Efficacy, Safety, Tolerability of Vabomere Compared to Best Available Therapy in Treating Serious Infections in Adults

• Sponsor: Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.) (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02168946
• Collaborator: Department of Health and Human Services (U.S. Fed)
• Enrollment: 77
• Locations: 50
• Arms: 2
• Duration (Months): 36.7
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Vabomere™, (meropenem-vaborbactam) is being compared to the Best Available Therapy in the treatment of adults with selected serious infections due to Carbapenem Resistant Enterobacteriaceae

Condition or Disease	Intervention/Treatment	Phase
Urinary Tract Infection Complicated; Acute Pyelonephritis; Hospital Acquired Bacterial Pneumonia; Ventilator-associated Bacterial Pneumonia; Bacteremia; Abdominal Infection	Drug: Vabomere; Drug: Best Available Therapy	Phase 3

Detailed Description

In the current era of increased resistance to extended spectrum cephalosporins and penicillin/beta-lactamase inhibitor combinations, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections. However, the recent dissemination of serine carbapenemases (e.g. KPC) in Enterobacteriaceae within many hospitals worldwide now poses a considerable threat to carbapenems and other members of the beta-lactam class of antimicrobial agents.

Infections caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with high mortality rates and have limited treatment options. The loss of the carbapenem class of antimicrobial agents for treatment of Enterobacteriaceae (the most frequently occurring pathogens in the hospital setting), Acinetobacter baumannii, and Pseudomonas aeruginosa represents a critical setback in modern patient care.

As a result of the current lack of an optimal treatment for patients who have infections due to a CRE, physicians manage these patients with the limited anti-infective options available, including aminoglycosides, polymyxin B, colistin, tigecycline, or various combinations of these. There are limited efficacy data available for many of these therapies when used to treat serious CRE infections, particularly in combination, but with limited or no alternative therapies currently available, such treatments have become the Best Available Therapy despite the toxicities associated with many of them.

Vaborbactam is a novel beta-lactamase inhibitor that has inhibitory activity against many serine beta-lactamases and was optimized for inhibition of the KPC beta-lactamase and the potentiation of carbapenems against Enterobacteriaceae. Vaborbactam is being developed for use with meropenem (a broad spectrum injectable carbapenem antibiotic) to address the challenges of treatment of serious infections caused by pathogens increasingly resistant to available treatments.

Vabomere, (meropenem-vaborbactam) administered as a fixed combination by intravenous (IV) infusion, is being developed to treat serious gram-negative infections, such as complicated urinary tract infections (cUTI), acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia, including those infections caused by bacteria resistant to currently available carbapenems.

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: Blinded adjudication committee
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multi-Center, Randomized, Open-Label Study of Vabomere(Meropenem-vaborbactam) Versus Best Available Therapy in Subjects With Selected Serious Infections Due to Carbapenem-Resistant Enterobacteriaceae (CRE)
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Jul 21, 2017
• Actual Study Completion Date: Jul 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vabomere Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Drug: Vabomere; Vabomere for IV injection, administered as a 2 g/2 g dose; Other Names: Combination meropenem and vaborbactam beta-lactamase inhibitor and carbapenem antibiotic
Active Comparator: Best Available Therapy Subjects will receive Best Available Therapy (IV antibiotics)	Drug: Best Available Therapy; Antibiotic(s) chosen by Investigator; Other Names: IV Antibiotics

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects in the Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-Treat (mCRE-MITT) Population With a Response of Overall Success [Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) Subjects] [at Test of Cure (TOC) visit (Day 12-23)]

   Overall success is defined as clinical cure & microbiological eradication. Eradication defined by FDA as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 colony forming unit (CFU)/mL urine. Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

2. All-cause Mortality Rate in the mCRE-MITT Population [Hospital-acquired Bacterial Pneumonia (HABP), Ventilator-associated Bacterial Pneumonia (VABP) and Bacteremia Subjects) [Day 28]

   The All-cause mortality rate at Day 28 in the mCRE-MITT population (HABP/VABP and Bacteremia)

3. Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure [Complicated Intra-abdominal Infection (cIAI) Subjects Only] [at TOC visit (Day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs and symptoms, no further antimicrobial warranted.

