Clinical trial NCT01345929: Study Comparing the Safety and Efficacy of Intravenous CXA-201 and Intravenous Levofloxacin in Complicated Urinary Tract Infection, Including Pyelonephritis
Official title: A Multicenter, Double-Blind, Randomized, Phase 3 Study to Compare the Safety and Efficacy of Intravenous CXA-201 and Intravenous Levofloxacin in Complicated Urinary Tract Infection, Including Pyelonephritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Urinary Tract Infection
Pyelonephritis
Keywords: cUTI
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2011-05-02
Enrollment: 558
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3, multicenter, prospective, randomized, double-blind, double dummy study of CXA 201 IV infusions (1500 mg q8h) versus levofloxacin IV infusions (750 mg qd) for the treatment of adults with a cUTI (including pyelonephritis).

Detailed description: Approximately 500 subjects will be enrolled into this study and randomized 1:1 to receive CXA-201 or comparator (levofloxacin) resulting in 250 subjects per treatment arm. Subject participation will require a minimum commitment of 35 days and a maximum of 42 days. Subjects will be hospitalized for the administration of all doses of IV study therapy. A test of cure visit will occur at 7 days after the last dose of study drug and a late follow-up evaluation or contact will occur a minimum of 28 days and a maximum of 35 days after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

1. Provide written informed consent prior to any study-related procedure not part of normal medical care (a legally acceptable representative may provide consent if the subject is unable to do so, provided this is approved by local country and institution specific guidelines).
2. Be males or females ≥ 18 years of age
3. If female, subject is non-lactating, and is either:

   1. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or
   2. Of childbearing potential and is practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives (for 3 months prior to study drug administration), or a vasectomized partner. Or, subject is practicing abstinence from sexual intercourse. Subjects must be willing to practice these methods for the duration of the trial and for at least 35 days after last dose of study medication.
4. Males are required to practice reliable birth control methods (condom or other barrier device) during the conduct of the study and for at least 35 days after last dose of study medication.
5. Pyuria (white blood cell \[WBC\] count \> 10/μL in unspun urine or ≥ 10 per high power field in spun urine).
6. Clinical signs and/or symptoms of cUTI, either of:

   1. Pyelonephritis, as indicated by at least 2 of the following:

      * Documented fever (oral temperature \> 38°C) accompanied by patient symptoms of rigors, chills, or "warmth";
      * Flank pain;
      * Costovertebral angle tenderness or suprapubic tenderness on physical exam; or
      * nausea or vomiting; OR
   2. Complicated lower UTI, as indicated by at least 2 of the following:

      * At least 2 of the following new or worsening symptoms of cUTI:

        * Dysuria; urinary frequency or urinary urgency;
        * Documented fever (oral temperature \> 38°C) accompanied by patient symptoms of rigors, chills, or "warmth";
        * Suprapubic pain or flank pain;
        * Costovertebral angle tenderness or suprapubic tenderness on physical exam; or
        * Nausea or vomiting; plus,
      * At least 1 of the following complicating factors:

        * Males with documented history of urinary retention;
        * Indwelling urinary catheter that is scheduled to be removed during IV study therapy and before the EOT;
        * Current obstructive uropathy that is scheduled to be medically or surgically relieved during IV study therapy and before the EOT; or
        * Any functional or anatomical abnormality of the urogenital tract (including anatomic malformations or neurogenic bladder) with voiding disturbance resulting in at least 100 mL residual urine.
7. Have a pretreatment baseline urine culture specimen obtained within 24 hours before the start of administration of the first dose of study drug.

   NOTE: Subjects may be enrolled in this study and start IV study drug therapy before the Investigator knows the results of the baseline urine culture.
8. Require IV antibacterial therapy for the treatment of the presumed cUTI.

