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

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).

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.