Secondary Outcome Measures

1. The All-cause Mortality Rate in the mCRE-MITT Population (All Indications) [at Day 28]

   All Cause Mortality at Day 28 in the mCRE-MITT population (all indications)

2. The All-cause Mortality Rate in the m-MITT Population (All Indications) [at Day 28]

   The All Cause Mortality rate at Day 28 in the m-MITT population (all indications)

3. The All-cause Mortality Rate in the mCRE-MITT Population (cUTI/AP) [at Day 28]

   All Cause Mortality at Day 28 in the mCRE-MITT population (cUTI/AP subjects only)

4. Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (All Indications) [at End of Therapy (EOT) visit (7-14 days) and TOC visit (12-23 days)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

5. Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (cUTI/AP Subjects Only) [at EOT visit (7-14) and TOC visit (day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

6. Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (HABP/VABP and Bacteremia) [at EOT visit (7-14) and TOC visit (day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

7. Proportion of Subjects in the Microbiological Modified Intent-to-Treat (m-MITT) Population With a Clinical Outcome of Cure (All Indications) [at EOT visit (7-14) and TOC visit (day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs and symptoms, no further antimicrobial warranted.

8. Proportion of Subjects in the m-MITT Population With a Clinical Outcome of Cure (cUTI/AP) [at EOT visit (7-14) and TOC visit (day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

9. Proportion of Subjects in the m-MITT Population With a Clinical Outcome of Cure (HABP/VABP and Bacteremia) [at EOT visit (7-14) and TOC visit (day 12-23)]

   Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

10. Proportion of Subjects in the mCRE-MITT Population With a Microbiological Outcome of Eradication (All Indications) [at EOT visit (7-14) and TOC visit (day 12-23)]

    Includes subjects with microbiologic eradication or presumed eradication as defined: microbiologic eradication of the baseline pathogen or absence of culture result (microbiologic outcome of indeterminate or not assesses) where subject is deemed as clinical cure at that visit. For cUTI/AP subjects, demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA).

11. Proportion of Subjects in the m-MITT Population With a Microbiological Outcome of Eradication (All Indications) [at EOT visit (7-14) and TOC visit (day 12-23)]

    Microbiological eradication defined for cUTI/AP as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA).

12. Proportion of Subjects in the m-MITT Populations With a With a Response of Overall Success (cUTI/AP) [at EOT visit (7-14) and TOC visit (day 12-23)]

    Proportion of subjects in m-MITT Population with response of cure and microbiological eradication or presumed eradication. Eradication defined for cUTI/AP as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA). Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

13. Proportion of Subjects in the m-MITT Populations With a With a Response of Overall Success (Bacteremia Only) [at EOT visit (7-14) and TOC visit (day 12-23)]

    Proportion of subjects in m-MITT Population with response of cure and microbiological eradication or presumed eradication. Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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 ≤185 kg.

4. Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, cIAI, HABP, VABP, and/or bacteremia, requiring administration of IV antibacterial therapy.

5. Have a known or suspected Carbapenem-Resistant Enterobacteriaceae (CRE) infection.

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. Expectation that subjects with an estimated creatinine clearance <10 ml/min (Cockcroft-Gault) will receive hemodialysis at least 2 times per week.

8. For cUTI & AP subjects only: 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.

For cIAI subjects only: • Expectation, in the judgment of the investigator, that operative drainage/debridement/removal (including open laparotomy, percutaneous drainage, or laparoscopic surgery) of any intra-abdominal collection or other potential source of intra abdominal infection will be performed;

• Expectation that cultures from the aforementioned procedure (including open laparotomy, percutaneous drainage, or laparoscopic surgery) will be sent for microbiological evaluation, including gram stain, culture and susceptibility testing, and Vabomere susceptibility testing.

