Safety and Efficacy Study of Cefepime-AAI101 in the Treatment of Complicated Urinary Tract Infections

A Phase 3, Randomized, Double-Blind, Study to Evaluate the Efficacy and Safety of Cefepime-AAI101 Compared to Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis.

Multi-center, randomized, double-blind, non-inferiority study of cefepime 2 g/AAI101 500 mg combination compared to piperacillin 4 g/tazobactam 500 mg in a population of adult patients with cUTI or AP. The study will be conducted in approximately 115 sites located in the EU, the US, Central, South America and South Africa.

Study Overview

• Status: Completed
• Conditions: Urinary Tract Infections
• Intervention / Treatment: Drug: cefepime/AAI101 combination; Drug: Piperacillin/tazobactam

• Study Type: Interventional
• Enrollment (Actual): 1043
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1706FWM
    • HIGA Dr Ramon Carrillo
• Belarus
  • Brest, Belarus, 224027
    • Brest Regional Hospital
• Bulgaria
  • Pernik, Bulgaria, 2300
    • MHAT Rahila Angelova AD, Pernik
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital for Infectious Diseases "Dr. Fran Mihaljevic" Department for general infectious diseases
• Estonia
  • Tartu, Estonia, 51014
    • Tartu University Hospital
• Georgia
  • Kutaisi, Georgia, 4600
    • Unimed Adjara - Kutaisi oncological centre
• Hungary
  • Gyöngyös, Hungary, 3200
    • Bugat Pal Korhaz
• Latvia
  • Riga, Latvia, LV-1006
    • Uroklinika, LLC
• Lithuania
  • Šiauliai, Lithuania, 76231
    • Republican Siauliai caunty hospital
• Mexico
  • Boca Del Río, Mexico, CP. 94290
    • Centro Especializado en Investigación Clínica S.C.
• Peru
  • Lima, Peru, 15036
    • Clínica Internacional - Sede San Borja
• Poland
  • Warsaw, Poland, 02-507
    • Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych i Administracji w Warszawie, Klinika Chorob Wewnetrznych, Nefrologii i Transplantologii
• Russian Federation
  • Saint Petersburg, Russian Federation, 196143
    • Scientific Research Center Eco-Safety
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Hospital Center Zvezdara
• Slovakia
  • Malacky, Slovakia, 90122
    • Interne oddelenie, Nemocnica Malacky, Nemocnicna a.s.
• South Africa
  • Worcester, South Africa, 6850
    • Clinical Projects Research
• Spain
  • Barcelona, Spain, 8003
    • Hospital del Mar, Department of Infectious Disease
• Ukraine
  • Chernihiv, Ukraine, 14034
    • Chernihiv City Hospital #2 of Chernihiv City Council, department of Urology
• United States
  • California
    • Anaheim, California, United States, 92804
      • St. Josephs Clinical Research
    • Buena Park, California, United States, 90620
      • Southbay Pharma Research
  • Florida
    • Tampa, Florida, United States, 33615
      • Florida Urology Partners
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Montana
    • Butte, Montana, United States, 59701
      • Mercury Street Medical
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Male or female patients >18 years of age at the time of signing of informed consent;
2. Expectation that the patient's cUTI or AP will require hospitalisation and initial treatment with at least 7 days of intravenous (i.v.) antibiotics;
3. Female patients who are no longer of childbearing potential
4. Female patients of childbearing potential must have a negative urine and/or serum pregnancy test (serum β-human chorionic gonadotropin) within 1 day prior to study entry;
5. Male patients, female patients receiving hormone replacement therapy (HRT), and female patients of childbearing potential must agree to use highly effective contraception methods
6. Pyuria, defined as: a. White blood cell count >10 cells/mm3 in unspun urine or ≥10 cells/high power field in spun urine sediment; or b. Urinalysis/dipstick analysis positive for leukocyte esterase;
7. Clinical signs and/or symptoms of cUTI or AP
8. Have a baseline urine culture specimen obtained within 48 hours prior to randomization
9. Expectation, in the judgment of the Investigator, that any implanted urinary instrumentation (e.g., nephrostomy tubes, ureteric stents, etc.) will be surgically removed or replaced before or within 24 hours after randomisation, unless removal or replacement is considered unsafe or contraindicated.

