Alanyl-glutamine Supplementation for C. Difficile Treatment (ACT) (ACT)

• ClinicalTrials.gov Identifier: NCT04305769
• Recruitment Status: Recruiting
• First Posted: March 12, 2020
• Last Update Posted: May 18, 2021
• Sponsor: University of Virginia
• Collaborator: Imperial College London
• Information provided by (Responsible Party): Cirle Warren, MD, University of Virginia

Study Description

Brief Summary:

This is a randomized, double-blind, placebo-controlled trial to determine the optimal dose and safety of oral alanyl-glutamine between 4, 24, and 44 g doses administered for 10 days with standard therapy among first time incident cases of uncomplicated C. difficile infection (CDI) in hospitalized persons aged 65 or older. Our hypothesis is that alanyl-glutamine supplementation will decrease recurrence and mortality from CDI and these outcomes will be associated with improvement of inflammatory markers and restoration of intestinal microbiota function.

Condition or disease	Intervention/treatment	Phase
Clostridioides Difficile Infection; Clostridium Difficile Infection; Clostridium Difficile Diarrhea; Clostridia Difficile Colitis	Drug: Alanyl-glutamine	Phase 2

Detailed Description:

This is a Phase II randomized, placebo-controlled, double-blinded, dose-ranging study to determine optimal effective dose and safety of AQ between 0, 4, 24, and 44 g doses administered orally for ten days concurrent with standard treatment (oral vancomycin at UVa) among first time incident cases of uncomplicated CDI in hospitalized persons age 50 and older. Our hypothesis is that AQ will reduce recurrence (primary outcome) and mortality (secondary outcome) at 60 days post-treatment. Furthermore, the investigators hypothesize that alanyl-glutamine supplementation will be associated with decreased intestinal and systemic inflammation and improvement of intestinal microbial and metabolic profiles. The investigators plan to enroll 260 patients, equally divided into 4 arms. Upon enrollment, participants will be randomized to either receive AQ at 4, 24, or 44 g or placebo (water). Study agent is administered once a day, orally or enterally, if feeding tube is present. Because the investigators are enrolling subjects over a longer period of time, block randomization will be used to ensure that relative temporal balance is maintained throughout the trial. Participants will be followed up daily during treatment for adverse event monitoring and weekly for 60 days post-treatment for recurrences and survival. Blood, urine and stool specimens will be collected at days 0, 10 and 70 to assay for markers of inflammation and microbial and metabolic profiling.

The data set utilized for all initial baseline feature and demographic reporting will be the Intention to Treat Analysis Dataset, which will be comprised of all randomized participants. The primary dataset will be a Modified Intention to Treat Analysis Dataset for all endpoints, comprised of all participants who took at least one dose of study intervention (placebo or treatment), regardless of completeness of follow-up outcome data. The Safety Analysis Dataset will be all participants who took at least one dose of study intervention. The Per Protocol Analysis Dataset will be those patients who took at least 9 doses of study intervention for 9 days of the treatment period (10 days). Analysis will utilize ANOVA unless statistically significant differences in the distribution of baseline characteristics or features of non-normality are detected and relevant, at which point contingency utilization of ANCOVA, logistic regression, or other approaches as appropriate will be implemented. Treatment group level rates will be presented as incidence risk ratios relative to the control (placebo) group with 95% confidence intervals.

Safety endpoints will be evaluated on an individual AE by AE event via the DSMB and utilizing summary statistics during treatment and through duration of follow up. Adverse events will be presented by System Organ Class and will include information on start and stop date, severity, projected relationship, expectedness, and outcome and duration (the latter two after the event is considered to have concluded).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 260 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Block randomization will be applied to assign participants to one of the four study groups, either one of the three experimental (AQ) or control (placebo) group in 1:1:1:1 allocation from a list containing the randomized and blinded treatment assignments.
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Alanyl-glutamine Supplementation of Standard Treatment for C. Difficile Infection: A Randomized, Double-blind, Placebo-controlled Trial
• Actual Study Start Date: January 1, 2021
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: June 2025

