E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated Intra-abdominal Infections |
|
E.1.1.1 | Medical condition in easily understood language |
Complicated Intra-abdominal Infections |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056570 |
E.1.2 | Term | Intra-abdominal infection |
E.1.2 | System Organ Class | 100000004862 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat (micro-ITT) population for subjects in the 2 treatment arms. |
|
E.2.2 | Secondary objectives of the trial |
1. To compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and follow-up (FU) visits in the following populations:
- Intent-to-treat (ITT) population
- All-treated (MITT)
- Clinically evaluable (CE) population
- Micro-ITT population (for EOT and FU)
- Microbiologically evaluable (ME) Population
2. To compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following populations:
- Micro-ITT population
- ME Population
3. To assess the safety and tolerability of eravacycline administration in the safety population
4. To explore pharmacokinetic (PK) parameters of eravacycline |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male or female subject hospitalized for cIAI with one of the following diagnoses:
a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera (including hepatic and splenic abscesses)
b. Gastric or intestinal perforation associated with diffuse peritonitis
c. Peritonitis: diffuse infection of the peritoneum (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
d. Appendicitis with perforation, peritonitis or abscess
e. Cholecystitis with perforation or abscess
f. Diverticulitis with perforation, peritonitis, or abscess
Note: Infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligible. Ischemic bowel disease without perforation is not eligible. Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible
2. At least 18 years of age
3. Evidence of a systemic inflammatory response with at least one of the following:
a. Fever (oral, rectal, tympanic, or by temporal artery temperature > 100.4˚F / 38˚C) or hypothermia (temperature ≤ 95.9˚F / 35.5˚C)
b. Elevated WBC (> ULN laboratory range); or proportion of band forms of the WBC differential beyond the ULN laboratory range
c. Increased pulse (HR > 90 beats per minute)
d. Increased respiratory rate (> 20 breaths per minute)
4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus
5. Able to provide informed consent.
6. Subjects must agree to use a highly reliable method of birth control:
a. Male subjects 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
b. Female subjects must not be pregnant or nursing. For females of childbearing potential, subjects must commit to either:
i. Use at least two medically accepted, effective methods of birth control (eg, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring, etc.) during study drug dosing and for 14 days following last study drug dose, OR
ii. Sexual abstinence
And either
7A. Meets All Inclusion Criteria for Pre-operative Enrollment:
- Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND
- Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 24-h
Or
7B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment:
- Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND
- Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, AND
- Intervention is adequate (ie, a procedure in which all communications between the GI tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the procedure), AND
- Subjects who are enrolled in the trial post-operatively must receive no more than one dose of effective antibacterial drug therapy post-operatively before randomization |
|
E.4 | Principal exclusion criteria |
1. Considered 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 (prior to enrollment) at therapeutic dosages (ie, dopamine > 5 μg/kg/min, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a systolic blood pressure ≥ 90 mm Hg or a mean arterial pressure ≥ 70 mm Hg following adequate fluid resuscitation
2. Creatinine clearance ≤ 50 mL/min as estimated by the Cockcroft-Gault equation
3. Presence or possible signs of significant hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 5 x ULN, OR
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process
4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 count < 300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (eg, > 20 mg prednisone or equivalent per day for greater than 2 weeks)
5. 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
6. Participation in any investigational drug or device study within 30 days prior to study entry
7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy)
8. Antibiotic-related exclusions:
a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding randomization [However, subjects with documented cIAI (ie, known baseline pathogen) who have received at least 72-h 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-h of antibiotic therapy], OR
b. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, OR
c. Need for concomitant systemic antimicrobial agents effective in cIAI other than study drug
9. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent
10. Known or suspected inflammatory bowel disease or associated visceral abscess
11. The anticipated need for systemic antibiotics for a duration of more than 14 days
12. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy or antineoplastic therapy within the previous 3 months or which is anticipated to begin prior to the TOC visit
13. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs
14. Any other unstable or clinically significant concurrent medical condition (ie, class IV heart or lung disease, end stage renal disease, or requiring hemodialysis, etc.) that would, in the opinion of the investigator, jeopardize the safety of a subject, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study will be the clinical response at the Test-of-cure (TOC) visit in the micro-ITT population.
NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the clinically evaluable (CE) populations. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Clinical response at the End of Therapy (EoT), Test-of-cure (TOC) and Follow Up (FU) visits
- Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits Version 1.0 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The End of Therapy, Test-of-Cure and Follow Up visits |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Czech Republic |
Estonia |
Georgia |
Hungary |
Latvia |
Lithuania |
Romania |
Russian Federation |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 15 |