| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| serious infections, specifically complicated urinary tract infection (cUTI) or acute pyelonephritis (AP), hospital acquired bacterial pneumonia (HABP), ventilator associated bacterial pneumonia (VABP), and/or bacteremia, known or suspected to be caused by carbapenem-resistant Enterobacteriaceae (CRE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| serious urinary infections, bacterial pneumonia infections and/or blood infections known or suspected to be caused by carbapenem-resistant Enterobacteriaceae |
|
| 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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003999 |
| E.1.2 | Term | Bacteremia |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001032 |
| E.1.2 | Term | Acute pyelonephritis |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004051 |
| E.1.2 | Term | Bacterial pneumonia, unspecified |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10046577 |
| E.1.2 | Term | Urinary tract infections |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 safety, tolerability and efficacy of Carbavance™ (meropenem/RPX7009) in treatment of subjects with selected serious infections, suspected or known to be due to CRE; and
To assess the pharmacokinetics (PK) of meropenem and RPX7009 in subjects with selected serious infections, suspected or known to be due to CRE. |
|
| E.2.2 | Secondary objectives of the trial |
| Not applicable |
| No aplicable |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Willingness to comply with all study activities and procedures and to provide signed, written informed consent prior to any study procedures. If a subject is unable to provide informed consent due to their medical condition, the subject’s legal representative will be provided with study information in order for consent to be obtained.
2.Hospitalized male or female, >18 years of age.
3.Weight >150 kg.
4.Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, HABP, VABP, and/or bacteremia, requiring administration of IV antibacterial therapy (See inclusion number 7 for criteria for all indications).
5.The following must be satisfied:
For known CRE infection:
-Have a known CRE infection based on evidence from CRE culture or other phenotypic or molecular testing within 72 hours prior to Day 1, alone or as a single isolate of a polymicrobial infection;
-Have received no more than 24 hours of a potentially effective (i.e., gram negative coverage) antimicrobial therapy prior to enrollment,
OR
-Have documented clinical evidence of failure (i.e., clinical deterioration or failure to improve) while on a potentially effective regimen.
For suspected CRE infection:
-Have a suspected CRE infection based on evidence from CRE culture (KPC producing) or other phenotypic or molecular testing, alone or as a single isolate of a polymicrobial infection, from any source within 90 days prior to Day 1;
-Have received no more than 24 hours of a potentially effective (i.e., gram negative coverage) antimicrobial therapy prior to enrollment,
OR
-Have documented clinical evidence of failure (i.e., clinical deterioration or failure to improve) while on a potentially effective regimen.
6.Expectation, in the opinion of the Investigator, that the subject’s infection will require treatment with IV antibiotics for a minimum of 7 days.
7.Diagnosis with either cUTI or AP, HABP, VABP, and/or bacteremia as defined per protocol.
8.Female subjects of child-bearing potential, including those who are less than 2 years post-menopausal, must agree to, and comply with, using 2 highly effective methods of birth control (i.e., condom plus spermicide, combined oral contraceptive, implant, injectable, indwelling intrauterine device, sexual abstinence, or a vasectomized partner) while participating in this study. In addition, all women of childbearing potential must agree to continue to use 2 forms of birth control throughout the study and for at least 30 days after administration of the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1.History of any significant hypersensitivity or severe allergic reaction to any beta lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams).
2.Known or suspected likely infection with New Delhi metallo- (NDM), Verona integron encoded metallo- (VIM), or IMP-metallo-beta-lactamases or oxacillinase- (OXA) beta lactamases (i.e., Class B or Class D beta lactamases).
3.For subjects to be enrolled with the primary indication of cUTI or AP, any of the following urologic conditions:
Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI (e.g., subjects with vesico-ureteral reflux);
Suspected or confirmed prostatitis;
Requirement for bladder irrigation with antibiotics or for antibiotics to be administered directly via urinary catheter;
Previous or planned cystectomy or ileal loop surgery;
Uncomplicated urinary tract infection (for example, female subjects with urinary frequency, urgency or pain or discomfort without systemic symptoms or signs of infection);
Complete, permanent obstruction of the urinary tract;
Suspected or confirmed perinephric or renal corticomedullary abscess; or Polycystic kidney disease.
4.For subjects to be enrolled with the primary indication of HABP or VABP, any of the following conditions:
Diagnosis of ventilator-associated tracheobronchitis
Inability to obtain proper respiratory specimens for culture
5.For subjects to be enrolled with the indication of bacteremia unrelated to cUTI or AP, HABP, and VABP, any of the following:
Unverified CRE infection
Source of infection thought to be related to or involving a non removable or implantable device or line.
6.Impairment of renal function including a calculated creatinine clearance of <20 mL/min (Cockcroft-Gault), requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (<20 mL urine output per hour over 24 hours).
7.Evidence of immediately life-threatening disease, including, but not limited to, acute heart failure, shock, acute coronary syndrome, unstable arrhythmias, hypertensive emergency, acute hepatic failure, active gastrointestinal bleeding, profound metabolic abnormalities (e.g., diabetic ketoacidosis), or acute cerebrovascular events, OR in the opinion of the Investigator, the subject is unlikely to survive the duration of the treatment.
8.Myasthenia gravis, Parkinsonism, or other neuromuscular disorder.
9.Acute Physiology and Chronic Health Evaluation (APACHE) II score >30. An APACHE II score is only required if calculated.
10.Known or suspected endocarditis, meningitis, intra-abdominal infection, or osteomyelitis.
