Clinical trial NCT04247542: ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection
Official title: ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection: A Phase 2A Open-Label Segment Followed by a Phase 2B Double-Blind Vancomycin-Controlled Segment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Clostridium Difficile Infection
Keywords: Clostridioides difficile
CDAD (Clostridioides difficile-associated diarrhea)
DNA polymerase IIIC
Lead sponsor: Acurx Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2020-01-30
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Segment 2B, approximately 64 patients will be randomly assigned in a 1:1 fashion to ibezapolstat or the standard of care positive control, vancomycin.
Primary purpose: TREATMENT

Brief summary: Segments 2A and 2B of this trial evaluate the safety, efficacy, pharmacokinetics, fecal concentrations, and fecal microbiome effects of ACX-362E \[ibezapolstat\] in patients with C. difficile infection (CDI).

Detailed description: This Phase 2, multicenter, open-label single-arm segment (2A) followed by a double-blind, randomized, active-controlled segment (2B) is designed to evaluate ACX-362E in the treatment of CDI. Segment 2A of this trial was an open-label study of up to 20 patients at 6 study centers and was terminated early at 10 patients based on the protocol-specified Trial Oversight Committee's assessment of the compelling efficacy and safety data. Patients were treated with 450 mg of oral ibezapolstat twice daily for 10 days. The trial will advance to Segment 2B which is a double-blind comparison of ibezapolstat to the standard of care, oral vancomycin, in approximately 64 subjects (1-1 randomization) at up to approximately 15 sites.

Subjects will be evaluated for cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles. Pharmacokinetic (PK) testing for systemic exposure will be performed on blood samples. Stool samples will be tested for study drug concentration.

Eligibility criteria: Inclusion Criteria:

1. Male or female 18 to 90 years of age, inclusive, at the time of Screening.
2. Capable of reading, understanding, and signing the written informed consent; able to adhere to all study procedures and attend all scheduled study visits.
3. Confirmed diagnosis of mild or moderate CDI as defined by the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America guidelines (McDonald et al. 2018). Subjects will be diagnosed with CDI based on clinical and laboratory findings:

   1. The presence of diarrhea, defined as passage of ≥ 3 UBMs within 24 hours before dosing; an unformed stool is defined as a Type 5, 6, or 7 on the Bristol Stool Chart (Appendix 2)
   2. A stool test result positive for the presence of C. difficile free toxins using tests that detect toxin A/B (and it is prospectively agreed with the Sponsor). The Sponsor will provide a toxin A/B test kit if the site does not have it as part of standard of care test.
   3. Mild or moderate CDI as defined as a white blood cell count of ≤ 15000 cells/mL and a serum creatinine level \< 1.5 mg/dL.

Exclusion Criteria:

1. Received more than 24 hours of dosing (\> 4 doses) of oral vancomycin for the current episode of CDI before first dose of study drug.
2. Received more than 24 hours of dosing (\> 2 doses) of oral fidaxomicin for the current episode of CDI before first dose of study drug.
3. Received more than 24 hours of dosing (\> 3 doses) of oral/IV metronidazole for the current episode of CDI before first dose of study drug.
4. Received any other antibacterial therapy for the current CDI episode within 48 hours before the first dose of study drug.
5. Subjects considered treatment failures on prior antibiotics for their current episode of CDI will be excluded.
6. More than 3 episodes of CDI in the previous 12 months or more than 1 prior episode in the last 3 months, excluding the current episode.
7. Severe, complicated, or life-threatening fulminant CDI with evidence of hypotension (systolic blood pressure less than 90 mmHg), septic shock, peritoneal signs or ileus, or toxic megacolon.
8. Elevated liver transaminases (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\]) greater than 2 times ULN.
9. Active inflammatory bowel disease (Crohn's disease, ulcerative colitis, Irritable Bowel Syndrome with chronic diarrhea).
10. Any other non-C. difficile diarrhea.
11. Active gastroenteritis because of Salmonella, Shigella, Escherichia coli 0157H7, Yersinia or Campylobacter, a parasite, or virus within the past 2 weeks.
12. Had a known positive diagnostic test for other relevant gastrointestinal \[GI\] pathogens in the 2 weeks before study drug treatment and/or colonization/infection by ova or parasites.
13. Major GI surgery (ie, significant bowel resection) within 3 months of enrollment (does not include appendectomy or cholecystectomy).
14. Prior or current use of anti-C. difficile toxin antibodies.
15. Have received a vaccine against C. difficile or its toxins.
16. Anticipated that systemic antibacterial therapy for a non-CDI infection will be required for \> 7 days after start of study therapy.
17. Actively taking anti-diarrheals, and unable to discontinue anti-diarrheal medication, or any medication with the potential to slow bowel movement (for opiates, a stable dose, including use as needed, is permitted).
18. Actively taking Saccharomyces boulardii and unwilling to discontinue during the study period.
19. Received a fecal transplant in the previous 3 months.
20. Received laxatives in the last 48 hours.
21. Unable or unwilling to stop taking oral probiotics for the duration of the study.
22. Received intravenous immunoglobulin within 3 months before study drug treatment.
23. Sepsis.
24. Have a known current history of significantly compromised immune system such as:

