| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Complicated Intra-Abdominal Infection |
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| E.1.1.1 | Medical condition in easily understood language |
Complicated intra-abdominal infections (infections situated within the cavity of the abdomen) requiring IV (administered into a vein) antibacterial therapy
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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 | 17.0 |
| 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 |
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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 |
1. To evaluate the efficacy of two doses of MK-7655 + imipenem/cilastatin (250 mg and 125 mg), as compared with imipenem/cilastatin alone, with respect to the clinical response assessment profile in the treatment of adult patients with cIAI at completion of IV study therapy (DCIV).
2. To evaluate the safety and tolerability profile of two doses of MK- 7655 + imipenem/cilastatin (250 mg and 125 mg). |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of two doses of MK-7655 + imipenem/cilastatin (250 mg & 125 mg) with respect to the clinical response assessment profile in the treatment of adult patients with imipenem-resistant gram-negative cIAI at completion of IV study therapy.
To evaluate the efficacy of two doses of MK-7655 + imipenem/cilastatin (250 mg & 125 mg) as compared to imipenem/cilastatin, with respect to the:
- clinical response assessment profile in the treatment of patients with cIAI at the 5 to 9-day posttreatment follow-up visit.
- microbiol. response assessment profile in the treatment of patients with cIAI at completion of IV study therapy.
- microbiol. response assessment profile in the treatment adult patients with cIAI at the 5 to 9-day posttreatment follow-up visit.
- proportion of patients with sustained microbiol. response and sustained clinical response in the treatment of patients with cIAI measured at the 28 to 42-day posttreatment follow-up visit.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is ≥18 years of age on the day of signing informed consent (Visit 1).
2. Patient or the patient’s legal representative understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent for the trial.
3. Sexually active females of childbearing potential with a negative urine pregnancy test are eligible for enrollment; however, this must be followed up with a confirmed
negative serum pregnancy test (β-HCG) within 48 hours following the screening visit.
A female who is of reproductive potential agrees to remain abstinent or use (or have their partner use) a medically acceptable effective method of birth control for 1 month after study entry. Female patients in regions in which abstinence is not a locally acceptable method of contraception must use another medically acceptable effective birth control method. per the protocol.
NOTE: A female patient who is not of reproductive potential is eligible without requiring the use of contraception. A female patient who is not of reproductive potential is defined as one who meets at least 1 of the following conditions:
- Has reached natural menopause
- Is at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy
- Has had a bilateral tubal ligation
- Is not sexually active
NOTE: A male patient who is not of reproductive potential is eligible without requiring the use of contraception. A male patient who is not of reproductive potential is defined by meeting at least 1 of the following conditions:
- Is not sexually active
- Has undergone a successful vasectomy.
4. Patient has a clinically suspected and/or bacteriologically documented cIAI requiring hospitalization and treatment with IV antibiotic therapy. Patients are to be enrolled intraoperatively or postoperatively on the basis of operative findings OR patients
may be enrolled preoperatively on the basis of compelling preoperative clinical findings, as described below:
a. Intraoperative/Postoperative Enrollment
Patients may be enrolled intraoperatively or postoperatively upon visual confirmation (e.g., presence of pus within the abdominal cavity) of an intraabdominal infection. Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery. The initial surgical
intervention should be adequate, as defined in the 2010 Infectious Disease Society of America/Surgical Infections Society (IDSA/SIS) guidelines for the management of cIAI.
Diagnoses considered eligible for this study are those in which there is evidence of intraperitoneal infection:
1) Cholecystitis (including gangrenous) with rupture, perforation, or progression of the infection beyond the gallbladder wall
2) Diverticular abscess
3) Appendiceal perforation and periappendiceal abscess
4) Acute gastric and duodenal perforations, only if operated on >24 hours after perforation occurs
5) Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
6) Peritonitis due to perforated viscus, surgical intervention, or other focus of infection. Spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites are not eligible.
7) Intra-abdominal abscess (including of liver and spleen)
b. For Preoperative Enrollment
The following clinical criteria must be met at screening, and the patient’s infection must be confirmed by a surgical intervention within 24 hours of entry:
1) Evidence of a systemic inflammatory response, with at least 1 of the following:
a) Fever (defined as ≥38.0°C [≥100.4°F] orally OR an oral equivalent [≥38.5°C (≥101.3°F) by tympanic or rectal measurement]
b) Elevated WBC ( 10,500/mm3)
c) Drop in blood pressure (systolic blood pressure must be <90 mm Hg without the need for pressor support)
d) Increased pulse and respiratory rates
e) Hypoxemia
f) Altered mental status
AND
2) At least 1 physical finding consistent with intra-abdominal infection, such as:
a) Abdominal pain and/or tenderness
b) Localized or diffuse abdominal wall rigidity
c) Abdominal mass
d) Ileus
AND
3) Supportive radiologic findings in abdomen, such as intraperitoneal abscess, detected on an abdominal CT scan
AND
4) Requirement for surgical intervention, including open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery.
