ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Clostridium Difficile Infection
• Intervention / Treatment: Drug: Ibezapolstat; Drug: Vancomycin

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 bid for 10 days. In segment 2A all (10 of 10) patients were cured of CDI at end of treatment and all (10 of 10) were sustained clinical cures 30 days after EOT. Ibezapolstat was well tolerated with no reported SAEs. 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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael H Silverman, MD; Phone Number: 7816318596; Email: msilverman@acurxpharma.com

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Acurx Site #118: Dr Janet Reiser
  • California
    • Apple Valley, California, United States, 92307
      • Acurx Site #115: Dr Neera Grover
    • Camarillo, California, United States, 93012
      • Acurx Site #125: Dr Karen Simon
    • Lancaster, California, United States, 93534
      • Acurx Site #111: Dr Jatinder Pruthi
    • Palm Springs, California, United States, 92262
      • Acurx Site #131: Dr Michael Jardula
    • Sacramento, California, United States, 95817
      • Acurx Site #129: Dr Stuart Cohen
  • Florida
    • Doral, Florida, United States, 33166
      • Acurx Site #105
    • Doral, Florida, United States, 33172
      • Acurx Site #122: Dr Faride Ramos
    • Miami, Florida, United States, 33015
      • Acurx Site #101: Dr Idalia Acosta
    • Miami, Florida, United States, 33125
      • Acurx Site #124: Dr Yunior Silva-Barrero
    • Miami, Florida, United States, 33142
      • Acurx Site #108: Dr Idania Garcia Del Sol
    • Miami, Florida, United States, 33155
      • Acurx Site #116: Dr Erick Juarez
    • Miami, Florida, United States, 33186
      • Acurx Site #119: Dr Jorge Paoli-Bruno
    • Miami Springs, Florida, United States, 33166
      • Acurx Site #107: Dr Belkis Delgado
    • Panama City, Florida, United States, 32405
      • Acurx Site #117: Dr Rafael Companioni
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Acurx Site #102: Dr Richard Nathan
  • Massachusetts
    • Newton, Massachusetts, United States, 02462
      • Acurx Site #123: Dr Harry Schrager
    • Worcester, Massachusetts, United States, 01655
      • Acurx Site #104: Dr JeanMarie Houghton
  • Montana
    • Butte, Montana, United States, 59701
      • Acurx Site #103: Dr John Pullman
  • New York
    • North Massapequa, New York, United States, 11758
      • Acurx Site #130: Dr Michael DiGiovanna
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Acurx Site #127: Dr Christopher Connolley
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Acurx Site #126: Dr Andrew Pearson
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Acurx Site #114: Dr Eugene Ryan
  • Texas
    • Houston, Texas, United States, 77024
      • Acurx Site #121: Dr Ramesh Gowrappala
    • Lampasas, Texas, United States, 76550
      • Acurx Site #120: Dr Vanna Gold
    • Temple, Texas, United States, 76508
      • Acurx Site #113: Dr Jennifer Vincent
  • Utah
    • Bountiful, Utah, United States, 84010
      • Acurx Site #110: Dr Val Hansen
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Acurx Site #106: Dr Bezawit Tekola
    • Lynchburg, Virginia, United States, 24501
      • Acurx Site #109: Dr Robert Brennan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibezapolstat; Active investigational antibacterial agent: ibezapolstat 450 mg po Q12H x 10 days	Drug: Ibezapolstat; Investigational antibacterial agent; Other Names: ACX-362E
Active Comparator: Vancomycin; Standard of care: Vancomycin 125 mg po Q6H x 10 days	Drug: Vancomycin; Active comparator; Other Names: Vancomycin oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure	Percentage of patients with clinical cure at the test of cure visit	12 days
Percentage of patients with adverse events	Safety	38 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with sustained clinical cure	Clinical cure at the test of cure visit (ie, at least 48 hours post end of treatment) and no recurrence within 28 days	38 days
Plasma and fecal concentrations of ACX-362E	Pharmacokinetics and systemic exposure	10 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome effects	Quantitative changes in relevant fecal bacterial communities and microbial diversity	38 days
Time to resolution of diarrhea	Time in days from outset of treatment to the first formed bowel movement	12 days
Time from outset of treatment to the first formed bowel movement	Time in days from outset of treatment to day of discharge	12 days
Change in EQ-5D-5L Quality of Life scores	Change from baseline in each of the 5 dimensions of the EQ-5D-5L score, each scored on a scale of 1-5, with 1 being normal and 5 indicating extreme difficulty or impairment	38 days

Collaborators and Investigators

• Sponsor: Acurx Pharmaceuticals Inc.
• Investigators: Study Director: Michael H Silverman, MD, Acurx Pharmaceuticals Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2020
• Primary Completion (Actual): October 3, 2023
• Study Completion (Estimated): February 1, 2024

Study Registration Dates

• First Submitted: January 23, 2020
• First Submitted That Met QC Criteria: January 29, 2020
• First Posted (Actual): January 30, 2020

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Clostridioides difficile; CDAD (Clostridioides difficile-associated diarrhea); DNA polymerase IIIC
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Communicable Diseases; Clostridium Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Vancomycin; Ibezapolstat
• Other Study ID Numbers: ACX-362E-201

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