| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Complicated Urinary Tract Infection at least 18 years of age, with a diagnosis of either complicated cUTI or acute pyelonephritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated urinary tract infections or kidney infections requiring intravenous therapy. |
|
| 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 | 10046544 |
| E.1.2 | Term | Urinary infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 | 10001032 |
| E.1.2 | Term | Acute pyelonephritis |
| 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 |
- To evaluate the efficacy of 2 doses of MK-7655 + imipenem/cilastatin (250 mg and 125 mg) with respect to the microbiological response assessment profile in the treatment of adult patients with cUTI, as compared to imipenem/cilastatin at completion of IV study therapy (DCIV).
- To evaluate the safety and tolerability profile of 2 doses of MK-7655 + imipenem/cilastatin (250 mg and 125 mg).
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of 2 doses of MK-7655 + imipenem/cilastatin (I/C) (250 mg and 125 mg) with respect to the:
1. microbiol. response assessment profile in the treatment of adult patients with imipenem-resistant gram-negative cUTI at completion of IV study therapy (DCIV).
2. microbiol. response assessment profile in the treatment of adult patients with cUTI as compared to I/C at the 5 to 9-day postantibiotic therapy (EFU) follow-up visit.
3. clinical response assessment profile in the treatment of patients with cUTI as compared to the I/C group at DCIV.
4. clinical response assessment profile in the treatment of patients with cUTI as compared to the I/C group at EFU follow-up visit.
5. proportion of patients with sustained microbiol. response and sustained clinical response in the treatment of patients with cUTI as compared to the I/C group, measured at the at the 28 to 42-day postantibiotic therapy (LFU) 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 day of signing informed consent.
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. Patient has been domiciled in a health care facility (e.g., hospital, nursing home) for at least 48 hours within the preceding 30 calendar days prior to signing informed consent.
4. 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 (B-HCG) as soon as possible (within 48 hours of the screening visit). A patient 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.5. Patient has a clinically suspected and/or bacteriologically documented cUTI OR acute pyelonephritis judged by the investigator to be serious (requiring hospitalization and treatment with IV antibiotic therapy) according to the following disease definitions:
a)Acute pyelonephritis is defined as a systemic, ascending urinary tract infection in a patient with normal urinary tract anatomy, clinically manifested by meeting at least 2 of the following criteria: 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]; Flank pain; Costovertebral angle (CVA) tenderness on physical examination; Nausea or vomiting
b) cUTI is defined as a clinical syndrome in men or women characterized by the development of at least 2 of the following local or systemic signs and symptoms: Local signs and symptoms: Dysuria, urinary frequency, suprapubic or pelvic pain, or urinary urgency. Systemic signs and symptoms: Fever (as defined above), chills or rigors (accompanied by fever), flank pain or CVA tenderness on physical examination.
The above symptoms must also occur in the presence of at least 1 of the following: Presence of indwelling urinary catheter or other urinary bladder instrumentation, Any functional or anatomical abnormality of the urogenital tract with voiding disturbance resulting in at least 100 mL of residual urine, Current obstructive uropathy that is scheduled to be medically or surgically relieved during IV study therapy,Males with documented history of urinary retention.
6. Patient has pyuria, determined by a midstream clean-catch (MSCC) or catheterized (indwelling or straight catheter) urine specimen with ≥10 white blood cells (WBCs) per high-power field (hpf) on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun urine.
7. Patient has one positive urine culture within 48 hours of enrollment, defined as: ≥10^5 CFU/mL of uropathogen either from a MSCC or indwelling catheter urine specimen, OR ≥10^4 CFU/mL of uropathogen either from a MSCC or indwelling catheter urine specimen if blood culture is also positive, OR ≥10^2 CFU/mL of uropathogen from a straight catheter specimen. |
|
| E.4 | Principal exclusion criteria |
1. Patient has complete obstruction of any portion of the urinary tract (requiring a
permanent indwelling urinary catheter or instrumentation), has a known ileal loop, or
intractable vesico-uretral reflux.
2. Patient has a cUTI in whom a temporary indwelling urinary catheter is in place and
cannot be removed at study entry
NOTE: All indwelling urinary catheters must be removed prior to the start of IV
study therapy. It is also anticipated that an indwelling urinary catheter will not be
reinserted during the study (at least while on IV study therapy).