1. Female subjects of childbearing 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.

• 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:

4. Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI (e.g., subjects with vesico-ureteral reflux);

5. Suspected or confirmed prostatitis;

6. Requirement for bladder irrigation with antibiotics or for antibiotics to be administered directly via urinary catheter;

7. Previous or planned cystectomy or ileal loop surgery;

8. Uncomplicated urinary tract infection (for example, female subjects with urinary frequency, urgency or pain or discomfort without systemic symptoms or signs of infection);

9. Complete, permanent obstruction of the urinary tract;

10. Suspected or confirmed perinephric or renal corticomedullary abscess;

11. Polycystic kidney disease; or

12. Any recent history of trauma to the pelvis or urinary tract.

13. For subjects to be enrolled with the primary indication of cIAI, any of the following conditions:

14. Incomplete drainage of suspected or known intra-abdominal source;

15. Likely to receive ongoing antibacterial drug prophylaxis or chronic suppressive therapy after intravenous treatment of cIAI;

16. Source of infection thought to be related to or involving a non-removable prosthesis (e.g. intra-abdominal mesh) or implantable device, line (e.g. peritoneal catheter) or stent (e.g. biliary stent);

17. Uncomplicated intra-abdominal infection, such as simple appendicitis, simple cholecystitis or gangrenous cholecystitis without rupture;

18. Patients with infected necrotizing pancreatitis or pancreatic abscess;

19. Patients whose surgery will include staged abdominal repair or "open abdomen" technique, or marsupialization (i.e. patients who undergo a surgical procedure where fascial closure is performed are eligible. The skin incision may be left open for purposes of wound management as long as fascial closure is accomplished);

20. Patients in whom the intra-abdominal process is deemed not likely to be infectious in origin (e.g. bowel obstruction, ischemic bowel without perforation, traumatic bowel perforation within past 12 hours, perforated gastroduodenal ulcer within 24 hours); or

21. Non-intra-abdominal infection (e.g. infection or abscess of the abdominal wall without extension into the intra-abdominal cavity).

22. For subjects to be enrolled with the primary indication of HABP or VABP, any of the following conditions:

23. Diagnosis of ventilator-associated tracheobronchitis

24. Inability to obtain proper respiratory specimens for culture.

25. For subjects to be enrolled with the indication of bacteremia unrelated to cUTI or AP, cIAI, HABP, and VABP, any of the following:

26. Unverified CRE infection

27. Source of infection thought to be related to or involving a non-removable or implantable device or line.

28. Evidence of immediately life-threatening disease where in the opinion of the Investigator, the subject is unlikely to survive more than 72 hours from randomization.

29. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30.

30. Known or suspected endocarditis, meningitis, intra-abdominal infection, or osteomyelitis.

31. Irremovable or implantable device or line thought to be the potential source of infection.

32. Evidence of significant hepatic, hematological, or immunologic disease or dysfunction.

33. Women who are pregnant or breastfeeding.

34. Require the use of inhaled antibiotics.

35. 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.

