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.

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.

Inclusion Criteria:

1. Patients should have major LARS (LARS score >29).
2. Patients should have undergone bowel continuity restoring surgery between the last 3 to 24 months.
3. Participants should be 18 years or older.
4. Participants must sign an informed consent form.

Exclusion Criteria:

1. Known allergic reaction to melatonin.
2. Dementia as determined by mini mental state examination score (MMSE) < 24.
3. Participation in another pharmacological intervention trial at the point of inclusion.
4. Completed any adjuvant oncological treatment within the last three months.
5. Ongoing oncological treatment.
6. Rotor or Dubin-Johnson syndrome, epilepsy, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Parkinson's disease, spinal cord injury and multiple sclerosis.
7. Severe liver disease defined as transaminases above 3 times the normal levels, and severe kidney disease defined as eGFR below 40 ml/min.
8. Daily ongoing hypnotic treatment.
9. Pre-existing medical sleep disorder diagnosed before the diagnosis of rectal cancer (i.e sleep apnea, restless legs, narcolepsy.)
10. Work involving nightshifts.
11. Daily alcohol consumption above 5 units of alcohol (1 unit = 12 g alcohol)
12. Predictable poor compliance (due to pre-existing psychiatric disease, dementia or not able to read or speak sufficient Danish)
13. Pregnant or breastfeeding.
14. Severe, life-threatening medical condition, that implies that the patient cannot participate in the study course. (e.g. metastatic disease, local recurrence, stroke, AMI).
15. 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.