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

Urinary Tract Infections Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03687255
• Other study ID #: AT-301
• Status: Completed
• Phase: Phase 3
• Start date: September 24, 2018
• Est. completion date: February 15, 2020

Study information

• Verified date: March 2020
• Source: Allecra
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1043
• Est. completion date: February 15, 2020
• Est. primary completion date: January 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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;

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Urinary Tract Infections

Intervention

Drug:
• cefepime/AAI101 combination
cefepime 2 g / AAI101 500 mg
• Piperacillin/tazobactam
piperacillin 4 GM / tazobactam 500 MG

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Allecra	Medpace, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Belarus,  Bulgaria,  Croatia,  Estonia,  Georgia,  Hungary,  Latvia,  Lithuania,  Mexico,  Peru,  Poland,  Russian Federation,  Serbia,  Slovakia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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