36. Previous participation in a study of vaborbactam.

37. Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Hartford	Connecticut	United States	06102
2		Tampa	Florida	United States	33606
3		Augusta	Georgia	United States	30912
4		Chicago	Illinois	United States	60611
5		Chicago	Illinois	United States	60612
6		Evanston	Illinois	United States	60201
7		Indianapolis	Indiana	United States	46202
8		Detroit	Michigan	United States	48201
9		Royal Oak	Michigan	United States	48073
10		New Brunswick	New Jersey	United States	08901
11		Bronx	New York	United States	10467
12		Buffalo	New York	United States	14215
13		Flushing	New York	United States	11355
14		New York	New York	United States	10032
15		Charlotte	North Carolina	United States	28207
16		Durham	North Carolina	United States	27710
17		Cleveland	Ohio	United States	44106
18		Philadelphia	Pennsylvania	United States	19104
19		Pittsburgh	Pennsylvania	United States	15213
20		Charlottesville	Virginia	United States	22908
21		Ciudad Autónoma de Buenos Aires		Argentina	C1405CNF
22		Córdoba		Argentina	5016
23		La Plata		Argentina	B1900AXI
24		Mendoza		Argentina	5500
25		Sao Jose do Rio Preto	São Paulo	Brazil	05652-900
26		Belo Horizonte		Brazil	30150-221
27		Curitiba		Brazil	81050-000
28		Porto Alegre		Brazil	90035-903
29		Sao Paulo		Brazil	SP
30		São Paulo		Brazil	05652-900
31		São Paulo		Brazil	14048-900
32		Barranquilla		Colombia
33		Bogota		Colombia	0
34		Medellin		Colombia	4
35		Athens		Greece	106 76
36		Athens		Greece	11527
37		Athens		Greece	12462
38		Thessaloniki		Greece	54636
39		Haifa		Israel	31096
40		Petah Tikva		Israel	49100
41		Ramat Gan		Israel	52621
42		Tel Aviv		Israel	64239
43		Bologna		Italy	40138
44		Firenze		Italy	50134
45		Genova		Italy	16132
46		Pisa		Italy	56124
47		Rome		Italy	00161
48		Udine		Italy	33100
49		Manchester		United Kingdom	M23 9LT
50		Manchester		United Kingdom	MI39WL

Sponsors and Collaborators

• Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.)
• Department of Health and Human Services

Investigators

• Study Director: Karen Fusaro, Sponsor GmbH
• Principal Investigator: Keith Kaye, Wayne State University

Study Documents (Full-Text)

• Study Protocol - Apr 24, 2015
• Statistical Analysis Plan - Jun 10, 2016

More Information

Publications

None provided.

• Responsible Party: Rempex (a wholly owned subsidiary of Melinta Therapeutics, Inc.)
• ClinicalTrials.gov Identifier: NCT02168946
• Other Study ID Numbers: Rempex 506
• First Posted: Jun 20, 2014
• Last Update Posted: Mar 4, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Infections; Communicable Diseases; Pneumonia; Urinary Tract Infections; Bacteremia; Intraabdominal Infections; Pneumonia, Bacterial; Pyelonephritis; Anti-Bacterial Agents; Meropenem; Vaborbactam; Antibiotics, Antitubercular; beta-Lactamase Inhibitors

Study Results

Participant Flow

Recruitment Details	The first patient enrolled November 2014 and last patient in June 2017. The patients were enrolled at 27 study sites in 8 countries. 77 patients (28 with bacteremia, 34 with cUTI, 8 with HABP/VABP and 7 with cIAI) were enrolled and 47 had confirmed Carbapenem-Resistant Enterobacteriaceae and therefore were included in the mCRE population.
Pre-assignment Detail	Randomization was stratified by presenting indication (cUTI or AP, cIAI, HABP, VABP, or bacteremia) and by region (North America, Europe, Asia Pacific, and Rest of World).

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days Vabomere: Vabomere for IV injection, administered as a 2 g/2 g dose	Subjects will receive Best Available Therapy (IV antibiotics) Best Available Therapy: Antibiotic(s) chosen by Investigator
Period Title: Overall Study
STARTED	50	25
COMPLETED	38	20
NOT COMPLETED	12	5

