Urinary Tract Infection ComplicatedPhase 3NCT02166476
Efficacy/Safety of Meropenem-Vaborbactam Compared to Piperacillin-Tazobactam in Adults With cUTI and AP
A Phase 3 study testing Meropenem-Vaborbactam, Piperacillin-Tazobactam and Levofloxacin in people with Urinary Tract Infection Complicated and Acute Pyelonephritis, run by Melinta Therapeutics, Inc. at 77 sites in 17 countries.
Trial summary
Meropenem-vaborbactam is being compared to piperacillin-tazobactam in the treatment of adults with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Urinary Tract Infection Complicated, Acute Pyelonephritis
- What is being tested?
- Meropenem-Vaborbactam, Piperacillin-Tazobactam and Levofloxacin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 550 participants
- Where
- 77 sitesin 17 countries
- Study dates
- 20 Nov 2014to 28 Apr 2016
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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;
- White blood cell count ≥10 cells/high-power field (hpf) in urine sediment
- At least 1 of the following associated risks:
- Indwelling urinary catheter;
- Neurogenic bladder with presence or history of urine residual volume of ≥100 mL;
- Obstructive uropathy (such as, nephrolithiasis, tumor, fibrosis) that is expected to be medically or surgically treated within 48 hours post randomization;
- Azotemia due to intrinsic renal disease;
- Urinary retention in men due to previously diagnosed benign prostatic hypertrophy
- AP
- 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°C [≥100.4°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/mm^3), or left shift (>15% immature PMNs);
- Nausea or vomiting;
- Dysuria, increased urinary frequency, or urinary urgency;
- Flank pain;
- Costo-vertebral angle tenderness on physical examination
- Pyuria evidenced by 1 of the following:
- Positive LCE on urinalysis;
- White blood cell count ≥10 cells/mm^3 in unspun urine;
- White blood cell count ≥10 cells/hpf in urine sediment
- 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.
- Expectation, in the judgment of the Investigator that the participant will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study.
- 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 2 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.
- Willingness to comply with all the study procedures, whether in the hospital or after discharge, for the duration of the study.
Who cannot join
- Presence of any of the following conditions:
- Perinephric abscess;
- Renal corticomedullary abscess;
- Uncomplicated urinary tract infection;
- Polycystic kidney disease;
- Chronic vesicoureteral reflux;
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- 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.
- Any of the following signs of severe sepsis:
- Shock or profound hypotension defined as systolic blood pressure <90 millimeters mercury (mmHg) or a decrease of >40 mmHg from baseline (if known) that is not responsive to fluid challenge;
- Hypothermia (temperature <35.6°C or <96.1°F); or
- 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.
- Pregnant or breastfeeding women.
- History of epilepsy or known seizure disorder requiring current treatment with anti-seizure medication.
- Treatment within 30 days prior to enrollment with valproic acid.
- Treatment within 30 days prior to enrollment with probenecid.
- Treatment within 30 days prior to enrollment with any cancer chemotherapy, immunosuppressive medications for transplantation, or medications for rejection of transplantation.
- Evidence of significant hepatic disease or dysfunction, including known acute viral hepatitis or hepatic encephalopathy.
- Aspartate aminotransferase or alanine aminotransferase >5 × ULN or total bilirubin >3 × ULN.
- Receipt of any potentially therapeutic antibiotic agent within 48 hours before randomization. Participants with a pathogen-causing cUTI or AP that is resistant to the prior therapy may be enrolled in this study (assuming the organism is known to be sensitive to piperacillin/tazobactam). Participants who develop signs and symptoms of cUTI or AP while on antibiotics may also be enrolled.
- Prior exposure to vaborbactam alone or in combination with another product.
- Receipt of any potentially therapeutic antibiotic agent within 48 hours before randomization.
- EXCEPTIONS:
- Participants who received a single dose of a short-acting oral or IV antibiotic (an antibiotic that is typically dosed every 4 hours, every 6 hours, or q8h in a participant with normal renal function). No more than 25% of participants will be enrolled who meet this criterion.
- Participants who received >48 hours of prior systemic antibiotic therapy for the current episode of cUTI with unequivocal clinical evidence of treatment failure (that is, worsening signs and symptoms).
- Participants who develop signs and symptoms of cUTI or AP while on antibiotics for another indication.
- 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.
- Likely to require the use of an antibiotic for cUTI prophylaxis during the participant's participation in the study (from enrollment through the last follow up visit).
- Known history of human immunodeficiency virus infection and known recent cluster of differentiation 4 count <200/mm^3.
- 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 (≥2 weeks) use of systemic corticosteroids.
- Presence of neutropenia (<1,000 PMNs/mm^3).
- Presence of thrombocytopenia (<60,000 platelets/mm^3).
