Evaluation of CRS3123 vs. Oral Vancomycin in Adult Patients With Clostridioides Difficile Infection

Crestone, Inc43 enrolled

Overview

The purpose of this research is to evaluate the primary objectives of safety and efficacy (rate of clinical cure) of 2 dosages of CRS3123 (200 mg and 400 mg) administered orally (po) twice daily (bid) and vancomycin administered 125 mg PO 4 times daily (qid) in adults \> or equal to 18 years of age with a primary episode or first recurrence of CDI. The study will investigate the plasma concentrations and HRQoL outcomes of CRS3123 and additional efficacy endpoints as secondary objectives.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Clostridioides Difficile Infection

Interventions

CRS3123DRUG

Study drug dosed PO BID for a total of 10 days

Active ComparatorDRUG

Active comparator dosed PO QID for 10 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Adults, ≥ 18 years of age. 2. More than or equal to 3 diarrheal (Bristol Stool Scale scores 5, 6, or 7) stools/day in a 24-hour period during screening prior to randomization and in the judgment of the investigator that C. difficile is the likely causative agent for the diarrhea. 3. Stool positive for C. difficile Toxin A and/or B antigen using an FDA or Health Canada approved/cleared EIA or ELISA laboratory test. 4. Participants with a primary episode or first recurrence of CDI are eligible. 5. In the judgment of the investigator, the expectation that the participant will survive with effective antibiotic therapy and appropriate supportive care for the anticipated duration of the study. 6. Female participants of childbearing potential must not be pregnant, plan to become pregnant during the study, or be breastfeeding; and must be willing to commit to either sexual abstinence or use highly effective methods of birth control contraception from screening through Day 70. 7. Males must use a condom and spermicide from screening through Day 70 (if the female partner(s) is of childbearing potential) and must not donate sperm from screening through Day 70. 8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form. Exclusion Criteria 1. Participants with any of the following conditions: 1. Intractable vomiting preventing oral medication intake 2. Severe underlying disease with an expected survival time less than the duration of the study (approximately 70 days). 3. More than 1 prior CDI occurrence within the last 3 months or more than 2 prior episodes of CDI in the last 12 months. 4. A history of a recent CDI episode within 3 months prior to enrollment that was non- responsive to vancomycin. 5. In the investigator's opinion, the participant is anticipated to require oral or intravenous systemic antibiotic therapy for a non-CDI infection between screening and Day 70. 6. Inflammatory bowel disease (Crohn's disease or ulcerative colitis), uncorrected Hirschsprung's disease, short gut syndrome, or any other condition known to significantly impact bowel motility and/or malabsorption. 7. Any other known pathogen associated with diarrhea. 8. Life-threatening or fulminant CDI as defined by IDSA/SHEA Guidelines. 9. Colonic perforation. 10. Need for concurrent laxatives or tube feeds, toxin binders, bile acid sequestrants during the study. Microbiota restoration therapy (MRT) or any phage therapy within 1 year of randomization. Receipt of bezlotoxumab within 3 months of randomization. 11. Participants treated with another antimicrobial agent directed at the current episode of CDI (metronidazole, fidaxomicin, rifaximin, tigecycline, or oral vancomycin) for \>24 hours of treatment within the 3 days prior to randomization will not be eligible for enrollment. 2. Pregnant or breastfeeding women. 3. Receipt of any investigational medication during the last month (30 days or 5 half lives, whichever is longer) prior to randomization. 4. Active and uncontrolled HIV with CD4 \<200/mm3. 5. Presence of active malignancy undergoing chemotherapy that is expected to cause significant immunosuppression, hematologic malignancy undergoing induction chemotherapy, or recent bone marrow or solid organ transplant (within 1 month prior to randomization) undergoing treatment with medications for the rejection of transplantation. In the investigator's opinion, is expected not to survive through the duration of the study (approximately 70 days) due to complications of the malignancy, or in the investigator's opinion will require oral or intravenous systemic antibiotic therapy during the study for malignancy related conditions. 6. Severe neutropenia defined as ANC \<500 cells/mm3 7. Severe hepatic impairment at screening including clinical signs of cirrhosis, end-stage hepatic disease (eg, ascites, hepatic encephalopathy), or Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x upper limit of normal (ULN) or total bilirubin ≥ 2x ULN. 8. Any other surgical or medical condition (including a clinically significant laboratory abnormality) as determined by the investigator or the medical monitor, that could interfere with the participant's ability to participate in the study, the administration of study treatment, and/or the interpretation of study results that, in the investigator's opinion, may confound study assessments or study procedures. 9. Known hypersensitivity to CRS3123 or oral vancomycin. 10. An employee of the investigator or study center with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as a family member of the employee or the investigator. 11. Unwillingness to stop consuming non-dietary probiotics from randomization to Day 70. 12. Participants currently taking digoxin within 1 week of screening. 13. Unwillingness to refrain from consumption of grapefruit and its juices as well as nutraceutical supplements containing curcumin from randomization until 24 hours after EOT. 14. Unwillingness to stop use of anti-diarrheals from randomization to Day 70.

Locations (20)

131

Fullerton, California, United States

117

Lancaster, California, United States

Outcomes

Primary Outcomes

Rate of Clinical Cure at the Test of Cure [TOC] Visit in the Intent-to-treat [ITT] Population

Clinical cure is defined as survival through TOC/Day 12 and resolution of diarrhea (i.e., \<3 unformed bowel movements \[UBM\] \[Bristol Stool Scale score of 5, 6, or 7\] at end-of-treatment (EOT)/Day 10 with maintenance of resolution through TOC/Day 12 and no further requirement for treatment of CDI through TOC/Day 12. Numbers reported below indicate participants from each cohort that were clinical cures, clinical failures, or indeterminate at the TOC/Day 12 visit.

