E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated Intra-abdominal Infections |
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E.1.1.1 | Medical condition in easily understood language |
Complicated Intra-abdominal Infections |
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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 | 14.1 |
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 |
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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 |
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 |
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E.2.2 | Secondary objectives of the trial |
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
- Clinically evaluable (CE) population
- Micro-ITT population (for EOT and FU)
- Microbiologically evaluable (ME) population
Compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following populations:
- Micro-ITT population
- ME population
Assess the safety and tolerability of eravacycline administration in the safety population
Explore pharmacokinetic (PK) parameters after eravacycline infusion including Cmax, Tmax, AUC0-12 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 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
b. Gastric or intestinal perforation associated with diffuse peritonitis
c. Peritonitis due to perforated viscus, or other focus of infection (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. Intra-abdominal abscess (single or multiple), including hepatic and splenic abscesses
g. Peritonitis (local or diffuse)
Note: infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligble. 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 (and not over 65 years of age for subjects in India)
3. Evidence of a systemic inflammatory response with at least one of the following:
a. Fever (oral, rectal or aural temperature > 100.4°F / 38°C) or hypothermia (oral temperature ≤ 95.9°F / 35.5°C)
b. Elevated WBC (>Upper Limit of Normal (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 breathes 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. 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:
a. Not pregnant or nursing
b. If of childbearing potential, will commit to either:
i. Use at least two medically accepted, effective methods of birth control (e.g., 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
ii. Sexual abstinence
And either
8A. Meets All Inclusion Criteria for Pre-operative Enrollment:
-Clinically obvious peritonitis or has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI
-Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 48-h
8B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment:
-Visual confirmation of cIAI (presence of pus within the abdominal cavity)
-Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess
- Initial intervention is adequate (i.e., a procedure in which all communications between the gastrointestinal (GI) tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the initial procedure) |
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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 at therapeutic dosages (i.e., 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. Renal failure as defined as:
a. Threefold increase of serum creatinine to a known previous value or
b. Decrease in estimated glomerular filtration rate to < 75% of a known previous value or
c. Urine output of < 0.3 mL/kg per h for > 24-h or
d. Anuria for > 12-h or
e. Serum creatinine of > 4 mg/dL (353.6 μmol/L) with an acute rise of 0.5 mg/dL (42.2 μmol/L) compared with a previous value or
f. Creatinine clearance of < 30 mL/min as estimated by the Cockcroft-Gault equation = (140-age [years]
* body weight [kg] * 0.85 [if female] / 72 * serum creatinine [mg/dL] or
g. Requires peritoneal dialysis, hemodialysis or hemofiltration
3. Presence or possible signs of significant hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 3 x ULN; > 5 x ULN for patients with hepatic abscess or
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process or
c. Alkaline phosphatase > 3 x ULN or
d. Subjects with diagnosis of hepatic failure
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 (e.g., > 40 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 (e.g., severe cerebral arteriosclerosis, epilepsy)
8. Previously received eravacycline in a clinical trial
9. Antibiotic-related exclusions:
a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding enrollment (however, subjects with documented cIAI (i.e., 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 ertapenem or any other carbapenem, or tigecycline for the current infection or
c. 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 TOC visit |
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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 visit in the micro-ITT population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The test-of-cure (TOC) visit |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of the study are:
Clinical response at the EOT, TOC, and FU visits
Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The End of Trial, Test-of-cure and Follow Up visits |
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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 | 42 |
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 |
Argentina |
Bulgaria |
Czech Republic |
Estonia |
France |
Germany |
India |
Latvia |
Lithuania |
Romania |
Russian Federation |
South Africa |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 13 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 13 |