- A corrected QT with Fridericia's Formula >480 milliseconds.
- History of significant hypersensitivity or allergic reaction to meropenem/vaborbactam, piperacillin/tazobactam, any of the excipients used in the respective formulations, or any beta-lactam antibiotics (such as, cephalosporins, penicillins, carbapenems, or monobactams).
- Known hypersensitivity or inability to tolerate all of the following: fluoroquinolones (including levofloxacin), trimethoprim/ sulfamethoxazole, cefdinir, cefixime, or cefpodoxime, based on prescribing information.
- Unable or unwilling, in the judgment of the Investigator, to comply with the protocol.
- 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.
- Acute Physiology and Chronic Health Evaluation II score >30 (if clinically indicated)
- Inability to tolerate intravenous fluids, due to medical reasons, of 1050 mL per day required for study drug administration.
- Any recent history of trauma to the pelvis or urinary tract.
Trial locations and contacts
77 sites in 17 countries.
77 sites in 17 countries
United States8 sites
Study site
Augusta, Georgia, 30912
Study site
Buffalo, New York, 14215
Study site
Chicago, Illinois, 60612
Study site
Denver, Colorado, 80246
Study site
Mobile, Alabama, 36608
Study site
New Brunswick, New Jersey, 08901
Study site
San Diego, California, 92120
Study site
Tampa, Florida, 33606
Ukraine8 sites
Study site
Chernivtsi, 58001
Study site
Dnipropetrovsk, 49005
Study site
Ivano-Frankivsk, 76014
Study site
Kharkiv, 6100
Study site
Odesa, 65074
Study site
Poltava, 36024
Study site
Vinnitsa, 21018
Study site
Zaporizhzhya, 69600
Belarus6 sites
Study site
Brest, 224027
Study site
Grodno, 230017
Study site
Homyel, 246027
Study site
Minsk, 220036
Study site
Minsk, 220049
Study site
Vitebsk, 210037
Brazil6 sites
Study site
Belo Horizonte, 30150-221
Study site
Belo Horizonte, 30170080
Study site
Campinas, 13060-904
Study site
Rio de Janeiro, 20725-090
Study site
São José do Rio Preto, São Paulo, 15090-000
Study site
São Paulo, SP
Bulgaria6 sites
Study site
Lovech, 5500
Study site
Montana, 3400
Study site
Silistra, 7500
Study site
Sofia, 1431
Study site
Sofia, 1606
Study site
Varna, 9100
Czechia5 sites
Study site
Hradec Králové, 50005
Study site
Karlovy Vary, 360 66
Study site
Opava, 74601
Study site
Ústí nad Labem, 40113
Study site
Zlín, 76275
Greece5 sites
Study site
Athens, 10676
Study site
Athens, 11527 Goudi
Study site
Athens, 11527
Study site
Athens, 12462
Study site
Thessaloniki, 54636
Italy5 sites
Study site
Bologna, 40138
Study site
Catania, 95123
Study site
Florence, 50134
Study site
Perugia, 6132
Study site
Torino, 10126
Peru5 sites
Study site
Arequipa
Study site
Cusco
Study site
Ica, 598
Study site
Lima
Study site
San Martín de Porres, 262
Poland5 sites
Study site
Częstochowa, 42-200
Study site
Gdansk, 80-402
Study site
Kutno, 99-300
Study site
Piaseczno, 05-500
Study site
Warsaw, 02-005
Hungary4 sites
Study site
Baja, H-6500
Study site
Budapest, 1145
Study site
Debrecen, H-4031
Study site
Sopron, 9400
Slovakia4 sites
Study site
Poprad, 058 01
Study site
Ružomberok, 034 26
Study site
Trnava, 971 75
Study site
Žilina, 012 07
Romania3 sites
Study site
Bucharest, 10825
Study site
Bucharest, 14461
Study site
Craiova, 200642
About this study
Official title: Phase III, Randomized, Double-Blind, Study Evaluating Efficacy/Safety/Tolerability of Meropenem-Vaborbactam Compared to Piperacillin/Tazobactam in Adult Patients With Complicated Urinary Tract Infections, Including Acute Pyelonephritis
Meropenem-vaborbactam is being compared to piperacillin-tazobactam in the treatment of adults with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP).
Read the detailed description
In the current era of increased resistance to extended spectrum cephalosporins, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections, including those found in cUTIs. The recent dissemination of serine carbapenemases in Enterobacteriaceae in many hospitals worldwide now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.
Rempex is developing meropenem-vaborbactam administered as a fixed combination by intravenous infusion to treat serious Gram-negative infections such as cUTIs, including those infections caused by bacteria resistant to currently available carbapenems.
