Efficacy/Safety of Meropenem-Vaborbactam Compared to Piperacillin-Tazobactam in Adults With cUTI and AP

NCT02166476 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: Rempex 505
• Study Type: interventional
• Target: 550
• Locations: 16 countries
• Sites: 73

Brief Summary

Meropenem-vaborbactam is being compared to piperacillin-tazobactam in the treatment of adults with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP).

Conditions

Urinary Tract Infection Complicated; Acute Pyelonephritis

Outcome Measures

Primary Outcomes (3)

• Proportion Of Participants In The Microbiological Modified Intent-To-Treat (m-MITT) Population Who Achieved Overall Success At The End Of Intravenous Treatment Visit

  This was the primary outcome measure for the Food and Drug Administration (FDA). For this composite outcome measure, overall success was achieved with a clinical outcome of Cure or Improvement and microbiologic outcome of Eradication at the end of intravenous treatment (EOIVT). Cure was defined as the complete resolution or significant improvement of the baseline signs and symptoms. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms. Eradication was defined using the FDA's colony-forming units (CFU)/mL criteria that the bacterial pathogen(s) found at baseline was/were reduced to \<10\^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture).

  EOIVT (Days 5-14)

• Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication At The Test Of Cure Visit

  This was the primary outcome measure for the European Medicines Agency (EMA). For this measure, a microbiologic outcome of Eradication was defined using the EMA's CFU/mL criteria: bacterial pathogen(s) found at baseline was reduced to \<10\^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture).

  Test of cure (TOC) (Days 15-23)

• Proportion Of Participants In The Microbiological Evaluable (ME) Population Who Achieved A Microbiologic Outcome Of Eradication At The TOC Visit

  This was the primary outcome measure for the EMA. For this measure, a microbiologic outcome of Eradication was defined using the EMA's CFU/mL criteria: bacterial pathogen(s) found at baseline was reduced to \<10\^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). The ME population included all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; received \<80% or \>120% of expected IV doses; missed no more than 1 IV dose in the first 48 hours, missed no more than 2 consecutive IV doses; received no less than 6 doses for failure or no less than 9 doses for cure.

  TOC (Days 15-23)

Secondary Outcomes (12)

• Proportion Of Participants In The m-MITT Population With Overall Success

  EOIVT (Days 5-14) and TOC (Days 15-23)

• Proportion Of Participants In The ME Population With Overall Success

  EOIVT (Days 5-14) and TOC (Days 15-23)

• Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication

  Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)

• Proportion Of Participants In The ME Population Who Achieved A Microbiologic Outcome Of Eradication

  Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)

• Proportion Of Participants With A Clinical Outcome Of Cure In The m-MITT Population

  Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)

Study Arms (2)

Meropenem-Vaborbactam

EXPERIMENTAL

Meropenem-vaborbactam (meropenem 2 grams \[g\] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered intravenously (IV) over 3 hours, every 8 hours (q8h), with 100 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-milligram (mg) dose every 24 hours (q24h) after a minimum of 15 doses of IV meropenem-vaborbactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of therapy could be administered IV.

Drug: Meropenem-Vaborbactam; Drug: Levofloxacin; Drug: Saline

Piperacillin-Tazobactam

ACTIVE COMPARATOR

Piperacillin-tazobactam (piperacillin 4 g plus tazobactam 0.5 g), infused in 100 mL normal saline, administered IV over 30 minutes, q8h, with 250 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV piperacillin-tazobactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of therapy could be administered IV.

Drug: Piperacillin-Tazobactam; Drug: Levofloxacin; Drug: Saline

Interventions

Meropenem-Vaborbactam DRUG

Meropenem-vaborbactam

Also known as: Combination vaborbactam and meropenem, beta-lactamase inhibitor and carbapenem antibiotic, Carbavance, Vabomere, Meropenem 2 g-Vaborbactam 2 g

Meropenem-Vaborbactam

Piperacillin-Tazobactam DRUG

Piperacillin-tazobactam

Also known as: Piperacillin 4 g-Tazobactam 0.5 g

Piperacillin-Tazobactam

Levofloxacin DRUG

Levofloxacin

Also known as: Levo

Meropenem-Vaborbactam; Piperacillin-Tazobactam

Saline DRUG

Saline

Meropenem-Vaborbactam; Piperacillin-Tazobactam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Male or female ≥18 years of age.
• Weight ≤185 kilograms (kg).
• Expectation, in the judgment of the Investigator, that the participant's cUTI or AP requires initial treatment with at least 5 days of IV antibiotics.
• Documented or suspected cUTI or AP as defined below:
• cUTI
• Signs or symptoms evidenced by at least 2 of the following:
• Chills, rigors, or fever (fever must be documented within 24 hours of the screening visit with a temperature of ≥38.0 degrees Celsius \[°C\] \[≥100.4 degrees Fahrenheit (°F)\] or rectal/core temperature ≥38.3°C \[≥100.9°F\], observed and documented by a health care provider);
• Elevated white blood cell count (\>10,000/ cubic millimeters \[mm\^3\]) or left shift (\>15% immature polymorphonuclear leukocytes \[PMNs\]);
• Nausea or vomiting;
• Dysuria, increased urinary frequency, or urinary urgency;
• Lower abdominal pain or pelvic pain
• Pyuria evidenced by 1 of the following:
• Positive leukocyte esterase (LCE) on urinalysis;
• White blood cell count ≥10 cells/mm\^3 in unspun urine;

You may not qualify if:

• Presence of any of the following conditions:
• Perinephric abscess;
• Renal corticomedullary abscess;
• Uncomplicated urinary tract infection;
• Polycystic kidney disease;
• Chronic vesicoureteral reflux;
• Previous or planned renal transplantation;
• Participants receiving hemodialysis;
• Previous or planned cystectomy or ileal loop surgery; or
• Known candiduria.
• Presence of suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination.
• Gross hematuria requiring intervention other than administration of study drug.
• 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).
• Renal function at screening as estimated by creatinine clearance \<50 mL/minute (min) using the Cockcroft-Gault formula.
• Known non-renal source of infection such as endocarditis, osteomyelitis, abscess, meningitis, or pneumonia diagnosed within 7 days prior to randomization.

