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Trial record 6 of 7 for:    RORA

Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

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ClinicalTrials.gov Identifier: NCT03955510
Recruitment Status : Recruiting
First Posted : May 20, 2019
Last Update Posted : May 27, 2019
Sponsor:
Information provided by (Responsible Party):
Faraz Bishehsari, MD, PhD, Rush University Medical Center

Brief Summary:

The purpose of this study is to study the impact of Western lifestyle, including moderate alcohol consumption and delayed eating patterns on studying individuals' susceptibility to colorectal cancer. This study aims to increase our ability to identify individuals at risk for colorectal cancer in the future.

Each subject will experience four conditions (each for one week in duration with a week +/- 2 days wash-out in between): (1) "right-time eating" / no alcohol, (2) "right-time eating" / with alcohol, (3) "delayed-eating" / no alcohol, (4) "delayed-eating" / with alcohol. The order of experiments will be randomized [concealed randomization]. All subjects will undergo unprepped sigmoidoscopy after each week of intervention. In Aim 2, all subjects will have an option to undergo a 24h circadian assessment in the Biological Rhythms Research Lab after each week of intervention. The Investigator will assess (i) central circadian rhythms by collecting hourly salivary samples for melatonin assays and (ii) peripheral rhythm in the intestinal tract by buccal swabs once every 2h (12 time points) as well as by rectal sampling twice (every 12 hr). For Aim 3, sigmoidoscopy without sedation will be used to obtain colonic samples as the safe method compared to colonoscopy, which has some small but finite risks associated with the procedure (e.g, bleeding or perforation) as well as sedation.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Other: Right time eating Other: Delayed time eating Procedure: Sigmoidoscopy Procedure: Optional 24h circadian assessment in the Biological Rhythms lab Other: Alcohol Not Applicable

Detailed Description:
Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. CRC's risk is closely linked to the modern lifestyle. Alcohol is commonly used in our society and is an established risk factor for both pre-cancerous (polyp) and cancerous lesions of the colon. However this knowledge has not been translated to our current risk stratifications for CRC as the process of alcohol-induced carcinogenesis is not predictable. Mucosal inflammation is a well-established mechanism that mediates the effect of alcohol induced tissue injury in the intestine. Inflammation also plays a crucial role in pathogenesis of CRC. Factors that promote a pro-tumorigenic inflammatory state in the setting of alcohol are unknown. Since CRC occurs only in a small subset of alcohol user, alcohol alone may not be sufficient to start the neoplastic process and additional cofactors are required. One such factor is circadian dysrhythmia that is another modern lifestyle habit, shown to be associated with an increased risk of CRC. Further, previous research has shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. The Investigator hypothesize that altered circadian rhythms due to "wrong-time" eating (abnormal eating) are an important determinant in alcohol induced mucosal inflammation and carcinogenesis. Our preliminary data supports our hypothesis and shows that abnormal eating patterns accelerate alcohol-induced polyposis in a mouse model of CRC. Each subject will experience four conditions (each for one week in duration with a week +/- 2 days wash-out in between): (1) "right-time eating" / no alcohol, (2) "right-time eating" / with alcohol, (3) "delayed-eating" / no alcohol, (4) "delayed-eating" / with alcohol. The order of experiments will be randomized [concealed randomization]. All subjects will undergo unprepped sigmoidoscopy after each week of intervention. In Aim 2, all subjects will have an option to undergo a 24h circadian assessment in the Biological Rhythms Research Lab after each week of intervention. The Investigator will assess (i) central circadian rhythms by collecting hourly salivary samples for melatonin assays and (ii) peripheral rhythm in the intestinal tract by buccal swabs once every 2h (12 time points) as well as by rectal sampling twice (every 12 hr). For Aim 3, sigmoidoscopy without sedation will be used to obtain colonic samples as the safe method compared to colonoscopy, which has some small but finite risks associated with the procedure (e.g, bleeding or perforation) as well as sedation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : November 2022

Arm Intervention/treatment
"Right-time eating" / no alcohol Other: Right time eating
"Right-time eating" means breakfast before 8am, lunch before 1 pm and dinner before 6pm. Subjects will be asked to stick to this eating schedule for 1 week. Subjects will randomly be assigned to each eating pattern during the 8 week study period. Each subject will be required to do this intervention twice during the study period. One time they will have right time eating with alcohol , the second time the will have this intervention without alcohol.

Procedure: Sigmoidoscopy
Subjects will undergo unprepped sigmoidoscopy to collect tissue and stool sample at each intervention visits (visit 2, 3, 4, and 5). Flexible sigmoidoscopy will not require any colon cleansing and it will be very limited to the most distal (closest to the end of the anus) 20 centimeters (approximately 8 inches) of the colon and thus will be far less uncomfortable than the routine flexible sigmoidoscopy.

