| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Community-acquired complicated intra-abdominal infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Community-acquired complicated intra-abdominal infection |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 of this study is to compare clinical response at the test-of-cure (TOC) visit
in the microbiologically evaluable (ME) population for subjects in the 3 treatment arms |
|
| E.2.2 | Secondary objectives of the trial |
Compare clinical response for subjects in the 3 treatment arms at end-of-treatment (EOT),
TOC, and follow-up (FU) visits in the following populations:
- Modified intent-to-treat (MITT) population
- Clinically modified intent-to-treat (c-MITT) population
- Microbiologically modified intent-to-treat (m-MITT) population
- Clinically evaluable (CE) population
- Microbiologically evaluable (ME) population (for EOT, FU)
To compare microbiologic response for subjects in the 3 treatment arms at EOT and TOC
visits in the following populations:
- m-MITT population
- CE population
- ME population
To assess safety and tolerability of TP-434 administration in the safety population
To explore pharmacokinetic (PK) parameters after TP-434 infusion, including:
Cmax, Tmax, AUC0-t, AUC0-inf, T½, Vss and C |
|
| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
|
| E.3 | Principal inclusion criteria |
1.Subjects must meet all of the following criteria:
1. Abdominal pain/discomfort with onset prior to hospitalization.
2. Evidence of a systemic inflammatory response with at least one of the following:
a. Fever (oral temperature > 100.4˚F / 38˚C) or hypothermia (oral temperature <
35˚C / 95˚F)
b. Elevated WBC ( > 10,500/mm3)
c. Tachycardia (Heart rate > 90 beats/min)
d. Tachypnea ( > 20 breaths/min)
3. Physical findings consistent with intra-abdominal infection (IAI), defined as localized or diffuse abdominal tenderness (Other supportive findings include presence of a mass, ileus, or rebound tenderness)
4. Clinical diagnosis of community-acquired intra-abdominal infection requiring urgent
surgical or percutaneous intervention and not expected to require antibacterial therapy for longer than 14 days
5. At least 18 years and no older than 75 years of age
6. Body mass index (BMI) of ≤ 30 kg/m2
7. Able to provide informed consent. If the patient is unable to provide informed consent, the patient's legally acceptable representative may provide written consent in accordance with institutional guidelines
8. If female:
a. Not pregnant or nursing
b. If of child-bearing 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
9A. Meets Inclusion Criteria for Pre-operative Enrollment:
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
Specimens from the surgical intervention representative of the material associated with infection will be collected by aspiration or tissue sample and sent for culture and
susceptibility testing
Clinical diagnoses consistent with one or more of the following:
1. Appendiceal perforation and periappendiceal abscess
2. Diverticular abscess
3. Acute gastric or duodenal perforation (only if operated on > 24 hrs after
perforation occurs)
4. Traumatic perforation of the intestines (only if operated on > 12 hrs after
perforation occurs)
5. Abscess or peritonitis due to other perforated viscus, or other gastrointestinal
source
or
9B. Meets Inclusion Criteria for Intra-operative/Post-operative Enrollment:
Visual confirmation (presence of pus within the abdominal cavity)
Samples taken for aerobic and anaerobic culture should be taken by aspiration or tissue sample and immediately inoculated to appropriate media
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 GI tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the initial procedure
Intra-operative diagnoses include one or more of the following:
1. Appendiceal perforation and periappendiceal abscess
2. Diverticular abscess
3. Acute gastric and duodenal perforations (only if operated on > 24 hrs after
perforation occurs)
4. Traumatic perforation of the intestines (only if operated on > 12 hrs after
perforation occurs)
5. Abscess or peritonitis due to perforated viscus, or other focus of infection (but not
spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
6. Other intra-abdominal abscess (excluding liver and spleen) from a gastrointestinal
source |
|
| E.4 | Principal exclusion criteria |
1. Symptoms related to diagnosis of complicated appendicitis (if current diagnosis) for < 24 hrs prior to current hospitalization
2. Previously hospitalized or admitted to a healthcare facility (includes nursing or
convalescent home) within the last 6 months
3. Managed by Staged Abdominal Repair or other open abdomen technique
4. Known at study entry to have an IAI caused by a pathogen(s) resistant to one of the study drug antibiotics
5. Acute Physiology and Chronic Health Evaluation (APACHE) II score > 25
6. Considered unlikely to survive the 6-8 week study period
7. Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock
8. Requirement for vasopressors at therapeutic dosages (i.e., dopamine greater than 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
9. Renal failure as defined as:
a. Threefold increase of serum creatinine to a known previous value or
b. Decrease in estimated glomerular filtration rate > 75% to 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
10. Creatinine clearance < 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 requires peritoneal dialysis, hemodialysis, or hemofiltration
11. Presence or possible signs of hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 3 x upper limit of
normal (ULN) 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
12. Hematocrit < 25% or hemoglobin < 8 g/dL
13. Neutropenia with absolute neutrophil count < 1000/mm3
14. Platelet count < 50,000/mm3
15. Coagulation tests > 1.5 x ULN (i.e., prothrombin time, partial thromboplastin time, or international normalized ratio)
16. Patient on anticoagulants prior to hospital admission, except low dose aspirin therapy
17. Immunocompromised condition, including known HIV positivity or 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)
18. History of moderate or severe hypersensitivity reactions to tetracyclines or carbapenems or β-lactam antibiotics
19. Participation in any investigational drug or device study within 30 days prior to study entry
20. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy)
21. Previously received TP-434 in a clinical trial
22. Antibiotic-related exclusions:
a. More than 24 hrs duration of systemic antibiotic coverage for current condition
(24 hrs duration defined by recommended dosing interval in the respective
prescribing information)
b. Received ertapenem or any other carbapenem, or tigecycline for the current
infection
c. Need for concomitant systemic antimicrobial agents other than study drug
(including female subjects with clinical diagnosis of pelvic inflammatory
disease)
d. Known to have received systemic (IV or oral) antibiotics in the last 3 months
(except for current acute condition or single dose such as for dental prophylaxis)
23. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent
24. Known or suspected inflammatory bowel disease or associated visceral abscess |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study will be clinical response at the TOC visit |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.3 |
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 | 16 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| Provided in the protocol, see section 10.2.6 |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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