Exclusion Criteria

1. Known urine culture with Gram-positive primary pathogen at ≥105 colony-forming units (CFU)/mL (not contaminant) or suspected Gram-positive pathogen by Gram staining (Note: Gram staining is optional);
2. History of significant hypersensitivity or allergic reaction to cefepime, piperacillin/tazobactam, any of the excipients used in the respective formulations, any beta-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams), or any beta-lactamase inhibitors (e.g., tazobactam, sulbactam, or clavulanic acid);
3. In the opinion of the Investigator, the patient is considered unlikely to survive the approximately 6-week study period;
4. Weight >180 kg;
5. Concurrent infection that would interfere with evaluation of response to the study antibiotics;
6. Need for or receipt of concomitant systemic antimicrobial agents after signing of informed consent, in addition to those designated in the study-treatment groups, with the exception of a single oral dose of any antifungal treatment for vaginal candidiasis;
7. Receipt of potentially effective systemic antibacterial therapy for a continuous duration of > 24 hours during the previous 72 hours before the study-qualifying baseline urine is obtained;
8. Complicated urinary tract infection (UTI) known at study entry to be caused by pathogens resistant to the study antibiotics;
9. Likely to require the use of an antibiotic for cUTI or AP prophylaxis during the patient's participation in the study;
10. Intractable UTI at baseline that the Investigator anticipates would require >14 days of study drug therapy;
11. Complete, permanent obstruction of the urinary tract that is not anticipated to be medically or surgically relieved during i.v. study therapy and before End of Treatment (EOT);
12. Gross hematuria requiring intervention other than administration of study drug or removal or exchange of a urinary catheter;
13. Presence of any known or suspected disease or condition that, in the opinion of the Investigator, may confound the assessment of efficacy.
14. Suspected or confirmed acute bacterial prostatitis, orchitis, epididymitis, or chronic bacterial prostatitis as determined by history and/or physical examination;
15. Impairment of renal function with estimated glomerular filtration rate <30 mL/min/1.73 m2 calculated by the 4-variable Modification of Diet in Renal Disease study equation,
16. Urinary tract surgery within 7 days prior to randomisation or urinary tract surgery planned during the study period (except surgery required to relieve an obstruction or place a stent or nephrostomy prior to EOT);
17. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of study data;
18. Any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure and respiratory failure;
19. Presence of sepsis, producing life-threatening organ dysfunction
20. A QT interval corrected using Fridericia's formula >450 msec;
21. Immunocompromising condition, including known history of acquired immune deficiency syndrome or known recent CD4 count <200/mm3, hematological malignancy, or bone marrow transplantation; or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids ≥20 mg of prednisone or equivalent per day administered continuously for >14 days prior to randomisation;
22. One or more of the following laboratory abnormalities in baseline specimens obtained at Screening: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or total bilirubin level >3 × upper limit of normal, or current clinically significant liver disease, including any form of known liver cirrhosis;
23. One or more of the following laboratory abnormalities at Screening: platelet count <50,000/μL, absolute neutrophil count <1,000/mm3, or hemoglobin <8 g/dL;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: cefepime/AAI101 combination; Cefepime 2 g in combination with AAI101 500 mg q8h (2 hour infusion)	Drug: cefepime/AAI101 combination; cefepime 2 g / AAI101 500 mg
ACTIVE_COMPARATOR: piperacillin/tazobactam; Piperacillin 4 g in combination with Tazobactan 500 mg q8h (2 hour infusion)	Drug: Piperacillin/tazobactam; piperacillin 4 GM / tazobactam 500 MG; Other Names: PIP/TAZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients in the Microbiological Modified Intent to Treat (m-MITT) Population who achieve overall treatment success at Test Of Cure (TOC)	Treatment success is defined as the composite of clinical outcome of Cure and the microbiological outcome of Eradication (<103 CFU/mL in urine culture).	7 days after EOT [±2 days] for patients receiving 7 days of treatment and 19 days after randomization [±2 days] for patients receiving more than 7 days of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients in the m-MITT Population with overall treatment success at End of Treatment (EOT)	Treatment success is defined as the composite of clinical outcome of Cure and the microbiological outcome of Eradication (<103 CFU/mL in urine culture).	7 days for patients with cUTI only and up to 14 days for patients cUTI and blood stream infections

Collaborators and Investigators

• Sponsor: Allecra
• Collaborators: Medpace, Inc.

Publications and helpful links

General Publications

• Kaye KS, Belley A, Barth P, Lahlou O, Knechtle P, Motta P, Velicitat P. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022 Oct 4;328(13):1304-1314. doi: 10.1001/jama.2022.17034.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 24, 2018
• Primary Completion (ACTUAL): January 30, 2020
• Study Completion (ACTUAL): February 15, 2020

Study Registration Dates

• First Submitted: September 26, 2018
• First Submitted That Met QC Criteria: September 26, 2018
• First Posted (ACTUAL): September 27, 2018

Study Record Updates

• Last Update Posted (ACTUAL): March 10, 2020
• Last Update Submitted That Met QC Criteria: March 9, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination; Cefepime; Enmetazobactam
• Other Study ID Numbers: AT-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No