Baseline Characteristics

Arm/Group Title	Vabomere	Best Available Therapy	Total
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator	Total of all reporting groups
Overall Participants	50	25	75
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 52%	14 56%	40 53.3%
>=65 years	24 48%	11 44%	35 46.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.6 (15.30)	63.2 (13.10)	63.5 (14.51)
Sex: Female, Male (Count of Participants)
Female	25 50%	7 28%	32 42.7%
Male	25 50%	18 72%	43 57.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 18%	5 20%	14 18.7%
Not Hispanic or Latino	41 82%	20 80%	61 81.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2%	1 4%	2 2.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 6%	2 8%	5 6.7%
White	43 86%	22 88%	65 86.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 6%	0 0%	3 4%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.90 (8.340)	27.14 (7.522)	27.64 (8.029)
Systemic Inflammatory Response Syndrome (SIRS) present (Count of Participants)
Count of Participants [Participants]	22 44%	10 40%	32 42.7%
Creatinine Clearance <50 mL/min (Count of Participants)
Count of Participants [Participants]	12 24%	9 36%	21 28%
Baseline Pathogen - Klebsiella pneumoniae (Count of Participants)
Count of Participants [Participants]	30 60%	14 56%	44 58.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects in the Microbiological Carbapenem-resistant Enterobacteriaceae Modified Intent-to-Treat (mCRE-MITT) Population With a Response of Overall Success [Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) Subjects]
Description	Overall success is defined as clinical cure & microbiological eradication. Eradication defined by FDA as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 colony forming unit (CFU)/mL urine. Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at Test of Cure (TOC) visit (Day 12-23)

Outcome Measure Data

Analysis Population Description

The mCRE-MITT population includes all patients who had confirmed Carbapenem-Resistant Enterobacteriaceae at Baseline. (cUTI/AP patients only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	12	4
Count of Participants [Participants]	4 8%	2 8%

2. Primary Outcome

Title	All-cause Mortality Rate in the mCRE-MITT Population [Hospital-acquired Bacterial Pneumonia (HABP), Ventilator-associated Bacterial Pneumonia (VABP) and Bacteremia Subjects)
Description	The All-cause mortality rate at Day 28 in the mCRE-MITT population (HABP/VABP and Bacteremia)
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

mCRE-MITT Population (HABP/VABP and Bacteremia subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	18	9
Count of Participants [Participants]	4 8%	4 16%

3. Primary Outcome

Title	Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure [Complicated Intra-abdominal Infection (cIAI) Subjects Only]
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs and symptoms, no further antimicrobial warranted.
Time Frame	at TOC visit (Day 12-23)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	2	2
Count of Participants [Participants]	2 4%	0 0%

4. Secondary Outcome

Title	The All-cause Mortality Rate in the mCRE-MITT Population (All Indications)
Description	All Cause Mortality at Day 28 in the mCRE-MITT population (all indications)
Time Frame	at Day 28

Outcome Measure Data

Analysis Population Description

mCRE-MITT population (all indications)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	32	15
Count of Participants [Participants]	5 10%	5 20%

5. Secondary Outcome

Title	The All-cause Mortality Rate in the m-MITT Population (All Indications)
Description	The All Cause Mortality rate at Day 28 in the m-MITT population (all indications)
Time Frame	at Day 28

Outcome Measure Data

Analysis Population Description

The m-MITT population includes all patients who receive at least one dose of study drug and have a baseline gram negative bacterial pathogen.

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	35	19
Count of Participants [Participants]	5 10%	5 20%

6. Secondary Outcome

Title	The All-cause Mortality Rate in the mCRE-MITT Population (cUTI/AP)
Description	All Cause Mortality at Day 28 in the mCRE-MITT population (cUTI/AP subjects only)
Time Frame	at Day 28

Outcome Measure Data

Analysis Population Description

mCRE-MITT (cUTI/AP subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	12	4
Count of Participants [Participants]	1 2%	0 0%

7. Secondary Outcome

Title	Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (All Indications)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at End of Therapy (EOT) visit (7-14 days) and TOC visit (12-23 days)

Outcome Measure Data

Analysis Population Description

mCRE-MITT population (all indications)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	32	15
EOT	21 42%	5 20%
TOC	19 38%	4 16%

8. Secondary Outcome

Title	Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (cUTI/AP Subjects Only)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

mCRE-MITT population (cUTI/AP subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	12	4
EOT	9 18%	2 8%
TOC	5 10%	2 8%

9. Secondary Outcome

Title	Proportion of Subjects in the mCRE-MITT Population With a Clinical Outcome of Cure (HABP/VABP and Bacteremia)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

mCRE-MITT (HABP/VABP or Bacteremia Subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	18	9
EOT	10 20%	3 12%
TOC	12 24%	2 8%