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| E.4 | Principal exclusion criteria |
1. Patient has an infection which should be managed by Staged Abdominal Repair (STAR) or open abdomen technique.
2. Patient with an APACHE II score >30 at screening.
3. Patient has received any amount of effective antibiotic therapy (defined as therapy known to be active against the identified pathogen) after obtaining the culture for admission to this study (admission culture) and prior to the administration of the first
dose of IV study therapy.
4. Patient has an infection which has been treated with >24 hours of systemic antibiotic therapy known to be effective against the presumed or documented etiologic pathogen(s) within the 72-hour period immediately prior to consideration for entry into the study (e.g., >3 doses of an every 8 hour [q8h] antibiotic before enrollment).
5. Patient has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to carbapenem antibiotics, any cephalosporins, penicillins, or other β-lactam agents.
6. Patient has a history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to other β-lactamase inhibitors (e.g., tazobactam, sulbactam, clavulanic acid).
7. Patient has a history of a seizure disorder (requiring ongoing treatment with anticonvulsive therapy or prior treatment with anti-convulsive therapy in the last 3 years).
8. Patient is currently being treated with valproic acid or has used valproic acid in the 2 weeks prior to screening.
9. Patient has a rapidly progressive or terminal illness (unlikely to survive the approximately 6- to 8-week study period).
10. Patient is pregnant or expecting to conceive, is breastfeeding, or plans to breast feed within 1 month of completion of the study.
11. Patient in whom a response to IV study therapy (imipenem/cilastatin + MK-7655 or imipenem/cilastatin alone) within the timeframe of treatment specified in this protocol is considered unlikely.
12. Patient has a concurrent infection that would interfere with evaluation of response to the study antibiotics (imipenem/cilastatin + MK-7655 or imipenem/cilastatin alone).
13. Patient has a need for concomitant systemic antimicrobial agents in addition to those designated in the various study treatment groups.
14. Patient has a cIAI due to a confirmed fungal pathogen.
15. Patient is currently receiving immunosuppressive therapy, including use of high-dose corticosteroids (i.e., ≥40 mg prednisone or prednisone equivalent per day).
16. Patient has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that, in the opinion of the investigator, might confound the results of the study, interfere with the patient’s participation for the full
duration of the study, or pose additional risk in administering the study drug to the patient.
17. Patient is a prior recipient of a renal transplantation.
18. Patient has estimated or actual creatinine clearance of <50 mL/minute.
19. The patient has any of the following laboratory abnormalities at the time of screening:
- Alanine aminotransferase (ALT) values ≥3 times the Upper Limit of Normal (ULN)
- Aspartate aminotransferase (AST) values ≥3 times ULN
- ALT or AST ≥2 times ULN accompanied by total bilirubin > ULN
- Total bilirubin value ≥2 times ULN
20. Patient is currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of presentation or during the previous 30 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial.
21. Patient has previously participated in this study at any time. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To evaluate the efficacy of 2 doses of MK-7655 + imipenem/cilastatin (250mg and 125mg), as compared to imipenem/cilastatin alone, with respect to the clinical response assessment profile in the treatment of adult patients with cIAI at completion of IV study therapy
To evaluate safety and tolerability of 2 dose levels of MK-7655 + imipenem/cilastatin (250 mg and 125 mg).
The safety endpoints will include all adverse experiences, including clinical adverse experiences (plus local tolerability) and laboratory adverse experiences. These adverse experiences will be identified based on careful assessment or measurement of patient symptoms, vital signs and/or physical examination findings, and laboratory safety measures (from blood and urine). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint (clinical response) will focus on the time point at the immediate conclusion of treatment with MK-7655 +
imipenem/cilastatin - 4 to 14 days post initiation of IV study therapy |
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| E.5.2 | Secondary end point(s) |
Microbiological response will also be evaluated as secondary endpoints at the early follow-up (EFU) and the late follow-up (LFU) visits and as an exploratory endpoint at the global follow-up (GFU) visit.
In the presence of a missing culture at a particular time point, a favorable clinical response (or global response at the GFU visit) will be required for presuming a favorable microbiological response. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A global response will also be evaluated in an exploratory fashion in this study at a fixed time-point following randomization (Day 28 [+ 7 days], also known as GFU visit) |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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 | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Estonia |
| Germany |
| Greece |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
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| 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
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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