The Effect of Melatonin in Patients With Low Anterior Resection Syndrome

Study Overview
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Brief Summary
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The primary objective of the study is to investigate whether treatment with melatonin has an alleviating effect on Low Anterior Resection Syndrome (LARS) symptoms. Secondarily, the effect of the treatment on bowel movements, other patient reported symptoms, quality of life, depression, anxiety, sleep disturbances, motilin levels, and microscopic changes in rectal mucosa will be investigated.

Detailed Description
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This trial which will be conducted in two phases. The first part of the study will be conducted as an internal feasibility test. Three patients with major LARS will be included. Patients will be recruited from the Department of Surgery, Zealand University Hospital. These patients will not be randomized nor blinded. They will receive a 4-week treatment with 25 mg melatonin and will undergo the same questionnaires and tests before and after treatment as in the randomized clinical trial. The preliminary results from the internal feasibility test will allow us to assess potential difficulties related to the administration or design, which then will be able to be corrected before the randomization part is initiated. The second part of the will be conducted as a randomized, blinded, placebo-controlled, crossover study and will be testing whether treatment with melatonin has an alleviating effect on Low Anterior Resection Syndrome (LARS) symptoms. Patients will be randomized to receive 4 weeks of treatment with melatonin, followed by a 4 week wash out period, and then 4 weeks of treatment with placebo (M-P) or 4 weeks of treatment with placebo, followed by a 4 week wash out period, and then 4 weeks of treatment with melatonin (P-M). Both participants and investigators will be blinded. Patients will be given questionnaires before and after each treatment period to assess outcomes. Blood samples and rectal biopsies will be taken after each treatment period.

Official Title
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The Effect of Melatonin in Patients With Low Anterior Resection Syndrome

Conditions
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Low Anterior Resection Syndrome

Intervention / Treatment
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* Drug: Melatonin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients should have major LARS (LARS score >29). Patients should have undergone bowel continuity restoring surgery between the last 3 to 24 months. Participants should be 18 years or older. Participants must sign an informed consent form. Exclusion Criteria: Known allergic reaction to melatonin. Dementia as determined by mini mental state examination score (MMSE) < 24. Participation in another pharmacological intervention trial at the point of inclusion. Completed any adjuvant oncological treatment within the last three months. Ongoing oncological treatment. Rotor or Dubin-Johnson syndrome, epilepsy, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Parkinson's disease, spinal cord injury and multiple sclerosis. Severe liver disease defined as transaminases above 3 times the normal levels, and severe kidney disease defined as eGFR below 40 ml/min. Daily ongoing hypnotic treatment. Pre-existing medical sleep disorder diagnosed before the diagnosis of rectal cancer (i.e sleep apnea, restless legs, narcolepsy.) Work involving nightshifts. Daily alcohol consumption above 5 units of alcohol (1 unit = 12 g alcohol) Predictable poor compliance (due to pre-existing psychiatric disease, dementia or not able to read or speak sufficient Danish) Pregnant or breastfeeding. Severe, life-threatening medical condition, that implies that the patient cannot participate in the study course. (e.g. metastatic disease, local recurrence, stroke, AMI). Females not in menopause (defined as no menstruation during the last 12 months) should not be pregnant. Furthermore, reproductive females should use a secure birth control (intrauterine devices, hormonal contraceptives including - oral pills, patches, vaginal rings and injections) during the entire period of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melatonin-Placebo sequence<br>50% of the included patients will receive 4 weeks of treatment with melatonin, followed by a 4 week wash out period, and then 4 weeks of treatment with placebo. The treatments are blinded. | Drug: Melatonin<br>* Enema with 25 mg melatonin<br>Drug: Placebo<br>* Enema without melatonin<br>|
| Experimental: Placebo-Melatonin sequence<br>50% of the included patients will receive 4 weeks of treatment with placebo, followed by a 4 week wash out period, and then 4 weeks of treatment with melatonin. The treatments are blinded. | Drug: Melatonin<br>* Enema with 25 mg melatonin<br>Drug: Placebo<br>* Enema without melatonin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Low Anterior Resection Syndrome Score | The LARS Score questionnaire is filled out by the participants before and after each treatment period. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily bowel function | The participants will fill out a diary on the daily bowel movements during the treatment phase | 4 weeks | 
| Self-reported quality of life | EORTC Quality of Life Questionnaire for cancer patients and specifically colorectal cancer patients | 4 weeks | 
| Other patient reported symptoms | Measure Yourself Medical Outcome Profile (MYMOP) is a self-administered questionnaire. Patients are asked to specify one or two symptoms that concern them the most. Subsequently they evaluate the severity on a 7-point Likert scale. The second part of the questionnaire uses the same scale to assess whether the symptom limits or prevent any daily activity, and also to rate general well-being. Follow-up questionnaires address the original issues completed in the initial form. Symptom 1, symptom 2, activity, and wellbeing each have a separate score between 0 and 6 with 0 indicating as good as it could be and 6 as bad as it could be. An overall score is calculated by taking the average of item scores. | 4 weeks | 
| Anxiety | Hospital Anxiety and Depression Scale (HADS-A): The anxiety subscale consists of 7 questions which are graded on a 4 point scale (0-1-2-3) and is summed into a total score between 0-21. A score of 7 or lower is negative case, a score of 8 - 10 is a doubtful case, and a score of 11 or above is a positive case. | 4 weeks | 
| Depression | Hospital Anxiety and Depression Scale (HADS-D): The depression subscale consists of 7 questions which are graded on a 4 point scale (0-1-2-3) and is summed into a total score between 0-21. A score of 7 or lower is negative case, a score of 8 - 10 is a doubtful case, and a score of 11 or above is a positive case. | 4 weeks | 
| Sleep | Participants will wear an actigraph during the treatment phases and fill out a sleep diary and this will allow to asses sleep time (minutes). | 4 weeks | 
| Insomnia | Insomnia Severity Index (ISI) | 4 weeks | 
| Incidence of treatment-emergent Adverse Effects [Safety and reactions] | Participants will be systematically interviewed before and after the treatment periods. | 4 weeks | 
| Melatonin | Blood samples will be taken after each treatment ends. | 4 weeks | 
| Multiplex gene assay - NanoString nCounter® Inflammation Panel analysis in blood | Difference in gene expressions between intervention and placebo groups | 4 weeks | 
| Motilin | Blood samples will be taken after each treatment ends. | 4 weeks | 
| Pathological assessment of inflammation | Rectal biopsies will be taken after each treatment ends.The FFPE treated biopsies will be assessed by pathologist using a routine inflammatory grading system to asses inflammation | 4 weeks | 
| Multiplex gene assay - NanoString nCounter® Inflammation Panel analysis in biopsies | Difference in gene expressions between intervention and placebo groups | 4 weeks | 
| Motilin receptors | Rectal biopsies will be taken after each treatment ends. | 4 weeks |