10. Secondary Outcome

Title	Proportion of Subjects in the Microbiological Modified Intent-to-Treat (m-MITT) Population With a Clinical Outcome of Cure (All Indications)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs and symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (all indications)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	35	19
EOT	24 48%	7 28%
TOC	21 42%	6 24%

11. Secondary Outcome

Title	Proportion of Subjects in the m-MITT Population With a Clinical Outcome of Cure (cUTI/AP)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (cUTI/AP subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	13	8
EOT	10 20%	4 16%
TOC	6 12%	4 16%

12. Secondary Outcome

Title	Proportion of Subjects in the m-MITT Population With a Clinical Outcome of Cure (HABP/VABP and Bacteremia)
Description	Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (HABP/VABP or Bacteremia Subjects only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	20	9
EOT	12 24%	3 12%
TOC	13 26%	2 8%

13. Secondary Outcome

Title	Proportion of Subjects in the mCRE-MITT Population With a Microbiological Outcome of Eradication (All Indications)
Description	Includes subjects with microbiologic eradication or presumed eradication as defined: microbiologic eradication of the baseline pathogen or absence of culture result (microbiologic outcome of indeterminate or not assesses) where subject is deemed as clinical cure at that visit. For cUTI/AP subjects, demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA).
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

mCRE-MITT Population (all indications)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	32	15
EOT	21 42%	6 24%
TOC	17 34%	5 20%

14. Secondary Outcome

Title	Proportion of Subjects in the m-MITT Population With a Microbiological Outcome of Eradication (All Indications)
Description	Microbiological eradication defined for cUTI/AP as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA).
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (all indications)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	35	19
EOT	23 46%	8 32%
TOC	17 34%	7 28%

15. Secondary Outcome

Title	Proportion of Subjects in the m-MITT Populations With a With a Response of Overall Success (cUTI/AP)
Description	Proportion of subjects in m-MITT Population with response of cure and microbiological eradication or presumed eradication. Eradication defined for cUTI/AP as the demonstration that the bacterial pathogen(s) found at baseline is reduced to <10x4 CFU/mL urine (FDA). Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (cUTI/AP Subjects Only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	13	8
EOT	10 20%	4 16%
TOC	4 8%	4 16%

16. Secondary Outcome

Title	Proportion of Subjects in the m-MITT Populations With a With a Response of Overall Success (Bacteremia Only)
Description	Proportion of subjects in m-MITT Population with response of cure and microbiological eradication or presumed eradication. Clinical cure defined as complete resolution or significant improvement of the baseline signs & symptoms, no further antimicrobial warranted.
Time Frame	at EOT visit (7-14) and TOC visit (day 12-23)

Outcome Measure Data

Analysis Population Description

m-MITT Population (Bacteremia Subjects Only)

Arm/Group Title	Vabomere	Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days	Best Available Therapy: Antibiotic(s) chosen by Investigator
Measure Participants	15	8
EOT	8 16%	3 12%
TOC	8 16%	2 8%