    1. Subjects with a known history of human immunodeficiency virus infection and CD4 \<200 cells/mm3 within 6 months of start of study therapy.
    2. Severe neutropenia with neutrophil count \< 500 cells/mL.
    3. Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy.
25. Pregnant or lactating women.

Primary outcomes:
measure: Segment 2A: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI) Per Protocol (PP)/Modified Intent-to-Treat (mITT) Population
timeFrame: 12 days
measure: Segment 2B Per Protocol (PP) Population: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI)
timeFrame: 12 days
measure: Segment 2B Intent-to-Treat (ITT) Population: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI)
timeFrame: 12 days
Secondary outcomes:
measure: Segment 2A: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI) Per Protocol (PP)/Modified Intent-to-Treat (mITT) Population
timeFrame: 38 days
measure: Segment 2B Per Protocol (PP) Population: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI)
timeFrame: 38 days
measure: Segment 2B Intent-to-Treat (ITT) Population: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI)
timeFrame: 38 days
measure: Segment 2A: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Plasma Concentrations
timeFrame: Days 1, 5, and 10: 2 and 4 hours post-dose
measure: Segment 2B: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Plasma Concentrations
timeFrame: Days 1 and 5: 2 and 4 hours post-dose
measure: Segment 2A: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Fecal Concentrations
timeFrame: Days -2, 3, 5, 8,10, 12, 20, 30, and 38
measure: Segment 2B: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Fecal Concentrations
timeFrame: Days -2, 3, 5, 8,10,12, 20, 30, and 38
Other outcomes:
measure: Segment 2A: Time to Resolution of Diarrhea
timeFrame: 10 days
measure: Segment 2B: Time to Resolution of Diarrhea
timeFrame: 40 days
measure: Segment 2A: Microbiome Effects
timeFrame: Days 10 and 40
measure: Segment 2B Per Protocol (PP) Population: Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Quality of Life Scores
timeFrame: Days 12, 38, 66, and 94
measure: Segment 2B Intent-to-Treat (ITT) Extension Population: Extended Clinical Cure (ECC) of Clostridioides Difficile Infection (CDI)
timeFrame: 56 days after end of treatment (Day 66) and 84 days after end of treatment (Day 94)
Locations:
city: Scottsdale
country: United States
facility: Acurx Site #118: Dr Janet Reiser
state: Arizona
city: Apple Valley
country: United States
facility: Acurx Site #115: Dr Neera Grover
state: California
city: Camarillo
country: United States
facility: Acurx Site #125: Dr Karen Simon
state: California
city: Lancaster
country: United States
facility: Acurx Site #111: Dr Jatinder Pruthi
state: California
city: Palm Springs
country: United States
facility: Acurx Site #131: Dr Michael Jardula
state: California
city: Sacramento
country: United States
facility: Acurx Site #129: Dr Stuart Cohen
state: California
city: Doral
country: United States
facility: Acurx Site #105
state: Florida
city: Doral
country: United States
facility: Acurx Site #122: Dr Faride Ramos
state: Florida
city: Miami Springs
country: United States
facility: Acurx Site #107: Dr Belkis Delgado
state: Florida
city: Miami
country: United States
facility: Acurx Site #101: Dr Idalia Acosta
state: Florida
city: Miami
country: United States
facility: Acurx Site #124: Dr Yunior Silva-Barrero
state: Florida
city: Miami
country: United States
facility: Acurx Site #108: Dr Idania Garcia Del Sol
state: Florida