Exclusion Criteria:

1. Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam or quinilone antibacterial (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
2. Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity \[e.g., vancomycin, linezolid\] are allowed.)
3. Receipt of any amount of potentially therapeutic antibacterial therapy after collection of the pretreatment baseline urine culture and before administration of the first dose of study drug.
4. Receipt of any dose of a potentially therapeutic antibacterial agent for the treatment of the current UTI within 48 hours before the study-qualifying pretreatment baseline urine is obtained (exceptions: subjects with an active cUTI who have received prior antibiotics may be enrolled provided a minimum of 48 hours have elapsed between the last dose of the prior antibiotic and the time of obtaining the baseline urine specimen. Subjects receiving current antibiotic prophylaxis for cUTI who present with signs and symptoms consistent with an active new cUTI may be enrolled provided all other eligibility criteria are met including obtaining a pre-treatment qualifying baseline urine culture).
5. Intractable urinary infection at baseline that the Investigator anticipates would require more than 7 days of study drug therapy.
6. Complete, permanent obstruction of the urinary tract.
7. Confirmed fungal urinary tract infection at time of randomization (with ≥ 103 fungal CFU/mL).
8. Permanent indwelling bladder catheter or urinary stent including nephrostomy.
9. Suspected or confirmed perinephric or intrarenal abscess.
10. Suspected or confirmed prostatitis.
11. Ileal loop or known vesico-ureteral reflux.
12. Severe impairment of renal function including an estimated CrCl \< 30 mL/min, requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (\< 20 mL/h urine output over 24 hours).
13. Current urinary catheter that is not scheduled to be removed before the EOT (intermittent straight catheterization during the IV study drug administration period is acceptable).
14. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of study data.
15. Any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, and septic shock.
16. Immunocompromising condition, including established AIDS, hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids equivalent to or greater than 40 mg of prednisone per day administered continuously for more than 14 days preceding randomization.
17. One or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase (AST \[SGOT\]), alanine aminotransferase (ALT \[SGPT\]), alkaline phosphatase, or total bilirubin level greater than 3 times the upper limit of normal (ULN), absolute neutrophil count less than 500/μL, platelet count less than 40,000/μL, or hematocrit less than 20%.
18. Participation in any clinical study of an investigational product within 30 days prior to the proposed first day of study drug.
19. Previous participation in any study of CXA-101 or CXA-201.
20. Women who are pregnant or nursing.

