Study to Compare TP-434 and Ertapenem in Community-acquired Complicated Intra-abdominal Infections

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, randomized, double-blind, double-dummy, multicenter, prospective study to assess the efficacy, safety, and pharmacokinetics of two dose regimens of TP-434 compared with ertapenem in the treatment of adult community-acquired complicated intra-abdominal infections (cIAIs).

Official Title
-----------------
A Phase 2, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy, Safety, and PK of 2 Dose Regimens of TP-434 Compared With Ertapenem in Adult Community-Acquired Complicated Intra-abdominal Infections

Conditions
-----------------
Complicated Intra-abdominal Infection

Intervention / Treatment
-----------------
* Drug: TP-434
* Drug: Ertapenem
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Abdominal pain/discomfort with onset prior to hospitalization Evidence of a systemic inflammatory response Physical findings consistent with intra-abdominal infection (IAI) Clinical diagnosis of community-acquired IAI requiring urgent surgical or percutaneous intervention and not expected to require antibacterial therapy for longer than 14 days Body mass index (BMI) of ≤ 30 kilograms per square meter (kg/m^2) Able to provide informed consent. If the participant is unable to provide informed consent, the participant's legally acceptable representative may provide written consent in accordance with institutional guidelines If female, not pregnant or nursing or, if of child-bearing 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: Symptoms related to diagnosis of complicated appendicitis (if current diagnosis) for < 24 hours prior to current hospitalization Previously hospitalized or admitted to a healthcare facility within the last 6 months Managed by Staged Abdominal Repair or other open abdomen technique Known at study entry to have an IAI caused by a pathogen(s) resistant to both study drug antibiotics Acute Physiology and Chronic Health Evaluation (APACHE) II score > 25 Unlikely to survive the 6-8 week study period Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock Requirement for vasopressors at therapeutic dosages Renal failure Presence or possible signs of hepatic disease Hematocrit < 25% or hemoglobin < 8 grams per deciliter (g/dL) Neutropenia with absolute neutrophil count < 1000 cells per cubic millimeter (mm^3) Platelet count < 50,000/mm3 Abnormal coagulation tests or participant on anticoagulants Immunocompromised condition, including known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS), organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (for example, > 40 milligrams [mg] prednisone or equivalent per day for greater than 2 weeks) History of hypersensitivity reactions to tetracyclines or carbapenems Participation in any investigational drug or device study within 30 days prior to study entry Known or suspected central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold Previously received TP-434 in a clinical trial More than 24 hours duration of systemic antibiotic coverage for current condition Received ertapenem or any other carbapenem, or tigecycline for the current infection Need for concomitant systemic antimicrobial agents other than study drug or received systemic (IV or oral) antibiotics in the last 3 months 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TP-434, 1.5 mg/kg q24h<br>TP-434 was administered intravenously (IV) at a dose of 1.5 milligrams per kilogram of body weight (mg/kg) every 24 hours (q24h) for a minimum of 4 days and a maximum of 14 days (7 days for participants in India). TP-434 treatment was to be stopped when symptoms of complicated intra-abdominal infection (cIAI) resolved, there was treatment failure, or the maximum allowed number of infusion days was reached. | Drug: TP-434<br> <br> * Other names: Eravacycline;Drug: Placebo<br>* Administered IV to maintain the blind.<br>|
| Experimental: TP-434, 1.0 mg/kg q12h<br>TP-434 was administered IV at a dose of 1.0 mg/kg every 12 hours (q12h) for a minimum of 4 days and a maximum of 14 days (7 days for participants in India). TP-434 treatment was to be stopped when symptoms of cIAI resolved, there was treatment failure, or the maximum allowed number of infusion days was reached. | Drug: TP-434<br> <br> * Other names: Eravacycline;Drug: Placebo<br>* Administered IV to maintain the blind.<br>|
| Active Comparator: Ertapenem, 1 g q24h<br>Ertapenem was administered IV at a dose of 1 gram (g) q24h for a minimum of 4 days and a maximum of 14 days (7 days for participants in India). Ertapenem treatment was to be stopped when symptoms of cIAI resolved, there was treatment failure, or the maximum allowed number of infusion days was reached. | Drug: Ertapenem<br> <br> * Other names: Invanz;Drug: Placebo<br>* Administered IV to maintain the blind.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Evaluable (ME) Population at the Test-of-Cure 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], persisting or recurrent infection within the abdomen, postsurgical wound infection, or administration of effective concomitant antibacterial therapy), or indeterminate (Test-of-Cure [TOC] assessment was not available, death unrelated to cIAI, or some other reason). | TOC Visit (10-14 days after last dose of study drug) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response to TP-434 and Ertapenem in the Modified Intent-to-treat (MITT) Population at the End-of-Treatment (EOT) Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Modified Intent-to-treat (MITT) Population at TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Modified Intent-to-treat (MITT) Population at the Follow-up Visit |  | Follow-up Visit (28-42 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Modified Intent-to-treat (c-MITT) Population at the EOT Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Modified Intent-to-treat (c-MITT) Population at the TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Modified Intent-to-treat (c-MITT) Population at the Follow-up Visit |  | Follow-up Visit (28-42 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Modified Intent-to-treat (m-MITT) Population at the EOT Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Modified Intent-to-treat (m-MITT) Population at the TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Modified Intent-to-treat (m-MITT) Population at the Follow-up Visit |  | Follow-Up Visit (28-42 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Evaluable (CE) Population at the EOT Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Evaluable (CE) Population at the TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Clinically Evaluable (CE) Population at the Follow-up Visit |  | Follow-up Visit (28-42 days after last dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Evaluable (ME) Population at the EOT Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Clinical Response to TP-434 and Ertapenem in the Microbiologically Evaluable (ME) Population at the Follow-up Visit |  | Follow-up Visit (28-42 days after last dose of study drug) | 
| Microbiologic Response to TP-434 and Ertapenem in the m-MITT Population at the EOT Visit | Microbiological response was classified as favorable (eradication or presumed eradication), unfavorable (persistence, presumed persistence, superinfection, or new infection), or indeterminate (assessment not possible). | EOT Visit (4-14 days after first dose of study drug) | 
| Microbiologic Response to TP-434 and Ertapenem in the m-MITT Population at the TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Microbiologic Response to TP-434 and Ertapenem in the ME Population at the EOT Visit |  | EOT Visit (4-14 days after first dose of study drug) | 
| Microbiologic Response to TP-434 and Ertapenem in the ME Population at the TOC Visit |  | TOC Visit (10-14 days after last dose of study drug) | 
| Pharmacokinetics: Maximum Concentration (Cmax) of TP-434 |  | Prior to first infusion and 1, 3, 7, 12, 48, and 108 hours after start of first infusion | 
| Pharmacokinetics: Area Under the Concentration Time Curve From Time 0 to 12 Hours (AUC[0-12]) of TP-434 |  | Prior to first infusion and 1, 3, 7, 12, 48, and 108 hours after start of first infusion |