city: Miami
country: United States
facility: Acurx Site #116: Dr Erick Juarez
state: Florida
city: Miami
country: United States
facility: Acurx Site #119: Dr Jorge Paoli-Bruno
state: Florida
city: Panama City
country: United States
facility: Acurx Site #117: Dr Rafael Companioni
state: Florida
city: Idaho Falls
country: United States
facility: Acurx Site #102: Dr Richard Nathan
state: Idaho
city: Newton
country: United States
facility: Acurx Site #123: Dr Harry Schrager
state: Massachusetts
city: Worcester
country: United States
facility: Acurx Site #104: Dr JeanMarie Houghton
state: Massachusetts
city: Butte
country: United States
facility: Acurx Site #103: Dr John Pullman
state: Montana
city: North Massapequa
country: United States
facility: Acurx Site #130: Dr Michael DiGiovanna
state: New York
city: Winston-Salem
country: United States
facility: Acurx Site #127: Dr Christopher Connolley
state: North Carolina
city: Myrtle Beach
country: United States
facility: Acurx Site #126: Dr Andrew Pearson
state: South Carolina
city: Chattanooga
country: United States
facility: Acurx Site #114: Dr Eugene Ryan
state: Tennessee
city: Houston
country: United States
facility: Acurx Site #121: Dr Ramesh Gowrappala
state: Texas
city: Lampasas
country: United States
facility: Acurx Site #120: Dr Vanna Gold
state: Texas
city: Temple
country: United States
facility: Acurx Site #113: Dr Jennifer Vincent
state: Texas
city: Bountiful
country: United States
facility: Acurx Site #110: Dr Val Hansen
state: Utah
city: Fairfax
country: United States
facility: Acurx Site #106: Dr Bezawit Tekola
state: Virginia
city: Lynchburg
country: United States
facility: Acurx Site #109: Dr Robert Brennan
state: Virginia
Study officials:
affiliation: Acurx Pharmaceuticals Inc.
name: Michael H Silverman, MD
role: STUDY_DIRECTOR
References:
citation: Xu WC, Silverman MH, Yu XY, Wright G, Brown N. Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections. Bioorg Med Chem. 2019 Aug 1;27(15):3209-3217. doi: 10.1016/j.bmc.2019.06.017. Epub 2019 Jun 11.
citation: Dvoskin S, Xu WC, Brown NC, Yanachkov IB, Yanachkova M, Wright GE. A novel agent effective against Clostridium difficile infection. Antimicrob Agents Chemother. 2012 Mar;56(3):1624-6. doi: 10.1128/AAC.06097-11. Epub 2011 Dec 27.
citation: Garey KW, Begum K, Lancaster C, Gonzales-Luna A, Bui D, Mercier J, Seng Yue C, Ducharme MP, Hu M, Vince B, Silverman MH, Alam MJ, Kankam M. A randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects. J Antimicrob Chemother. 2020 Dec 1;75(12):3635-3643. doi: 10.1093/jac/dkaa364.
citation: Garey KW, McPherson J, Dinh AQ, Hu C, Jo J, Wang W, Lancaster CK, Gonzales-Luna AJ, Loveall C, Begum K, Jahangir Alam M, Silverman MH, Hanson BM. Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial. Clin Infect Dis. 2022 Sep 30;75(7):1164-1170. doi: 10.1093/cid/ciac096.
citation: Eubank TA, Alam MJ, Begum K, McPherson JK, Jo J, Silverman MH, and Garey KW. A phase 2b, randomized double-blind study of ibezapolstat compared with vancomycin for the treatment of C. difficile infection: clinical and microbiome evaluation. Poster session presented at: IDWeek 2024; 2024 October 16-19; Los Angeles, CA.
citation: Garey KW, Alam MJ, Begum K, McPherson JK, Eubank TA, Jo J, and Silverman MH. Microbiome Results from the phase 2, randomized, double-blind study of ibezapolstat compared with vancomycin for the treatment of Clostridioides difficile infection. Slide presentation at: 8th International Clostridioides difficile Symposium; 2024 September 17-19; Bled, Slovenia.