Primary outcomes:
measure: The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the Test of Cure (TOC) Visit in the Microbiological Modified ITT (mMITT) Population
timeFrame: Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)
Secondary outcomes:
measure: The Percentage of Subjects Who Have Both a Per-subject Microbiological Outcome of Eradication and a Clinical Outcome of Cure at the TOC Visit in the Microbiologically Evaluable (ME) Population.
timeFrame: Test of Cure Visit (7 Days [± 2 days] after completion of study drug administration)
Other outcomes:
Locations:
city: San Diego
country: United States
state: California
city: Wheat Ridge
country: United States
state: Colorado
city: Hialeah
country: United States
state: Florida
city: Teaneck
country: United States
state: New Jersey
city: Charleston
country: United States
state: South Carolina
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Porto Alegre
country: Brazil
state: Rio Grande De Sul
city: Joinville
country: Brazil
state: Santa Catarina
city: Campinas
country: Brazil
state: Sao Paulo
city: Sao Jose De Rio Preto
country: Brazil
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Cali
country: Colombia
state: Valle Del Cauca
city: Armenia
country: Colombia
city: Barranquilla
country: Colombia
city: Bogota
country: Colombia
city: Kohtla-Jarve
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: Tbilsi
country: Georgia
city: Giessen
country: Germany
state: Hessen
city: Lubeck
country: Germany
state: Schleswig-Holstein
city: Miskolc
country: Hungary
state: Borsod-Abauj-Zemplen
city: Gyor
country: Hungary
state: Budapest
city: Szentes
country: Hungary
state: Csongrad
city: Sopron
country: Hungary
state: Gyor-moson-sopron
city: Salgotarjan
country: Hungary
state: Nograd
city: Nyiregyhaza
country: Hungary
state: Szabolcs-Szatmar-Bereg
city: Zalaegerszeg
country: Hungary
state: Zala
city: Budapest
country: Hungary
city: Tatabánya
country: Hungary
city: Kfar Saba
country: Israel
state: Sharon
city: Petach Tikva
country: Israel
state: Teah Tiqwa
city: Tel Hashomer
country: Israel
state: Tel Aviv
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Safed
country: Israel
city: Daugavpils
country: Latvia
city: Liepaja
country: Latvia
city: Riga
country: Latvia
city: Valmiera
country: Latvia
city: Ventspills
country: Latvia
city: Guadalajara
country: Mexico
state: Jalisco
city: Chihuahua
country: Mexico
city: San Luis Potosi
country: Mexico
city: Veracruz
country: Mexico
city: Chisinau
country: Moldova, Republic of
city: Oradea
country: Romania
state: Bihor
city: Bucharest
country: Romania
state: Bucuresti
city: Timisoara
country: Romania
state: Timis
city: Brasov
country: Romania
city: Bucuresti
country: Romania
city: Iasi
country: Romania
city: Sibiu
country: Romania
city: Kemerovo
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhniy Novgorod
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Penza
country: Russian Federation
city: Saratov
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Belgrade
country: Serbia
city: Banska Bystrica
country: Slovakia
city: Levice
country: Slovakia
city: Martin
country: Slovakia
city: Presov
country: Slovakia
city: Skalica
country: Slovakia
city: Bloemfontein
country: South Africa
state: Free State
city: Pretoria
country: South Africa
state: Gauteng
city: Soweto
country: South Africa
state: Gauteng
city: Middleburg
country: South Africa
state: Mpumalanga
city: Bellville
country: South Africa
state: Western Cape
city: Nakorn Ratchasima
country: Thailand
state: Nakhon Ratchasima
city: Chiang Mai
country: Thailand
city: Lop Buri
country: Thailand
city: Prachuap Khiri Khan
country: Thailand
Study officials:
affiliation: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
name: Obiamiwe Umeh, M.D., MSc.
role: STUDY_DIRECTOR
References:
citation: Popejoy MW, Long J, Huntington JA. Analysis of patients with diabetes and complicated intra-abdominal infection or complicated urinary tract infection in phase 3 trials of ceftolozane/tazobactam. BMC Infect Dis. 2017 May 2;17(1):316. doi: 10.1186/s12879-017-2414-9.
citation: Xiao Y, Tong ML, Liu LL, Lin LR, Chen MJ, Zhang HL, Zheng WH, Li SL, Lin HL, Lin ZF, Xing HQ, Niu JJ, Yang TC. Novel predictors of neurosyphilis among HIV-negative syphilis patients with neurological symptoms: an observational study. BMC Infect Dis. 2017 Apr 26;17(1):310. doi: 10.1186/s12879-017-2339-3.
citation: Armstrong ES, Mikulca JA, Cloutier DJ, Bliss CA, Steenbergen JN. Outcomes of high-dose levofloxacin therapy remain bound to the levofloxacin minimum inhibitory concentration in complicated urinary tract infections. BMC Infect Dis. 2016 Nov 25;16(1):710. doi: 10.1186/s12879-016-2057-2.
citation: Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015 May 16;385(9981):1949-56. doi: 10.1016/S0140-6736(14)62220-0. Epub 2015 Apr 27.
citation: Kullar R, Wagenlehner FM, Popejoy MW, Long J, Yu B, Goldstein EJ. Does moderate renal impairment affect clinical outcomes in complicated intra-abdominal and complicated urinary tract infections? Analysis of two randomized controlled trials with ceftolozane/tazobactam. J Antimicrob Chemother. 2017 Mar 1;72(3):900-905. doi: 10.1093/jac/dkw486.
citation: Huntington JA, Sakoulas G, Umeh O, Cloutier DJ, Steenbergen JN, Bliss C, Goldstein EJ. Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin-resistant pathogens: results from the ASPECT-cUTI trial. J Antimicrob Chemother. 2016 Jul;71(7):2014-21. doi: 10.1093/jac/dkw053. Epub 2016 Mar 18.