Melatonin and Ulcerative Colitis: A Pilot Clinical Trial

Problem of Interest:

Current treatments for ulcerative colitis are not always effective, and often have serious side effects. Therefore, there is considerable interest in finding alternative treatments for this disease. Physiologic data suggest that melatonin is important in gastrointestinal (GI) tract physiology and health, and data from in vitro studies, animal experiments, and some studies in humans suggest that supplemental melatonin may have an ameliorative effect on colitis. However, experimental data on the ability of melatonin to improve ulcerative colitis in humans are lacking. The long-term goal of this proposal is to examine whether melatonin supplementation helps alleviate mild-to-moderate colitis symptoms. To this end, we plan to conduct a pilot randomized, double-blind, placebo-controlled trial (n = 60) that will obtain preliminary data about the effectiveness of melatonin supplementation as a treatment for ulcerative colitis in adult men and women with mild to moderate flare-up of the disease. The specific aims of the trial are: (i) to estimate the effect of 12 weeks of 5 mg/day supplementation with melatonin on ulcerative colitis remission, (ii) to estimate the effects of melatonin supplementation on tissue levels of cytokines and other markers of inflammation, (iii) to determine whether melatonin's effects vary according to baseline (endogenous) melatonin levels, (iv) to determine the feasibility of recruiting and retaining a sufficient number of ulcerative colitis patients for a larger, more definitive study, and (v) to determine whether melatonin supplementation has any adverse side-effects when taken daily for 12 weeks in adults with ulcerative colitis.

How the Problem Will Be Studied:

The overall study design of this trial is that of a randomized, double-blind, placebo-controlled clinical trial. Patients will be recruited from those seeing their IBD clinicians at one of three study sites: Emory University, Atlanta Gastroenterology Associates, or the Atlanta VA Medical Center. Eligibility will be based first on the severity of disease, determined by physician exam, and through sigmoidoscopy (as part of the Mayo Scoring System). The Project Coordinator will meet with patients to further determine eligibility, as there are restrictions based on age, medical history, medications taken, pregnancy, and others. Willing patients who are otherwise eligible at that point will undergo a one-week placebo run-in to assess compliance and any reported side-effects. Eligible patients will undergo their first study sigmoidoscopy, will provide biological samples for processing (blood, urine, and rectal biopsy tissue), and will be randomized into treatment (5 mg/d at bedtime) or placebo (also at bedtime). They will be given sleep logs and symptoms logs to fill out weekly during the trial, and they will fill out a colitis-related quality of life questionnaire. They will be called once per week by the Project Coordinator to check on the study participants, to assess compliance and side-effects, and to answer any questions. There will be a clinical visit two weeks after randomization, to assess symptoms and any side effects. The next scheduled clinical visit is at the end of the trial, where another sigmoidoscopy and sample collection will take place. Any other interim clinical visit will be at the discretion of the patients and his or her study physician. Lastly, patients will complete a questionnaire about colitis-related quality of life during the trial and will be asked as to whether they suspected which treatment arm they were in. The following period will be devoted to data analysis, publication of study results, and closeout. Please see attached protocol for details.

Importance of the Knowledge to be Gained:

The proposed research will have both public health and scientific importance. Ulcerative colitis is not a rare condition, and sufferers often deal with debilitating symptoms. Thus, a greater understanding of ways of treat ulcerative colitis would be of potential relevance to a great number of people.

How the Research Will Advance Scientific Knowledge and/or Human Health

UC is a common gastrointestinal disorder in adults, one that can have debilitating symptoms and severe health consequences. Current treatments are not always effective, and often have serious side effects. Therefore, there is considerable interest in finding alternative treatments for this disease. Physiologic data suggest that melatonin is important in GI tract physiology and health, and data from in vitro studies, animal experiments, and some studies in humans, suggest that supplemental melatonin may have an ameliorative effect on colitis. Given our newly-funded pilot clinical trial was awarded the maximum funding available from the Broad Foundation, with no funds allocated to explore potentially important biological mechanisms, we feel that this is an excellent opportunity to validate potential clinical benefits of melatonin as an adjunctive therapy for UC in humans, with mechanistic insights into the various levels of the inflammatory process that may be influenced by melatonin in vivo. Thus, the proposed study is a) innovative, b) supported by experimental data, and c) may ultimately lead to improved treatment of UC based on clinical and mechanistic knowledge gained through this study conducted in human patients.

To date, there has been no formal clinical trial of melatonin therapy for UC in humans, and there have been few mechanistic investigations into the potential mode of action of this compound on the pathomechanisms identified thus far. Given the very low toxicity documented for even high levels of melatonin in animals and human subjects, this relatively inexpensive treatment may represent an attractive alternative for patient suffering from mild to mid-grade UC given the low incidence of side effects.