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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 53
- 试验地点
- 29
- 主要终点
- Segment 2A: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI) Per Protocol (PP)/Modified Intent-to-Treat (mITT) Population
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Vancomycin capsules will be over-encapsulated to have identical appearance to ibezapolstat capsules. Placebo capsules will be used to enable a double-dummy, double-blind design.
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female 18 to 90 years of age, inclusive, at the time of Screening.
- •Capable of reading, understanding, and signing the written informed consent; able to adhere to all study procedures and attend all scheduled study visits.
- •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:
- •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)
- •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.
- •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.
排除标准
- •Received more than 24 hours of dosing (> 4 doses) of oral vancomycin for the current episode of CDI before first dose of study drug.
- •Received more than 24 hours of dosing (> 2 doses) of oral fidaxomicin for the current episode of CDI before first dose of study drug.
- •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.
- •Received any other antibacterial therapy for the current CDI episode within 48 hours before the first dose of study drug.
- •Subjects considered treatment failures on prior antibiotics for their current episode of CDI will be excluded.
- •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.
- •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.
- •Elevated liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) greater than 2 times ULN.
- •Active inflammatory bowel disease (Crohn's disease, ulcerative colitis, Irritable Bowel Syndrome with chronic diarrhea).
- •Any other non-C. difficile diarrhea.
- •Active gastroenteritis because of Salmonella, Shigella, Escherichia coli 0157H7, Yersinia or Campylobacter, a parasite, or virus within the past 2 weeks.
- •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.
- •Major GI surgery (ie, significant bowel resection) within 3 months of enrollment (does not include appendectomy or cholecystectomy).
- •Prior or current use of anti-C. difficile toxin antibodies.
- •Have received a vaccine against C. difficile or its toxins.
- •Anticipated that systemic antibacterial therapy for a non-CDI infection will be required for > 7 days after start of study therapy.
- •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).
- •Actively taking Saccharomyces boulardii and unwilling to discontinue during the study period.
- •Received a fecal transplant in the previous 3 months.
- •Received laxatives in the last 48 hours.
- •Unable or unwilling to stop taking oral probiotics for the duration of the study.
- •Received intravenous immunoglobulin within 3 months before study drug treatment.
- •Have a known current history of significantly compromised immune system such as:
- •Subjects with a known history of human immunodeficiency virus infection and CD4 <200 cells/mm3 within 6 months of start of study therapy.
- •Severe neutropenia with neutrophil count < 500 cells/mL.
- •Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy.
- •Pregnant or lactating women.
研究组 & 干预措施
Ibezapolstat
Active investigational antibacterial agent: ibezapolstat 450 mg po Q12H x 10 days
干预措施: Ibezapolstat (Drug)
Vancomycin
Standard of care: Vancomycin 125 mg po Q6H x 10 days
干预措施: Vancomycin (Drug)
结局指标
主要结局
Segment 2A: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI) Per Protocol (PP)/Modified Intent-to-Treat (mITT) Population
时间窗: 12 days
Percentage of patients with CC at the test of cure (TOC) visit on day 12. CC was defined as survival and the resolution of diarrhea in the 24-hour period immediately before end of treatment (EOT--day 10) that was maintained for 48 hours post EOT without a requirement for additional CDI treatment. Diarrhea was defined as 3 or more unformed bowel movements (UBMs) in a 24-hour period; fewer than 3 UBMs was considered as resolution of diarrhea. A UBM was defined as a Type 5, 6, or 7 bowel movement on the Bristol Stool Chart.
Segment 2B Per Protocol (PP) Population: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI)
时间窗: 12 days
Percentage of patients with CC at the test of cure (TOC) visit on day 12. CC was defined as survival and the resolution of diarrhea in the 24-hour period immediately before end of treatment (EOT--day 10) that was maintained for 48 hours post EOT without a requirement for additional CDI treatment. Diarrhea was defined as 3 or more unformed bowel movements (UBMs) in a 24-hour period; fewer than 3 UBMs was considered as resolution of diarrhea. A UBM was defined as a Type 5, 6, or 7 bowel movement on the Bristol Stool Chart.
Segment 2B Intent-to-Treat (ITT) Population: Clinical Cure (CC) of Clostridioides Difficile Infection (CDI)
时间窗: 12 days
Percentage of patients with CC at the test of cure (TOC) visit on day 12. CC was defined as survival and the resolution of diarrhea in the 24-hour period immediately before end of treatment (EOT--day 10) that was maintained for 48 hours post EOT without a requirement for additional CDI treatment. Diarrhea was defined as 3 or more unformed bowel movements (UBMs) in a 24-hour period; fewer than 3 UBMs was considered as resolution of diarrhea. A UBM was defined as a Type 5, 6, or 7 bowel movement on the Bristol Stool Chart.
次要结局
- Segment 2A: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI) Per Protocol (PP)/Modified Intent-to-Treat (mITT) Population(38 days)
- Segment 2A: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Plasma Concentrations(Days 1, 5, and 10: 2 and 4 hours post-dose)
- Segment 2B: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Fecal Concentrations(Days -2, 3, 5, 8,10,12, 20, 30, and 38)
- Segment 2B Per Protocol (PP) Population: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI)(38 days)
- Segment 2B Intent-to-Treat (ITT) Population: Sustained Clinical Cure (SCC) of Clostridioides Difficile Infection (CDI)(38 days)
- Segment 2B: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Plasma Concentrations(Days 1 and 5: 2 and 4 hours post-dose)
- Segment 2A: Pharmacokinetics and Systemic Exposure to Ibezapolstat (ACX-362E), Fecal Concentrations(Days -2, 3, 5, 8,10, 12, 20, 30, and 38)