Procedure: Optional 24h circadian assessment in the Biological Rhythms lab

Subjects may choose to participate in the 24 hour circadian assessment in the Biological Rhythms Research Lab. During this assessment, a saliva sample will be taken every hour, a mouth swab will be done every 2 hours, and rectal swab will be done twice (every 12 hours). Subjects will be kept awake in dim light on a recliner chair. Subjects can watch a television with dimmed light. Subjects will be provided with food and drink during the assessment.

If subjects choose this intervention they will be asked to complete 4 assessment during the course of the study period.


"Right-time eating" / with alcohol Other: Right time eating
"Right-time eating" means breakfast before 8am, lunch before 1 pm and dinner before 6pm. Subjects will be asked to stick to this eating schedule for 1 week. Subjects will randomly be assigned to each eating pattern during the 8 week study period. Each subject will be required to do this intervention twice during the study period. One time they will have right time eating with alcohol , the second time the will have this intervention without alcohol.

Procedure: Sigmoidoscopy
Subjects will undergo unprepped sigmoidoscopy to collect tissue and stool sample at each intervention visits (visit 2, 3, 4, and 5). Flexible sigmoidoscopy will not require any colon cleansing and it will be very limited to the most distal (closest to the end of the anus) 20 centimeters (approximately 8 inches) of the colon and thus will be far less uncomfortable than the routine flexible sigmoidoscopy.

Procedure: Optional 24h circadian assessment in the Biological Rhythms lab

Subjects may choose to participate in the 24 hour circadian assessment in the Biological Rhythms Research Lab. During this assessment, a saliva sample will be taken every hour, a mouth swab will be done every 2 hours, and rectal swab will be done twice (every 12 hours). Subjects will be kept awake in dim light on a recliner chair. Subjects can watch a television with dimmed light. Subjects will be provided with food and drink during the assessment.

If subjects choose this intervention they will be asked to complete 4 assessment during the course of the study period.


Other: Alcohol
Moderate alcohol drinking means 0.5 g/kg alcohol daily, which will be not more than 3-4 glasses of wine depending on subject's weight. Alcohol will always be consumed in the evening with food or after food (e.g., dinner). The timing of alcohol consumption will be consistent for each individual. Subjects will be provided with red wine for the 2 alcohol intervention weeks. The order of conditions will be random.

"Delayed-eating" / no alcohol Other: Delayed time eating
"Delayed-eating" means eating each meal 3 hours later than the "Right-time eating."Subjects will be asked to stick to this eating schedule for 1 week. Subjects will randomly be assigned to each eating pattern during the 8 week study period. Each subject will be required to do this intervention twice during the study period. One time they will have delayed time eating with alcohol , the second time the will have this intervention without alcohol.

Procedure: Sigmoidoscopy
Subjects will undergo unprepped sigmoidoscopy to collect tissue and stool sample at each intervention visits (visit 2, 3, 4, and 5). Flexible sigmoidoscopy will not require any colon cleansing and it will be very limited to the most distal (closest to the end of the anus) 20 centimeters (approximately 8 inches) of the colon and thus will be far less uncomfortable than the routine flexible sigmoidoscopy.

Procedure: Optional 24h circadian assessment in the Biological Rhythms lab

Subjects may choose to participate in the 24 hour circadian assessment in the Biological Rhythms Research Lab. During this assessment, a saliva sample will be taken every hour, a mouth swab will be done every 2 hours, and rectal swab will be done twice (every 12 hours). Subjects will be kept awake in dim light on a recliner chair. Subjects can watch a television with dimmed light. Subjects will be provided with food and drink during the assessment.

If subjects choose this intervention they will be asked to complete 4 assessment during the course of the study period.


"Delayed-eating" / with alcohol Other: Delayed time eating
"Delayed-eating" means eating each meal 3 hours later than the "Right-time eating."Subjects will be asked to stick to this eating schedule for 1 week. Subjects will randomly be assigned to each eating pattern during the 8 week study period. Each subject will be required to do this intervention twice during the study period. One time they will have delayed time eating with alcohol , the second time the will have this intervention without alcohol.

Procedure: Sigmoidoscopy
Subjects will undergo unprepped sigmoidoscopy to collect tissue and stool sample at each intervention visits (visit 2, 3, 4, and 5). Flexible sigmoidoscopy will not require any colon cleansing and it will be very limited to the most distal (closest to the end of the anus) 20 centimeters (approximately 8 inches) of the colon and thus will be far less uncomfortable than the routine flexible sigmoidoscopy.

Procedure: Optional 24h circadian assessment in the Biological Rhythms lab

Subjects may choose to participate in the 24 hour circadian assessment in the Biological Rhythms Research Lab. During this assessment, a saliva sample will be taken every hour, a mouth swab will be done every 2 hours, and rectal swab will be done twice (every 12 hours). Subjects will be kept awake in dim light on a recliner chair. Subjects can watch a television with dimmed light. Subjects will be provided with food and drink during the assessment.

If subjects choose this intervention they will be asked to complete 4 assessment during the course of the study period.