Sponsors & Collaborators

• Melinta Therapeutics, Inc.: lead
• Department of Health and Human Services: collaborator

Study Sites (77)

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Mobile, Alabama, 36608, United States

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San Diego, California, 92120, United States

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Denver, Colorado, 80246, United States

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Tampa, Florida, 33606, United States

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Augusta, Georgia, 30912, United States

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Chicago, Illinois, 60612, United States

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New Brunswick, New Jersey, 08901, United States

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Buffalo, New York, 14215, United States

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Brest, 224027, Belarus

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Grodno, 230017, Belarus

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Homyel, 246027, Belarus

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Minsk, 220036, Belarus

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Minsk, 220049, Belarus

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Vitebsk, 210037, Belarus

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São José do Rio Preto, São Paulo, 15090-000, Brazil

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Belo Horizonte, 30150-221, Brazil

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Belo Horizonte, 30170080, Brazil

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Campinas, 13060-904, Brazil

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Rio de Janeiro, 20725-090, Brazil

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São Paulo, SP, Brazil

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Lovech, 5500, Bulgaria

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Montana, 3400, Bulgaria

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Silistra, 7500, Bulgaria

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Sofia, 1431, Bulgaria

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Sofia, 1606, Bulgaria

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Varna, 9100, Bulgaria

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Hradec Králové, 50005, Czechia

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Karlovy Vary, 360 66, Czechia

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Opava, 74601, Czechia

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Ústí nad Labem, 40113, Czechia

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Zlín, 76275, Czechia

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Athens, 10676, Greece

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Athens, 11527 Goudi, Greece

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Athens, 11527, Greece

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Athens, 12462, Greece

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Thessaloniki, 54636, Greece

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Baja, H-6500, Hungary

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Budapest, 1145, Hungary

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Debrecen, H-4031, Hungary

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Sopron, 9400, Hungary

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Bologna, 40138, Italy

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Catania, 95123, Italy

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Florence, 50134, Italy

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Perugia, 6132, Italy

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Torino, 10126, Italy

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Arequipa, Peru

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Cusco, Peru

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Ica, 598, Peru

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Lima, Peru

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San Martín de Porres, 262, Peru

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Częstochowa, 42-200, Poland

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Gdansk, 80-402, Poland

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Kutno, 99-300, Poland

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Piaseczno, 05-500, Poland

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Warsaw, 02-005, Poland

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Bucharest, 10825, Romania

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Bucharest, 14461, Romania

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Craiova, 200642, Romania

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Poprad, 058 01, Slovakia

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Ružomberok, 034 26, Slovakia

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Trnava, 971 75, Slovakia

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Žilina, 012 07, Slovakia

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Golnik, 4204, Slovenia

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Ljubljana, 1000, Slovenia

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Gyeonggi-do, 442-723, South Korea

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Barcelona, 08003, Spain

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Madrid, 28033, Spain

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Kaohsiung City, 807, Taiwan

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Taichung, 40705, Taiwan

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Chernivtsi, 58001, Ukraine

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Dnipropetrovsk, 49005, Ukraine

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Ivano-Frankivsk, 76014, Ukraine

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Kharkiv, 6100, Ukraine

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Odesa, 65074, Ukraine

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Poltava, 36024, Ukraine

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Vinnitsa, 21018, Ukraine

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Zaporizhzhia, 69600, Ukraine

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Related Publications (1)

• Kaye KS, Bhowmick T, Metallidis S, Bleasdale SC, Sagan OS, Stus V, Vazquez J, Zaitsev V, Bidair M, Chorvat E, Dragoescu PO, Fedosiuk E, Horcajada JP, Murta C, Sarychev Y, Stoev V, Morgan E, Fusaro K, Griffith D, Lomovskaya O, Alexander EL, Loutit J, Dudley MN, Giamarellos-Bourboulis EJ. Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. JAMA. 2018 Feb 27;319(8):788-799. doi: 10.1001/jama.2018.0438.

  PMID: 29486041 DERIVED

MeSH Terms

Interventions

meropenem and vaborbactam; Meropenem; beta-Lactamase Inhibitors; vaborbactam; Piperacillin, Tazobactam Drug Combination; Piperacillin; Tazobactam; Levofloxacin; Sodium Chloride

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Anti-Bacterial Agents; Anti-Infective Agents; Therapeutic Uses; Penicillanic Acid; Penicillins; Ampicillin; Penicillin G; Sulfur Compounds; Sulfones; Drug Combinations; Pharmaceutical Preparations; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Global Health Science Center
• Organization: The Medicines Company

medical.information@themedco.com

888-977-6326

Study Officials

• Karen Fusaro

  Sponsor GmbH

  STUDY DIRECTOR

• Keith Kaye

  Wayne State University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind-double dummy
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2014
• First Posted: June 18, 2014
• Study Start: November 20, 2014
• Primary Completion: April 28, 2016
• Study Completion: April 28, 2016
• Last Updated: June 11, 2018
• Results First Posted: October 26, 2017

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

BE (6); HU (4); ES (2); PL (5); US (8); KR (1); PE (5); TW (2); SL (2); CZ (5); UA (8); BU (6); GR (5); BR (6); IT (5); RO (3)