Adverse Events

Time Frame	Day 1 Through the Late Follow-Up Visit (LFU)- LFU defined as 14 days (+ or - 2 days) after the EOT Visit (7-14 days)
Arm/Group Title	Vabomere		Best Available Therapy
Arm/Group Description	Vabomere (meropenem 2g plus vaborbactam 2g) IV q8h, for up to 14 days		Best Available Therapy: Antibiotic(s) chosen by Investigator
All Cause Mortality
	Vabomere		Best Available Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/50 (20%)		6/25 (24%)
Serious Adverse Events
	Vabomere		Best Available Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/50 (34%)		11/25 (44%)
Blood and lymphatic system disorders
Anemia	0/50 (0%)		1/25 (4%)
Cardiac disorders
Cardiac Arrest	2/50 (4%)		0/25 (0%)
Cardiac Failure Congestive	0/50 (0%)		1/25 (4%)
Gastrointestinal disorders
Gastrointestinal Hemorrhage	1/50 (2%)		0/25 (0%)
General disorders
General Physical Health Deterioration	2/50 (4%)		0/25 (0%)
Multi-organ Failure	1/50 (2%)		0/25 (0%)
Infections and infestations
Clostridium difficile colitis	0/50 (0%)		1/25 (4%)
Enterococcal bacteremia	1/50 (2%)		0/25 (0%)
Gangrene	1/50 (2%)		0/25 (0%)
Klebsiella Bacteremia	1/50 (2%)		0/25 (0%)
Peritonitis	0/50 (0%)		1/25 (4%)
Sepsis	2/50 (4%)		4/25 (16%)
Septic Shock	1/50 (2%)		4/25 (16%)
Superinfection Bacterial	1/50 (2%)		0/25 (0%)
Urosepsis	1/50 (2%)		0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma	1/50 (2%)		0/25 (0%)
Nervous system disorders
Cerebral Hemorrhage	0/50 (0%)		1/25 (4%)
Convulsion	0/50 (0%)		1/25 (4%)
Renal and urinary disorders
Renal Failure Acute	0/50 (0%)		1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Pneumonia Aspiration	1/50 (2%)		0/25 (0%)
Pulmonary Embolism	1/50 (2%)		0/25 (0%)
Pulmonary Edema	1/50 (2%)		0/25 (0%)
Vascular disorders
Arterial Hemorrhage	1/50 (2%)		0/25 (0%)
Hypotension	0/50 (0%)		1/25 (4%)
Shock Hemorrhagic	1/50 (2%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Vabomere		Best Available Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/50 (56%)		20/25 (80%)
Blood and lymphatic system disorders
Anemia	5/50 (10%)		2/25 (8%)
Thrombocytopenia	2/50 (4%)		2/25 (8%)
Leukopenia	2/50 (4%)		1/25 (4%)
Leukocytosis	1/50 (2%)		1/25 (4%)
Sickle Cell Anemia with Crisis	0/50 (0%)		1/25 (4%)
Cardiac disorders
Atrial Fibrillation	1/50 (2%)		1/25 (4%)
Extrasystoles	1/50 (2%)		1/25 (4%)
Tachycardia	1/50 (2%)		1/25 (4%)
Endocrine disorders
Adrenal Insufficiency	0/50 (0%)		1/25 (4%)
Gastrointestinal disorders
Diarrhea	6/50 (12%)		4/25 (16%)
Nausea	2/50 (4%)		2/25 (8%)
Vomiting	4/50 (8%)		0/25 (0%)
Abdominal Pain Upper	1/50 (2%)		2/25 (8%)
Constipation	2/50 (4%)		1/25 (4%)
Abdominal Distension	2/50 (4%)		0/25 (0%)
Abdominal Pain	2/50 (4%)		0/25 (0%)
Melaena	2/50 (4%)		0/25 (0%)
Rectal Hemorrhage	2/50 (4%)		0/25 (0%)
Stomatitis	1/50 (2%)		1/25 (4%)
Ascites	0/50 (0%)		1/25 (4%)
Paraesthesia Oral	0/50 (0%)		1/25 (4%)
Salivary Hypersecretion	0/50 (0%)		1/25 (4%)
General disorders
Asthenia	0/50 (0%)		2/25 (8%)
Generalized Edema	1/50 (2%)		1/25 (4%)