Other: Alcohol
Moderate alcohol drinking means 0.5 g/kg alcohol daily, which will be not more than 3-4 glasses of wine depending on subject's weight. Alcohol will always be consumed in the evening with food or after food (e.g., dinner). The timing of alcohol consumption will be consistent for each individual. Subjects will be provided with red wine for the 2 alcohol intervention weeks. The order of conditions will be random.




Primary Outcome Measures :
  1. The investigator will identify RNA seq signatures that represent field defect in colonic mucosa of susceptible host (APC mice), that promote carcinogenesis. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
    Intestinal circadian dyssynchrony induced by delayed eating, enhances alcohol-induced intestinal inflammation, and markers of colonic neoplastic process including epithelial proliferation in susceptible host.


Secondary Outcome Measures :
  1. Determine whether abnormal eating promotes alcohol-induced carcinogenesis using RNA-seq data. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
    RNA-seq data will be used to distinguish immune cells, providing an accurate inflammatory signature, confirmed by gold standard (FlowCytometery).

  2. Each subject will complete a validated food frequency questionnaire assessing dietary habits over the prior three months. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
  3. Sleep patterns will be recorded by wrist actigraphy using an Actiwach 2, or Phillips. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
  4. A 24h food recall will be completed by participants using Automated Self-Administered 24-Hour at baseline and once during each intervention. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
  5. Subjects will enter the Biological Rhythms Research Lab after each week of the intervention period for 24h for assessments of central circadian rhythms. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
    Subjects will enter the Biological Rhythms Research Lab after each week of the intervention period for 24h for assessments of central circadian rhythms (hourly salivary melatonin) and peripheral clock genes of the digestive tract from mucosal cells taken from buccal swaps once every 2h (12 time points). Extracted cells will be analyzed for expression levels of clock genes (Per2, BMAL1, Clock, Cry1, Reverb-alpha, ROR-alpha). The investigator expect delayed eating with alcohol to exhibit a phase shift in the expression of digestive tract clock genes (buccal mucosa) in relation to the central circadian rhythm assessed by the timing of melatonin rhythms relative to sleep (dim light melatonin onset, DLMO).

  6. Sigmoid mucosal biopsy specimens and stool are collected at baseline and at the end of each intervention week. [ Time Frame: Through study completion and data analysis in 3 years (2022) ]
    Individuals recruited for Aim 2 will undergo unprepped sigmoidoscopy before admission to the Biological Rhythms Research Lab (4 times).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adults (greater than 21 years old)
  2. Have had advanced tubular adenoma within the last year

Exclusion Criteria:

  1. Asian ethnicity (Due to common polymorphisms of enzymes involved in alcohol metabolism)
  2. Does not drink alcohol
  3. Alcohol use disorder/Alcohol Abuse
  4. A known genetic predisposition to colorectal cancer (FAP, Lynch syndrome)
  5. A history of colorectal cancer or inflammatory bowel diseases
  6. Presence of comorbidities that might affect the circadian system

    1. Chronic renal failure
    2. Cirrhosis
    3. Advanced neurological conditions (e.g., Parkinson's, MS, epilepsy)
    4. Psychological disorders (e.g., PTSD, major depression)
    5. Sleep apnea
    6. Restless Leg Syndrome
    7. Inpatient Status
    8. Advanced cardiac failure
    9. Night shift workers with active shift work in the past month
    10. Planned shift work that will occur during the study
    11. Crossed more than two time zones in the previous week
  7. Conditions that alter or necessitate a particular eating pattern (e.g., uncontrolled diabetes, eating disorders)
  8. Conditions that alter the microbiota (infection or recent history of antibiotic use within three months, or use of pro/prebiotics within one month prior to recruitment)
  9. Regular use of medications that can potentially affect melatonin profiles (e.g., Melatonin, Metoclopramide, Psychotropic medications, Hypnotics during the four weeks prior to the study)
  10. Any active cancer
  11. Inability to sign an informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03955510


Contacts
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Contact: Faraz Bishehsari, MD 312-563-4092 Faraz_Bishehsari@rush.edu
Contact: GI Research 312-942-3466 GI_Research@rush.edu

Locations
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United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: GI research    312-942-3466    GI_research@rush.edu   
Principal Investigator: Faraz Bishehsari, MD         
Sponsors and Collaborators
Rush University Medical Center
  Study Documents (Full-Text)

Documents provided by Faraz Bishehsari, MD, PhD, Rush University Medical Center:
Study Protocol: AFT with cover page  [PDF] March 3, 2019
Informed Consent Form  [PDF] March 3, 2019


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Responsible Party: Faraz Bishehsari, MD, PhD, Assistan Professor, Rush University Medical Center
ClinicalTrials.gov Identifier: NCT03955510     History of Changes
Other Study ID Numbers: 16051904
First Posted: May 20, 2019    Key Record Dates
Last Update Posted: May 27, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No identifying information will be shared with other researchers

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Colorectal Neoplasms
Carcinogenesis
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Ethanol
Anti-Infective Agents, Local
Anti-Infective Agents
Central Nervous System Depressants
Physiological Effects of Drugs