Melatonin & Ulcerative Colitis

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.

Inclusion Criteria:

- Age 18-69 years.

- Diagnosed with ulcerative colitis and currently experiencing a flare up of
mild-moderate severity according to Mayo Scoring system (>=4 and <=10).

- Has a regular GI physician(s).

- Availability for 14 weeks after enrolling in the study.

- Female patients of child bearing potential must be surgically sterile or have a
negative urine pregnancy test and practice acceptable contraception (i.e.,
abstinence, oral, intramuscular, or implanted hormonal contraception, 2-barrier
methods such as condom, diaphragm or spermicide).

Exclusion Criteria:

- Night shift workers; otherwise, inability to attend morning study visits.

- Current severe colitis according to the Mayo Scoring System (>10) or requiring
hospital admission, or current very mild colitis (<4).

- Current supplemental intake of melatonin or currently using tobacco products.

- Proctitis or Crohn's disease

- Previous gastrectomy or small or large bowel resection

- Malabsorption syndrome (e.g., pancreatic insufficiency).

- History of large bowel resection for any reason.

- Diagnosed narcotic or alcohol dependence.

- On renal dialysis.

- Active liver disease (a chronic condition or under current therapy)

- Seizure disorders

- Immune system disorders

- Any history of hypo- or hyperparathyroidism.

- Unable to be off aspirin for 7 days.

- Use of systemic or rectal steroids in the past 8 weeks.

- Have a history of allergy or hypersensitivity to melatonin.

- History of bleeding disorder or current use of anticoagulant medication.

- Current use of calcium channel blockers, anticonvulsants, sedatives, hypnotics, or
psychotropic medications.

- Women who are pregnant, breast-feeding, attempting conception, or planning to attempt
conception over the following 6 months, or are currently taking hormone replacement
therapy (HRT).