Circadian Misalignment in Inflammatory Bowel Disease

Ulcerative Colitis Clinical Trial

Official title:

Circadian Misalignment as a Disease Risk Factor in Inflammatory Bowel Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04637399
• Other study ID #: 16080305
• Status: Completed
• Start date: November 22, 2016
• Est. completion date: November 2021

Study information

• Verified date: June 2022
• Source: Rush University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study is to explore the role the sleep/wake cycle (Circadian Rhythm) has on Inflammatory Bowel Disease. Participants will be asked to attend two clinic visits 14 days apart. Participants will complete a packet of questionnaires regarding their health and sleep habits. Over the 14 days between visits participants will be asked to wear a wrist actigraphy device that will measure their sleep-wake activity along with filling in a sleep diary. During the visits, participants will have a physical exam on visit 1 and on visit 2 participants will be asked to give blood, stool, and urine samples. Additionally, participants may also give sigmoid tissue samples during an optional unprepped limited flexible sigmoidoscopy procedure.

Description:

The long term goal of this Research proposal is to establish that circadian misalignment is a factor for disease flare in inflammatory bowel disease (IBD). In order to achieve this goal this project will focus on two aspects that are critical to address in the management of IBD

• disease course and subclinical inflammation. One of the most challenging aspects of IBD medical care is that IBD has a very heterogeneous disease course. Some patients will quickly progress to surgery despite aggressive medical therapy while others have no disease flares on any medications. In order to address these factors, the investigator will access multiple factors about each IBD patient to determine what their previous disease course has been (history), known factors of their disease that are associated with disease course (location, age of diagnosis, etc), and markers of subclinical inflammation that are established predictors of disease flare. Our overall hypothesis is that circadian misalignment is an important factor in the disease course in IBD. To test this hypothesis, the investigator will conduct a series of experiments in humans to elucidate the role of circadian rhythms in IBD. In Aim 1, the investigator will test the hypothesis that circadian misalignment is present in IBD with an aggressive disease course by analyzing circadian rhythms by wrist actigraphy, urinary melatonin, and chronotype questionnaires. In Aim 2, the investigator will assess markers of subclinical inflammation in the same subjects from Aim1, and analyze established predictors of disease flare such as CRP, intestinal permeability, fecal calprotectin, and mucosal inflammation markers. The goal of this research proposal is to identify whether circadian misalignment is a factor in disease course in IBD. It is not to determine if IBD patients have increased circadian misalignment compared to healthy controls, therefore healthy controls are not used as a comparison group. However, Dr. Burgess and Dr. Levi's labs do have a large historical cohort of over 100 healthy controls that have completed wrist actigraphy measurements and chronotype questionnaires that can be used as a comparison if our hypothesis is proven incorrect.

Experimental Design: Subjects with biopsy proven IBD (N=68) will be recruited, 24 CD (Crohn's Disease) and 24 UC (Ulcerative Colitis). All subjects will be between 18-70 years old. Subjects will be recruited from the Rush University GI Clinic. All subjects will complete questionnaires including IBD demographic history, an IBD quality of life, food timing, sleep questionnaires - PROMIS and RUSATED, and chronotype questionnaires - Owl and Lark and Munich. Each subject will be accessed by the PI for exclusion criteria including: 1) Active IBD (HBI ≥ 5 or Modified HBI ≥5); 2) Major depression (score ≥ 15 or any endorsement of suicidal intent on the Beck Depression; 3) Sleep apnea (score high risk ≥ 2 or more categories on the Berlin Questionnaire)(43); 4) Restless leg syndrome (score ≥ 15 on the IRLS Study Group Rating Scale(44)); 5) Regular use of medications that affect intestinal permeability, and/or endogenous melatonin including metoclopramide, NSAIDs, beta blocker, psychotropic medication, hypnotics and exogenous melatonin products during 4 weeks prior to the study; 6) People who have worked night shifts or crossed more than 2 time zones in the previous month; 7) Any major organ disease - renal impairment (creatinine>1.2 mg/dL - previous EMR labs must be within the past 12 months), diabetes (Hgb-A1c > 6.5% - no history of any form of diabetes); liver disease (LFTs > 1.5x nl - previous EMR labs must be within the past 12 months), or significant cardiac problems; 8) Inability to sign an informed consent.