Hypothermia	2/50 (4%)		0/25 (0%)
Infusion Site Phlebitis	1/50 (2%)		1/25 (4%)
Edema Peripheral	0/50 (0%)		2/25 (8%)
Pain	1/50 (2%)		1/25 (4%)
Malaise	0/50 (0%)		1/25 (4%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/50 (4%)		0/25 (0%)
Infections and infestations
Oral Candidiasis	2/50 (4%)		1/25 (4%)
Systemic Candida	3/50 (6%)		0/25 (0%)
Candiduria	1/50 (2%)		1/25 (4%)
Clostridium Difficile Colitis	1/50 (2%)		1/25 (4%)
Bacteremia	0/50 (0%)		1/25 (4%)
Perinephric Abscess	0/50 (0%)		1/25 (4%)
Pseudomonal Bacteremia	0/50 (0%)		1/25 (4%)
Sepsis	0/50 (0%)		1/25 (4%)
Urinary Tract Infection	0/50 (0%)		1/25 (4%)
Urinary Tract Infection Enterococcal	0/50 (0%)		1/25 (4%)
Injury, poisoning and procedural complications
Wound	1/50 (2%)		1/25 (4%)
Incision Site Pain	0/50 (0%)		1/25 (4%)
Investigations
Blood Alkaline Phosphatase Increased	1/50 (2%)		1/25 (4%)
Transaminases Increased	0/50 (0%)		2/25 (8%)
Urine Output Decreased	2/50 (4%)		0/25 (0%)
Alanine Aminotransferase Increased	0/50 (0%)		1/25 (4%)
Blood Bilirubin Increased	0/50 (0%)		1/25 (4%)
Blood Fibrinogen Decreased	0/50 (0%)		1/25 (4%)
Blood Urea Increased	0/50 (0%)		1/25 (4%)
Electrocardiogram QT Prolonged	0/50 (0%)		1/25 (4%)
Metabolism and nutrition disorders
Hypokalemia	5/50 (10%)		2/25 (8%)
Hypoglycemia	4/50 (8%)		0/25 (0%)
Hypomagnesemia	3/50 (6%)		1/25 (4%)
Hypocalcemia	0/50 (0%)		1/25 (4%)
Malnutrition	0/50 (0%)		1/25 (4%)
Metabolic Acidosis	0/50 (0%)		1/25 (4%)
Type 2 Diabetes Mellitus	0/50 (0%)		1/25 (4%)
Vitamin B Complex Deficiency	0/50 (0%)		1/25 (4%)
Musculoskeletal and connective tissue disorders
Back Pain	2/50 (4%)		0/25 (0%)
Myalgia	2/50 (4%)		0/25 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma	0/50 (0%)		1/25 (4%)
Nervous system disorders
Tremor	3/50 (6%)		1/25 (4%)
Headache	2/50 (4%)		0/25 (0%)
Dizziness	0/50 (0%)		1/25 (4%)
Parasthesia	0/50 (0%)		1/25 (4%)
Somnolence	0/50 (0%)		1/25 (4%)
Psychiatric disorders
Confusional State	0/50 (0%)		2/25 (8%)
Restlessness	0/50 (0%)		2/25 (8%)
Delirium	0/50 (0%)		1/25 (4%)
Disorientation	0/50 (0%)		1/25 (4%)
Hallucination	0/50 (0%)		1/25 (4%)
Renal and urinary disorders
Renal Failure Acute	1/50 (2%)		3/25 (12%)
Renal Impairment	1/50 (2%)		2/25 (8%)
Hematuria	1/50 (2%)		1/25 (4%)
Renal Failure	0/50 (0%)		1/25 (4%)
Reproductive system and breast disorders
Penile Hemorrhage	0/50 (0%)		1/25 (4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/50 (4%)		1/25 (4%)
Pleural Effusion	0/50 (0%)		1/25 (4%)
Pneumothorax	0/50 (0%)		1/25 (4%)
Skin and subcutaneous tissue disorders
Pruritus	1/50 (2%)		1/25 (4%)
Rash Macular	0/50 (0%)		1/25 (4%)
Skin Exfoliation	0/50 (0%)		1/25 (4%)
Vascular disorders
Hypotension	4/50 (8%)		3/25 (12%)
Hypertension	2/50 (4%)		0/25 (0%)
Embolism	0/50 (0%)		1/25 (4%)
Extremity Necrosis	0/50 (0%)		1/25 (4%)

Limitations/Caveats

Enrollment Challenges required the Sponsor to terminate the study early which led to a smaller number of patients being enrolled.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.