC visit: 25-31 days after first dose
Population: All randomized participants who received at least 1 dose of study drug (MITT population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Indeterminate | 16 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Cure | 235 participants |
| Eravacycline, 1.0 mg/kg q12h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Failure | 19 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Indeterminate | 15 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Cure | 238 participants |
| Ertapenem, 1.0 g q24h | Clinical Response of Eravacycline and Ertapenem Treatment Arms in the Modified Intent-to-treat (MITT) Population at the TOC Visit | Failure | 15 participants |