3. Patient has a perinephric or intrarenal abscess or known or suspected prostatitis.
4. Patient has an uncomplicated UTI (e.g., a female patient with urinary frequency,
urgency or pain/discomfort without any risk factors for infection as outlined in
Inclusion Criteria #5b).
5. Patient has any history of recent accidental trauma to the pelvis or urinary tract.
6. Patient has received any amount of effective antibiotic therapy (defined as therapy known to be active against the identified uropathogen) after obtaining the urine culture for admission to this study (admission urine culture) and prior to the
administration of the first dose of IV study therapy.
7. 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 (only patients with a urine culture positive for the presence of at least 1 gram-negative enteric(s) and/or anaerobic pathogen(s) commonly isolated in UTI will be considered microbiologically evaluable).
NOTE: Patients on prophylactic antibiotic therapy should be enrolled only if their
admission culture is confirmed to be positive for at least 1 gram-negative enteric(s) and/or anaerobic pathogen(s) commonly isolated in UTI. Culture results must be available from those patients on prophylactic antibiotics prior to enrollment.
NOTE: If a patient has received >24 hours of systemic antimicrobial therapy, there
must be clear evidence that the patient has failed this regimen or developed the cUTI
while on the previous antibiotic regimen. Such evidence would include new or
continued fever or persistence or worsening of symptoms related to the index infection and persistent positive cultures and persistent laboratory or radiographic changes (if previously present). These measures should be confirmed prior to study entry.
8. 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.
NOTE: Patients with history of mild rash to penicillins or other β-lactams may be
enrolled and closely monitored.
9. 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).
NOTE: Patients with history of mild rash to other β-lactamase inhibitors may be
enrolled and closely monitored.
10. Patient has a history of a seizure disorder.
11. Patient is currently being treated with valproic acid or has received treatment with
valproic acid in the 2 weeks prior to screening.
12. Patient has a rapidly progressive or terminal illness (unlikely to survive the
approximately 6- to 8-week study period).
13. Patient is pregnant or expecting to conceive, is breast feeding, or plans to breast feed within 1 month of completion of the study.
14. Patient in whom a response to all study therapy (IV study therapy or subsequent oral ciprofloxacin) within the timeframe of treatment specified in this protocol is
considered unlikely.
15. Patient has a concurrent infection that would interfere with evaluation of response to the study antibiotics (imipenem/cilastatin with or without MK-7655).
16. Patient has a need for concomitant systemic antimicrobial agents in addition to those designated in the various study treatment groups.
NOTE: Use of IV vancomycin to treat confirmed or suspected methicillin-resistant S. aureus (MRSA) infection or use of linezolid to treat confirmed or suspected MRSA or vancomycin-resistant Enterococcus spp. (VRE) infection is allowed
17. Patient has a cUTI due to a confirmed fungal pathogen.
NOTE: Use of antifungal therapy for treatment of mucocutaneous infections (e.g., vaginal candidiasis onychomycosis) is allowed
18. Patient is currently receiving immunosuppressive therapy, including use of high-dose corticosteroids (i.e., >40 mg prednisone or prednisone equivalent per day).
NOTE: Prior short term use (≤5 days) of steroid therapy in the 30 days prior to study entry is allowed.
19. Patient is a prior recipient of a renal transplantation.
20. Patient has estimated or actual creatinine clearance of <50 mL/min. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients with a favorable microbiological response ("eradication") as assessed at the DCIV visit (4 to 14 days post initiation of IV study therapy). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 4 to 14 days post initiation of IV study therapy |
|
| E.5.2 | Secondary end point(s) |
Microbiological response will also be evaluated as a secondary endpoint at the EFU visit (5 to 9 days following all antibiotic therapy) and the LFU visit (28 to 42 days following all antibiotic therapy) as well as at the DCIV visit in the subset of patients with imipenem-resistant Gram-negative cUTI.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| EFU visit (5 to 9 days following all antibiotic therapy) and the LFU visit (28 to 42 days following all antibiotic therapy) |
|
| 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 |
|
| 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 | 29 |
| 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 |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Greece |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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