- Being tested
- Meropenem-Vaborbactam, Piperacillin-Tazobactam, Levofloxacin, Saline
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Meropenem-VaborbactamDrug
Also called Combination vaborbactam and meropenem, beta-lactamase inhibitor and carbapenem antibiotic, Carbavance, Vabomere
Meropenem-vaborbactam
Piperacillin-TazobactamDrug
Also called Piperacillin 4 g-Tazobactam 0.5 g
Piperacillin-tazobactam
LevofloxacinDrug
Also called Levo
Levofloxacin
SalineDrug
Saline
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Piperacillin-Tazobactam; Drug: Levofloxacin; Drug: Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: 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.
Measured: TOC (Days 15-23)
Secondary outcomes (12)
Proportion Of Participants In The m-MITT Population With Overall Success
This secondary outcome measure focused on the overall success in the ME population at the EOIVT and TOC visits. Overall success at TOC was defined as a clinical outcome of Cured and a microbiologic outcome of Eradication. Overall success at EOIVT was defined as a clinical outcome of Cured or Improvement and a microbiologic outcome of Eradication. Cured was defined as the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms of cUTI or AP, but continued IV therapy was warranted. Eradication was defined using the FDA's 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).
Measured: EOIVT (Days 5-14) and TOC (Days 15-23)
Proportion Of Participants In The ME Population With Overall Success
This secondary outcome measure focused on the overall success in the ME population at the EOIVT and TOC visits. Overall success was defined as a clinical outcome of Cured or Improvement and a microbiologic outcome of Eradication. Cured was defined as the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms of cUTI or AP, but continued IV therapy was warranted. Eradication was defined using the FDA's 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).
Measured: EOIVT (Days 5-14) and TOC (Days 15-23)
Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication
This secondary outcome measure focused on a microbiological outcome of Eradication in the m-MITT population at 5 time points: Day 3, EOIVT, end of treatment (EOT), TOC, and late follow up (LFU). Eradication was defined as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture (FDA) or <10^3 CFU/mL (EMA), and a negative blood culture for an organism that was identified as a uropathogen (if repeated after positive at baseline blood culture).
Measured: 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
This secondary outcome measure focused on a microbiological outcome of Eradication in the ME population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture (FDA) or <10^3 CFU/mL (EMA), and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture).
Measured: 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
This secondary outcome measure focused on a clinical outcome of Cure in the m-MITT Population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at Day 3, EOIVT, and EOT visits.
Measured: 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 Clinical Evaluable (CE) Population
This secondary outcome measure focused on a clinical outcome of Cure in the CE population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at the Day 3, EOIVT, and EOT visits.
Measured: 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 ME Population
This secondary outcome measure focused on a clinical outcome of Cure in the ME population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at the Day 3, EOIVT, and EOT visits.
Measured: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (FDA) In The m-MITT Population
This secondary outcome measure focused on the per-pathogen (Enterobacter cloacae [E. cloacae], Enterococcus faecalis [E. faecalis], Escherichia coli [E. coli], Klebsiella pneumoniae [K. pneumoniae]) microbiological outcome of Eradication in the m-MITT population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the FDA criteria as a reduction in baseline bacterial pathogen(s) 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).
Measured: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (FDA) In The ME Population
This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the ME population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the FDA criteria as a reduction in baseline bacterial pathogen(s) 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).
Measured: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (EMA) In The m-MITT Population
This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the m-MITT population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the EMA criteria as a reduction in baseline bacterial pathogen(s) 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).
Measured: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (EMA) In The ME Population
This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the ME population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the EMA criteria as a reduction in baseline bacterial pathogen(s) 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).
Measured: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Pharmacokinetic (PK) Characterization Of Plasma Exposure Of Meropenem/Vaborbactam
This outcome measure focused on PK assessment of participants in the meropenem/vaborbactam group who met MITT criteria and had at least 1 plasma PK sample drawn. Sparse PK sampling on Day 1 was performed 3-3.5 hours and 5-6 hours after the start of the first 3-h IV study drug infusion. Samples were not collected around the 30-minute infusions. Samples were collected from both groups to maintain the blind; however, only PK samples for the meropenem/vaborbactam group were analyzed. The area under the curve (AUC) was generated using a Population PK model and post hoc estimates of each participants' PK parameters, including AUC0-24, were generated.
The AUC during 24 hours (AUC0-24) for Day 1 and at steady-state are presented in micrograms (ug)·hour/mL.