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Alanyl-glutamine 0g	Drug: Alanyl-glutamine; The study agent is AQ, a dipeptide with a glutamine amino group joined to an alanyl residue. It has the following chemical structure: C8H15N3O4. It is a non-animal product available in the form of white crystals or crystalline powder. It is odorless, tasteless, stable and highly soluble.; Other Names: Alagln; AQ; glutamine
Experimental: Alanyl-glutamine 4g	Drug: Alanyl-glutamine; The study agent is AQ, a dipeptide with a glutamine amino group joined to an alanyl residue. It has the following chemical structure: C8H15N3O4. It is a non-animal product available in the form of white crystals or crystalline powder. It is odorless, tasteless, stable and highly soluble.; Other Names: Alagln; AQ; glutamine
Experimental: Alanyl-glutamine 24g	Drug: Alanyl-glutamine; The study agent is AQ, a dipeptide with a glutamine amino group joined to an alanyl residue. It has the following chemical structure: C8H15N3O4. It is a non-animal product available in the form of white crystals or crystalline powder. It is odorless, tasteless, stable and highly soluble.; Other Names: Alagln; AQ; glutamine
Experimental: Alanyl-glutamine 44g	Drug: Alanyl-glutamine; The study agent is AQ, a dipeptide with a glutamine amino group joined to an alanyl residue. It has the following chemical structure: C8H15N3O4. It is a non-animal product available in the form of white crystals or crystalline powder. It is odorless, tasteless, stable and highly soluble.; Other Names: Alagln; AQ; glutamine

Outcome Measures

Primary Outcome Measures :

1. Number of participants with recurrent CDI. [ Time Frame: Within 60 days post-treatment ]
   Documented C difficile infection defined by presence of recurrent diarrhea with stool positive for C difficile assay necessitating treatment with anti-C. difficile antibiotic.

Secondary Outcome Measures :

1. Number of participants who died post-study treatment [ Time Frame: Until 60 days post-treatment ]
   Documentation of death from any cause occurring during study treatment and 60 days after study treatment

Eligibility Criteria

• Ages Eligible for Study: 65 Years to 110 Years (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged > 65 years
4. Admitted in the hospital
5. Presence of diarrhea*
6. Stool positive for C. difficile tcdB and TcdB
7. 1st episode of C. difficile infection, non-severe or severe uncomplicated
8. Within 48 hours of receiving standard therapy (oral vancomycin at UVA)

Exclusion Criteria:

1. At enrollment, presence of any of the following:

   • Hypotension or shock
   • Megacolon or moderate to severe ileus
   • Acute abdomen
   • Admission to intensive care unit
2. Inability to tolerate oral or enteral medication
3. Presence of other known infectious etiology of diarrhea
4. Inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis) or other etiology of non-infectious diarrhea
5. Enrollment in another investigational drug trial
6. Current use of alternative treatment for CDI (e.g. antibiotics other than vancomycin or fidaxomicin; IVIg; fecal transplant).
7. On probiotics and not willing to discontinue.
8. Cirrhosis or in participants with ALT > 3X normal
9. End stage renal disease, on dialysis, or creatinine clearance or estimated GFR of <30mL/min even after adequate hydration
10. Life expectancy of < 6 months.

Contacts and Locations

Locations

United States, Virginia

UVA Health Systems; Recruiting

Charlottesville, Virginia, United States, 22903

Contact: Cirle Warren, M.D. 434-270-1082 CA6T@hscmail.mcc.virginia.edu

Contact: MaryJane Strickland, B.S.,M.ed 4347601267 mjs7w@virginia.edu

Principal Investigator: Cirle Warren, M.D.

Sponsors and Collaborators

University of Virginia

Imperial College London

More Information

• Responsible Party: Cirle Warren, MD, Associate Professor, University of Virginia
• ClinicalTrials.gov Identifier: NCT04305769
• Other Study ID Numbers: 200046
• First Posted: March 12, 2020
• Last Update Posted: May 18, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All IPD that underlie results in publication
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 6 months after publication
• Access Criteria: To be determined later.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infection; Communicable Diseases; Clostridium Infections; Diarrhea; Signs and Symptoms, Digestive; Gram-Positive Bacterial Infections; Bacterial Infections