Chronotherapy of 5-Aminosalicylic Acid in Ulcerative Colitis

Study Overview
=================
Brief Summary
-----------------
The hypothesis of this study is that appropriate time of day of administration of oral, once daily 5-ASA therapy in alignment with the host circadian rhythms will improve subclinical inflammation and microbial structure/function and increase mucosal 5-ASA levels. All subjects will be randomized to once daily 5-ASA medications at two different times of the day: between 06:00 - 10:00 h or 18:00 - 22:00 h. Three disease assessments will performed at: 1) enrollment just before randomization; 2) month 3, at the completion of first arm (Condition 1), and 3) month 6, after completion of the second arm (Condition 2). During these study time points, participants will be asked to complete questionnaires, track their 5-ASA medication usage, provide a stool sample, blood draw, urine test, wear a watch to measure sleep patterns, and complete a flexible sigmoidoscopy.

Official Title
-----------------
Chronotherapy of 5-Aminosalicylic Acid in Ulcerative Colitis: A Randomized Crossover Trial

Conditions
-----------------
Ulcerative Colitis

Intervention / Treatment
-----------------
* Behavioral: Chronotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: M/F, 18-65 years of age Ulcerative Colitis with Inactive Disease (Mayo Score ≤ 2; partial Mayo Score ≤ 1 with endoscopic score 0-1) Subclinical inflammation (stool calprotectin >50 or CRP > 8 mg/L) Stable medications with no disease flares for the > 3 months Normal psychological evaluation and negative drug screen (See Below) Exclusion Criteria: Active UC at enrollment (Mayo > 2 and/or sigmoidoscopy score of 2 or 3) Prior ostomy or subtotal colectomy Recent prednisone or antibiotic use in last 12 weeks Use of biologic or immunomodulatory medications (i.e. Infliximab, Adalimumab, azathioprine, Vedolizumab, methotrexate, etc.) Major Depression identified as Beck Depression Inventory (score ≥14) Restless leg syndrome (score ≥ 15 on the IRLS Study Group Rating Scale) Sleep apnea (score high risk ≥ 2 or more categories on the Berlin Questionnaire) Clinically significant diabetes (Hgb-A1c>7) Regular use of medications that affect intestinal permeability, intestinal motility and/or NSAIDs, products during 4 weeks prior to the study Atypical American diet (FFQ 5-15 g fiber per day) Clinically significant cardiac, renal (creatinine > twice normal) or liver disease Alcohol use disorder (AUDIT>8) Chronic use of illicit drugs Shift Work Children under 6 months Inability to sign an informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Morning Medication Administration<br>Subjects are directed to take their medication between 06:00 and 10:00. | Behavioral: Chronotherapy<br>* Chronotherapy is a behavioral intervention that has the intended effect of maximizing therapeutic benefit of a drug by coordinating intake times and biological rhythms.<br>|
| Other: Night Medication Administration<br>Subjects are directed to take their medication between 18:00 and 22:00. | Behavioral: Chronotherapy<br>* Chronotherapy is a behavioral intervention that has the intended effect of maximizing therapeutic benefit of a drug by coordinating intake times and biological rhythms.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Stool Calprotectin from Baseline to Morning Medication Administration to Night Medication Administration | ELISA | 10 minute stool collection at Baseline, 10 minute stool collection at Morning Medication Administration, and 10 minute stool collection at Night Medication Administration | 
| Change in Mucosal 5-ASA Concentration from Baseline to Morning Medication Administration to Night Medication Administration | HPLC of tissue samples taken during flexible sigmoidoscopy at Baseline, Morning Medication Administration and Night Medication Administration | 30 minute flexible sigmoidoscopy at Baseline, 30 minute flexible sigmoidoscopy at Morning Medication Administration, and 30 minute flexible sigmoidoscopy at Night Medication Administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Intestinal Permeability from Baseline to Morning Medication Administration to Night Medication Administration | Intestinal permeability is assessed through spectrophotometric measurements of sucralose, sucrose, maltose and lactulose concentrations in urine following ingestion of a sugar cocktail. | 24 hour urine collection at baseline, 24 hour urine collection at Morning Medication Administration, and 24 hour urine collection at Night Medication Administration | 
| Change in Serum Cytokines from Baseline to Morning Medication Administration to Night Medication Administration | LBP, LPS, zonulin, and sCD14 | Single blood draw at baseline, single blood draw at Morning Medication Administration, and single blood draw at Night Medication Administration | 
| Change in Mayo Score from Baseline to Morning Medication Administration to Night Medication Administration | Mayo Score | 5 minute questionnaire at Baseline, 5 minute questionnaire at Morning Medication Administration, 5 minute questionnaire at Night Medication Administration | 
| Change in Circadian Rhythms from Baseline to Morning Medication Administration to Night Medication Administration | Wrist Actigraphy | Wrist Actigraphy Watch worn for two weeks at Baseline, two weeks at Morning Medication Administration, and two weeks at night medication administration |