Measured: Day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2014 (estimated)
- Study start20 Nov 2014
- Primary completion28 Apr 2016
- Study completion28 Apr 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Urinary Tract Infection ComplicatedStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 550 participants (actual)
Sponsor and investigators
- Lead sponsor
- Melinta Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Department of Health and Human Services
- Responsible party
- Sponsor
- Investigators
- Karen Fusaro, Study director, Sponsor GmbHKeith Kaye, Principal investigator, Wayne State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02166476
- Sponsor's protocol ID
- Rempex 505
- Status last verified
- Apr 2018
- First submitted
- 16 Jun 2014
- Last updated
- 11 Jun 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 29486041
Study at a glance
From the registry record, last updated by the sponsor on 11 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase III, Randomized, Double-Blind, Study Evaluating Efficacy/Safety/Tolerability of Meropenem-Vaborbactam Compared to Piperacillin/Tazobactam in Adult Patients With Complicated Urinary Tract Infections, Including Acute Pyelonephritis
- ClinicalTrials.gov ID
- NCT02166476
- Acronym / sponsor ID
- Rempex 505
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 550 participants (actual)
- Lead sponsor
- Melinta Therapeutics, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Department of Health and Human Services
- Study start
- 20 Nov 2014 (actual)
- Primary completion
- 28 Apr 2016 (actual)
- Study completion
- 28 Apr 2016 (actual)
- First posted
- 18 Jun 2014 (estimated)
- Results
- Posted 26 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Meropenem-vaborbactam is being compared to piperacillin-tazobactam in the treatment of adults with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP).
Detailed description
In the current era of increased resistance to extended spectrum cephalosporins, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections, including those found in cUTIs. The recent dissemination of serine carbapenemases in Enterobacteriaceae in many hospitals worldwide now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.
Rempex is developing meropenem-vaborbactam administered as a fixed combination by intravenous infusion to treat serious Gram-negative infections such as cUTIs, including those infections caused by bacteria resistant to currently available carbapenems.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Meropenem-Vaborbactam | Experimental | Drug: Meropenem-Vaborbactam, Drug: Levofloxacin, Drug: SalineMeropenem-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. |
| Piperacillin-Tazobactam | Active comparator | Drug: Piperacillin-Tazobactam, Drug: Levofloxacin, Drug: SalinePiperacillin-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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (38 listed)
- 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:
Key exclusion criteria (47 listed)
- Presence of any of the following conditions:
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Meropenem-VaborbactamAlso: Combination vaborbactam and meropenem, beta-lactamase inhibitor and carbapenem antibiotic, Carbavance, VabomereMeropenem-vaborbactam | Drug | Meropenem-Vaborbactam |
| Piperacillin-TazobactamAlso: Piperacillin 4 g-Tazobactam 0.5 gPiperacillin-tazobactam | Drug | Piperacillin-Tazobactam |
| LevofloxacinAlso: LevoLevofloxacin | Drug | Meropenem-Vaborbactam, Piperacillin-Tazobactam |
| SalineSaline | Drug | Meropenem-Vaborbactam, Piperacillin-Tazobactam |
Primary outcome
Proportion Of Participants In The Microbiological Modified Intent-To-Treat (m-MITT) Population Who Achieved Overall Success At The End Of Intravenous Treatment Visit
Time frame: EOIVT (Days 5-14)
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).
Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication At The Test Of Cure Visit
Time frame: Test of cure (TOC) (Days 15-23)
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).
Proportion Of Participants In The Microbiological Evaluable (ME) Population Who Achieved A Microbiologic Outcome Of Eradication At The TOC Visit
Time frame: TOC (Days 15-23)
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.
12 secondary outcomes
Proportion Of Participants In The m-MITT Population With Overall Success
Time frame: EOIVT (Days 5-14) and TOC (Days 15-23)
Proportion Of Participants In The ME Population With Overall Success
Time frame: EOIVT (Days 5-14) and TOC (Days 15-23)
Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication
Time frame: 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
Time frame: 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
Time frame: 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 Clinical Evaluable (CE) Population
Time frame: 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 ME Population
Time frame: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (FDA) In The m-MITT Population
Time frame: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (FDA) In The ME Population
Time frame: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (EMA) In The m-MITT Population
Time frame: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Per-Pathogen Microbiological Outcome (EMA) In The ME Population
Time frame: Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Pharmacokinetic (PK) Characterization Of Plasma Exposure Of Meropenem/Vaborbactam
Time frame: Day 1
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jun 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29486041Kaye 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Karen Fusaro study director
Sponsor GmbH
Keith Kaye principal investigator
Wayne State University
77 sites in 17 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Meropenem-Vaborbactam, Piperacillin-Tazobactam and Levofloxacin in people with Urinary Tract Infection Complicated and Acute Pyelonephritis, run by Melinta Therapeutics, Inc. at 77 sites in 17 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 38 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 77 sites in United States, Ukraine, Belarus, Brazil, Bulgaria and 12 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion Of Participants In The Microbiological Modified Intent-To-Treat (m-MITT) Population Who Achieved Overall Success At The End Of Intravenous Treatment Visit (time frame: EOIVT (Days 5-14)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02166476, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2018.