11.Unremovable or implantable device or line thought to be the potential source of infection.
12.Evidence of significant hepatic, hematological, or immunologic disease or dysfunction determined by any of the following:
Known acute viral hepatitis;
Aspartate aminotransferase or alanine aminotransferase level >5 × upper limit of normal (ULN) or total bilirubin >3 × ULN;
Manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy;
Current or anticipated neutropenia defined as <500 neutrophils/mm3;
Thrombocytopenia with platelet count <60,000 cells/mm3;
Human immunodeficiency virus with either a CD4 count <200 cells/mm3 at the last measurement, or current diagnosis of another Acquired Immune Deficiency Syndrome-defining illness;
Bone marrow-ablative chemotherapy or radiation therapy within the prior 3 months; or Requiring chronic treatment of >20 mg of prednisone (or equivalent systemic corticosteroid) per day for over 2 weeks.
13.Past or current history of epilepsy or seizure disorder requiring current treatment with anti-seizure medications.
14.Ongoing receipt of sodium valproate or probenecid.
15.Women who are pregnant or breastfeeding.
16.Require the use of inhaled antibiotics.
17.Participation in any study involving administration of an investigational agent or device within 30 days prior to randomization into this study or previous participation in the current study.
18.Previous participation in a study of RPX7009.
19.Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for cUTI or Ap is the proportion of subjects in the mCRE-MITT who demonstrate Microbiological eradication; Population who demonstrate a response of Overall Success at the TOC visit.
A response of overall success is defined asachieved in a subject whose gram-negative antimicrobial therapy to treat the baseline infection is not altered (other than dose adjustment or modification of Best Available Therapy based on susceptibility of baseline pathogen within the first 72 hours after first dose of study drug) after randomization due to concerns of microbiological failure, clinical failure, or tolerability AND at TOC per protocol.
Primary Endpoint for HABP and VABP
The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28 for all patients with HABP, VABP, and bacteremia (not related to cUTI/AP or HABP/VABP;
Primary Endpoint for Bacteremia
The all-cause mortality rate in the mCRE-MITT Population at Day 28 for all patients with HABP, VABP, and bacteremia (not related to cUTI/AP or HABP/VABP; |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| LPLV as per details listed in above section. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints for cUTI or AP
- The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28;
- Proportion of subjects in the m MITT and ME Populations who demonstrate a response of overall success at the TOC visit;
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is assigned to failure;
- Proportion of subjects in the mCRE-MITT, m MITT, CRE-ME, and ME Populations with a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU;
Relapse/recurrence rates of baseline cUTI or AP at the LFU visit; and
- Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at Day 3, EOT, TOC, and LFU.
Secondary Endpoints for HABP and VABP
- The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28
- The proportion of subjects in the mCRE-MITT Population who demonstrate a response of Success cure at the TOC visit;.
A clinical outcome of cure is defined as a subject whose gram-negative antimicrobial therapy to treat the baseline infection is not altered (other than dose adjustment or modification of Best Available Therapy based on susceptibility of baseline pathogen within the first 72 hours after first dose of study drug) after randomization due to concerns of microbiological failure, clinical failure, or tolerability AND at TOC per protocol.
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is assigned to failure;
-Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at Day 3, EOT, TOC, and LFU;
- Relapse/recurrence rates of baseline bacterial pneumonia at the LFU visit;
- Total ventilator days measured from time of randomization;
- Change in the partial pressure arterial oxygen to fraction of inspired oxygen (PaO2:FiO2) ratio from baseline to Day 3, Day 7, and EOT;
- Time (days) to extubation in subjects who are on the ventilator at baseline (i.e., Day 1).
Secondary Endpoints for Bacteremia
- The all-cause mortality rate in the mCRE-MITT and m-MITT Populations at Day 28;
- The proportion of subjects in the mCRE-MITT Population who demonstrate a response of overall success at the TOC visit.
A response of Success is defined as a subject whose gram-negative antimicrobial therapy to treat the baseline infection is not altered (other than dose adjustment or modification of Best Available Therapy based on susceptibility of baseline pathogen within the first 72 hours after first dose of study drug) after randomization due to concerns of microbiological failure, clinical failure, or tolerability AND at TOC per protocol;
- Proportion of subjects in the m-MITT, CRE-ME, and ME Populations who demonstrate a response of overall success at the TOC visit;
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at Day 3, EOT, TOC, and LFU;
- Proportion of subjects in the mCRE-MITT, m MITT, CE, CRE-ME, and ME Populations with a clinical outcome of cure at TOC, where the use of an aminoglycoside beyond 72 hours in subjects with a pathogen susceptible to Carbavance (meropenem/RPX7009) is assigned to failure;
Proportion of subjects in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations with a microbiological outcome of eradication at Day 3, EOT, TOC, and LFU;
- Relapse/recurrence rates of baseline bacteremia at the LFU visit; and
- Per-pathogen outcome in the mCRE-MITT, m-MITT, CRE-ME, and ME Populations at Day 3, EOT, TOC, and LFU.
- Time to bacterial clearance in mCRE-MITT, m-MITT, CRE-ME, and ME Populations
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| LPLV as per details listed in above section |
|
| 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 |
| tolerability |
| tolerabilidad |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| 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 | 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 |
| Colombia |
| Greece |
| Israel |
| Italy |
| Spain |
| Taiwan |
| United Kingdom |
| 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
|
| LPLV as per the end point criteria |
|
| 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 | 10 |
| 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 | 6 |
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