Alanyl-glutamine Supplementation of Standard Treatment for C. Difficile Infection

Alanyl-glutamine Supplementation of Standard Treatment for C. Difficile Infection: A Randomized, Double-blind, Placebo-controlled Trial

The aim of this study is to test the efficacy of alanyl-glutamine supplementation in the treatment of C. difficile infection. We hypothesize that alanyl-glutamine when given with standard antibiotic treatment for C. difficile infection will decrease diarrhea, mortality and recurrent disease.

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, we hypothesize that alanyl-glutamine supplementation will be associated with decreased intestinal and systemic inflammation and improvement of intestinal microbial and metabolic profiles. We 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 we are enrolling subjects over a longer period of time, we will utilize block randomization 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).

Inclusion Criteria:

• Adult of either gender, 18 years or older, with C. difficile infection (CDI)
• Diarrhea associated with C. difficile positive stool assay
• Within 48 hours of receiving either metronidazole for mild-moderate disease or vancomycin for severe uncomplicated disease
• Admitted in the hospital at the time of enrollment
• Ability to provide informed consent
• Have an understanding of study procedures
• Ability to comply with study procedures for the entire length of the study

Exclusion Criteria:

• Hypotension or shock
• Megacolon or moderate to severe ileus
• Acute abdomen
• Severe leukocytosis (WBC > 20,000 cells /µL)
• Admission to intensive care unit on enrollment
• Inability to tolerate oral medication
• Other known etiology of diarrhea (e.g. other enteric pathogen, other intestinal disease)
• Inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis)
• Enrollment in another investigational drug trial
• Currently receiving other alternative treatment for CDI (e.g. antibiotics other than metronidazole or vancomycin; probiotics; immunoglobulin therapy; fecal transplant)
• Pregnancy
• Unavailable for follow-up visits
• Life expectancy of < 6 months
• Chronic liver disease or in subjects without known liver disease, ALT > 3x normal
• Chronic kidney disease or in subjects without known kidney disease, estimated Creatinine clearance of < 30 ml/min, even after rehydration