Subjects that meet these inclusion/exclusion criteria will be assessed by the PI, who will perform a physical exam, take a history, and review prior medical testing. Subjects will matched 1:1 during recruitment so N=12 in both CD and UC with aggressive disease and N=12 in both CD and UC with nonaggressive disease (See Experimental Design). All subjects will then have their sleep patterns recorded by wrist actigraphy (30 sec epochs, Actiwatch Spectrum, Phillips Inc.) for 14 days (±3 days). Wrist actigraphy is a reliable standard means of assessing sleep-wake activity,(45) and will be used to calculate circadian rhythm by dichotomy index and r24. During the 14days (±3 days) subjects will also keep a detailed consensus sleep diary which is a standardized prospective sleep measure.(46) At the end of the 14 days (±3 days), and a day prior to their visit, all subjects will complete an online self-administered 24 hour food recall (ASA24) and 24 h urine collection for urinary melatonin which is also a marker of central circadian rhythm.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: November 2021
• Est. primary completion date: November 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Age of Diagnosis is < 40 years

• Documented biopsy proven Crohn's Disease or Ulcerative Colitis

• Willing to sign study consent form

• At starting and during the study subject is free of prescription and over the counter medication that can affect melatonin over the past month: over the counter melatonin formulation, NSAID, alpha blocker, beta blocker, calcium channel blocker, benzodiazepine, hypnotic, barbiturate, antiepileptic, antidepressant, antipsychotic, metoclopramide

Exclusion Criteria:

• Active IBD flare (HBI=5)

• Use of prednisone in the past 4 weeks

• Other forms of colitis, such as indeterminate colitis

• Moderate/severe depression or suicidal thoughts

• Restless leg syndrome

• Sleep apnea

• Surgical history of ileostomy or colectomy with ileal pouch

• Antibiotic use within the last 14 days prior to stool collection

• Active or recent infection in the last 14 days prior to stool collection

• Abnormal bleeding parameters (i.e., prolonged INR), history of easy bruising or bleeding (except rectal bleeding during flare-ups)

• Psychiatric disorder (diagnosis reported or EMR)

• Use of anticoagulants and anti-platelet drugs

• Documented chronic disease (history or current) such as diabetes, lung, heart, eye, autoimmune, seizures, kidney (creatinine >1.2 mg/dL in last 12 months),or liver (AST/ALT >1.5x ULN in last 12 months)

• Night shift work (3 or more nights/week) or more than 2 time zones crossed in past 4 weeks

• Any children <2 years old living at home

• WOMEN ONLY: Currently pregnant

• Non-English speaking

• Participating in other research studies involving research interventions

Related Conditions & MeSH terms

• Crohn Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Ulcerative Colitis

Locations

Country	Name	City	State
United States	Rush University Medical Center	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Rush University Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (46)

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* Note: There are 46 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Harvey Bradshaw Activity Index	Disease Activity: Score 0-4	1 Day
Primary	Beck's Depression Index	Score: 0-14	Past Two Weeks from Date of Visit
Primary	International Restless Leg Syndrome Scale	Score 0-14	Past Week from Date of Visit
Primary	Berlin OSA Questionnaire	Meet 0-1 Category	Past 3 Months
Primary	Short Inflammatory Bowel Disease Questionnaire	Score: 1-7	Past Two Weeks from Date of Visit
Primary	Munich Chronotype Questionnaire	Typical Sleep and Wake Habits	Past 3 Months
Primary	Owl and Lark Questionnaire	Extreme morning type 70-86 Moderately morning type 59-69 Neutral type 42-58 Moderately evening type 31-41 Extreme evening type 16-30	Past 3 Months
Primary	ActiWatch	Sleep-Wake Activity Wrist Monitor	14 Day Period
Primary	Food Timing Questionnaire	Food and Sleep Habit Diary	14 Day Period
Primary	Sleep Diary	Sleep Record	14 Day Period
Secondary	Urine Samples	Volume: First 5 hours, Second 19 hours, 24 hours	1 Day
Secondary	C-Reactive Protein	milligrams per deciliter	10 Weeks +/- 3 Days
Secondary	Left Sided Colon Tissue Samples	10 Double Bites with Forceps	1 Day

External Links

•   Randomised clinical trial: Deep remission in biologic and immunomodulator naïve patients with crohn's disease - a SONIC post hoc analysis. - PubMed - NCBI [homepage on the Internet]. [cited 6/9/2016].