Time frame: TOC/Day 12

Secondary Outcomes

Rate of Clinical Cure at Test of Cure (TOC) in the Microbiological-ITT (mITT) Population

Time frame: TOC/Day 12

Rate of Clinical Cure at Test of Cure (TOC) in the Per Protocol (PP) and Microbiologically Evaluable (ME) Populations

Time frame: TOC/Day 12

Rate of Total Relief of Symptoms of Clostridioides Difficile Infection at Test of Cure (TOC) in the Microbiological-ITT (mITT) Population

Total relief of symptoms at TOC/Day 12 is defined as resolution (\< 3 per day) of unformed bowel movements, an investigator's assessment of clinical cure, and the resolution of signs or symptoms of CDI recorded at baseline. Numbers reported below indicate participants from each cohort that had total relief of symptoms at TOC/Day 12 and those that did not.

Data from ClinicalTrials.gov

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Mission Hills, California, United States

138

Orange, California, United States

146

Miami, Florida, United States

122

Miami, Florida, United States

140

Marietta, Georgia, United States

110

Idaho Falls, Idaho, United States

129

Winfield, Illinois, United States

130

Royal Oak, Michigan, United States

...and 10 more locations

Time frame: TOC/Day 12

Rate of Total Relief of Symptoms of Clostridioides Difficile Infection at Test of Cure (TOC) in the Per Protocol (PP) and Microbiologically Evaluable (ME) Populations

Time frame: TOC/Day 12

Time to Resolution of Diarrhea Through Test of Cure (TOC) in the Microbiological-ITT (mITT) Population

The time to resolution of diarrhea is defined as the time elapsed from the first dose of study treatment to the last unformed bowel movement before 2 consecutive days of \< 3 unformed bowel movements (Bristol Stool Scale score of 5, 6, or 7) per day through TOC/Day 12. Values reported below are median days to resolution for each cohort.

Time frame: Study Day 1 until the date of documented resolution, assessed up to TOC/Day 12

Time to Resolution of Diarrhea Through Test of Cure (TOC) in the Per Protocol (PP) and Microbiologically Evaluable (ME) Populations

Time frame: Study Day 1 until the date of documented resolution, assessed up to TOC/Day 12

Rate of Early Recurrence of Clostridioides Difficile Infection Through Day 40 in the Microbiological-ITT (mITT) Population

Rate of early recurrence of C. difficile infection (CDI) is defined as a new episode of diarrhea (≥ 3 unformed bowel movements \[Bristol Stool Scale score of 5, 6, or 7\] in a 24-hour period) with a positive toxin result and requires retreatment for CDI before Day 40. The table below shows the number of participants per cohort that experienced a recurrence before Day 40 and those that did not. Only participants that were clinical cures at TOC/Day 12 were included in the analysis.

Time frame: Post TOC/Day 12 visit through Day 40

Rate of Early Recurrence of Clostridioides Difficile Infection Through Day 40 in the Microbiologically Evaluable (ME) Population

Time frame: Post TOC/Day 12 visit through Day 40

Rate of Late Recurrence of Clostridioides Difficile Infection (Between Day 40 and Day 70) in the Microbiological-ITT (mITT) Population

Rate of late recurrence of CDI is defined as a new episode of diarrhea (≥ 3 unformed bowel movements \[Bristol Stool Scale score of 5, 6, or 7\] in a 24-hour period), with a positive toxin result and requires retreatment of CDI between Day 40 and Day 70. The table below shows the number of participants per cohort that experienced a recurrence between Day 40 and Day 70 and those that did not. Analysis populations for this assessment only includes participants that had an investigator assessment of clinical cure at TOC/Day 12. Participants that were indeterminate at TOC/Day 12 or recurrent prior to Day 40 were excluded.

Time frame: Day 40 - Day 70

Rate of Late Recurrence of Clostridioides Difficile Infection (Between Day 40 and Day 70) in the Microbiologically Evaluable (ME) Population

Time frame: Day 40 - Day 70

Rate of Recurrence of Clostridioides Difficile Infection Through Day 70 in the Microbiological-ITT (mITT) Population

Rate of recurrence of CDI is defined as a new episode of diarrhea (≥3 unformed bowel movements \[Bristol Stool Scale score of 5, 6, or 7\] in a 24-hour period) with a positive toxin result and requires retreatment for CDI at any point between TOC/Day 12 and Day 70. The table below shows the number of participants per cohort that experienced a recurrence between TOC/Day 12 and Day 70 and those that did not. Analysis populations for this assessment only includes participants that had an investigator assessment of clinical cure at TOC/Day 12.

Time frame: Post TOC/Day 12 visit through Day 70

Rate of Recurrence of Clostridioides Difficile Infection Through Day 70 in the Microbiologic Evaluable (ME) Population

Time frame: Post TOC/Day 12 visit through Day 70

Rate of Global Cure in the Microbiological-ITT (mITT) Population

Global cure is defined as a clinical cure at TOC/Day 12 without recurrence through Day 40. The table below shows the number of participants per cohort that experienced a recurrence between TOC/Day 12 and Day 40 and those that did not.

Time frame: Post TOC/Day 12 visit through Day 40

Rate of Global Cure in the Per Protocol (PP) and Microbiologically Evaluable (ME) Populations

Time frame: Post TOC/Day 12 visit through Day 40