| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) with or without concurrent bacteremia |
|
| E.1.1.1 | Medical condition in easily understood language |
| urinary tract infection or acute pyelonephritis |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037597 |
| E.1.2 | Term | Pyelonephritis acute |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| 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 assess the efficacy of Carbavance (meropenem/RPX7009) administered by IV infusion in subjects with cUTI or acute pyelonephritis (AP);
To assess the safety and tolerability of Carbavance (meropenem/RPX7009) administered by IV infusion in subjects with cUTI or AP; and
To assess the population PK of meropenem and RPX7009 in subjects with cUTI or AP. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A signed informed consent form, the ability to understand the study
conduct and tasks that are required for study participation, and a
willingness to cooperate with all tasks, tests, and examinations as
required by the protocol.
2. Male or female ≥ 18 years of age.
3. Weight ≤ 185 kg.
4. Expectation, in the judgment of the Investigator, that the subject's
cUTI or AP requires initial treatment with at least 5 days of IV
antibiotics.
5. Documented or suspected cUTI or AP as defined in the protocol amendment 2.
6. Expectation, in the judgment of the Investigator, that any indwelling
urinary catheter or instrumentation (including nephrostomy tubes
and/or indwelling stents) will be removed or replaced (if removal is not clinically acceptable) before or as soon as possible, but not longer than
12 hours, after randomization.
7. Expectation, in the judgment of the Investigator, that the subject will
survive with effective antibiotic therapy and appropriate supportive care
for the anticipated duration of the study.
8. Women of childbearing potential must have a negative pregnancy test
before randomization, and be willing to use a highly effective method of
contraception between randomization and for 7 days after the
completion of the study. A highly effective method of contraception
includes two of the following: hormonal implants/patch, injectable
hormones, oral hormonal contraceptives, prior bilateral oophorectomy,
prior hysterectomy, prior bilateral tubal ligation, intra-uterine device,
approved cervical ring, condom, true abstinence (if approved by the
Investigator), or a vasectomized partner.
9. Willingness to comply with all the study procedures, whether in the
hospital or after discharge, for the duration of the study. |
|
| E.4 | Principal exclusion criteria |
1. Presence of any of the following conditions:
a. Perinephric abscess;
b. Renal corticomedullary abscess;
c. Uncomplicated UTI;
d. Polycystic kidney disease;
e. Chronic vesicoureteral reflux;
f. Previous or planned renal transplantation;
g. Subjects receiving hemodialysis;
h. Previous or planned cystectomy or ileal loop surgery; or
i. Known candiduria.
2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination.
3. Gross hematuria requiring intervention other than administration of study drug.
4. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery planned during the study period (except surgery required
to relieve an obstruction or place a stent or nephrostomy).
5. Renal function at screening as estimated by creatinine clearance <30 mL/min using the Cockcroft-Gault formula.
6. Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization.
7. Any of the following signs of severe sepsis:
a. Shock or profound hypotension defined as systolic blood pressure <90 mmHg or a decrease of >40 mmHg from baseline (if known) that is not
responsive to fluid challenge;
b. Hypothermia (oral or tympanic temperature <35.6°C [<96.1°F] or rectal/core temperature <35.9°C [<96.6°F]);
c. Disseminated intravascular coagulation as evidenced by prothrombin time or partial thromboplastin time ≥ 2 × the upper limit of normal (ULN)
or platelets <50% of the lower limit of normal.
8. Pregnant or breastfeeding women.
9. History of epilepsy or known seizure disorder requiring current treatment with anti-seizure medication.
10. Treatment within 30 days prior to enrollment with valproic acid.
11. Treatment within 30 days prior to enrollment with probenecid.
12. Treatment within 30 days prior to enrollment with any cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation.
13. Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy.
14. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × ULN, or total bilirubin > 1.5 × ULN.
15. Receipt of any investigational medication or investigational device during the last 30 days prior to randomization.
16. Prior exposure to RPX7009 alone or in combination with another product.
17. Receipt of any potentially therapeutic antibiotic agent within 48 hours before randomization. Please refer to the protocol for more details.
18. Requirement at time of enrollment for any reason for additional systemic antibiotic therapy (other than study drug) or antifungal
therapy. Topical antifungal or a single oral dose of any antifungal treatment for vaginal candidiasis will be allowed.
19. Likely to require the use of an antibiotic for cUTI prophylaxis during the subject's participation in the study (from enrollment through the LFU
visit).
20. Known history of human immunodeficiency virus infection with a CD4 count <200/mm3.
21. Presence of immunodeficiency or an immunocompromised condition including hematologic malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as cancer chemotherapy, medications for the rejection of transplantation, and long-term use of systemic corticosteroids (equivalent to ≥ 20 mg a day of prednisone or systemic equivalent for ≥2 weeks).
22. Presence of neutropenia (<1,000 polymorphonuclear leukocytes [PMNs]/mm3).
23. Presence of thrombocytopenia (<60,000 platelets/mm3).
24. A corrected QT (Fridericia) (QTcF) >480 msec.
25. History of significant hypersensitivity or allergic reaction to Carbavance, piperacillin/tazobactam, any of the excipients used in the
respective formulations, or any beta-lactam antibiotics.
26. Known hypersensitivity or inability to tolerate all of the following: fluoroquinolones or unable to receive, trimethoprim/ sulfamethoxazole, cefdinir, cefixime or cefpodoxime, based on prescribing information.
27. Unable or unwilling, in the judgment of the Investigator, to comply with the protocol.
28. An employee of the Investigator or study center with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, or a family member of the employee or the Investigator.
29. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30. An APACHE II score is only required if calculated.
30. Inability to tolerate intravenous fluids, due to medical reasons, of 1050 ml per day required for study drug administration.
31. Any recent history of trauma to the pelvis or urinary tract. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for EMA
The primary efficacy endpoint for this study for the European Medicines
Agency (EMA) will be the proportion of subjects in the co-primary m-
MITT and ME Populations who achieve a microbiologic outcome of Eradication at the TOC visit.
A microbiologic outcome of Eradication is defined as the demonstration
that the bacterial pathogen(s) found at baseline is reduced to <103
CFU/mL of urine.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
The secondary endpoints for this study are the following:
Proportion of subjects in the m-MITT Population with overall success
at both the EOIVT and TOC visits;
Proportion of subjects in the m-MITT and ME Populations with a
microbiologic outcome of Eradication to <104 CFU/mL of urine for FDA
and <103 CFU/mL of urine for EMA at Day 3, EOIVT, EOT, TOC, and LFU;
Proportion of subjects with a clinical outcome of Cure in the m-MITT,
CE, and ME Populations at Day 3, EOIVT, EOT, TOC, and LFU;
Per-pathogen outcome in the m-MITT and ME Populations at Day 3,
EOIVT, EOT, TOC, and LFU;
Pharmacokinetic characterization of plasma exposure of meropenem
and RPX7009; and
Safety and tolerability profile of Carbavance (meropenem/RPX7009)
by incidence and severity of adverse events and serious adverse events,
vital signs, clinical laboratory tests, electrocardiograms (ECGs), and
physical examinations in the Safety Population. |
|
| 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 | No |
| 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 | 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) | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Belarus |
| Brazil |
| Bulgaria |
| Czech Republic |
| Germany |
| Greece |
| Hungary |
| Italy |
| Korea, Republic of |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| Spain |
| Taiwan |
| Ukraine |
| United States |
|
| 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
|
|
| 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 |
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