Study of the effects of melatonin supplementation on clinical status and metabolic profiles in patients with rheumatoid arthritis

Objective: The aim of this study is to determine the effects of melatonin supplementation on clinical status and metabolic profiles in patients with rheumatoid arthritis.

Study design: randomized double-blind placebo-controlled trial. Patients will be assigned into two groups to receive melatonin supplement (n=33) or placebo (n=33).

Among patients with rheumatoid arthritis referred to Beheshti Clinic, 66 patients will be selected according to inclusion and exclusion criteria. Participants, investigators or the assessors of the outcomes are unaware of the study groups. Supplements and placebos are similar in shape and size. Fasting blood samples will be taken at baseline and end of the intervention. intervention: 12 weeks.

Inclusion criteria: patients with rheumatoid arthritis.; aged 20 to 80 years. Exclusion criteria: Patients with infectious, malignant and other inflammatory diseases, those taking melatonin supplements or antioxidant supplements within 3 months prior to enrollment in the study, the night shift workers, subjects taking antibiotics medications, patients with thyroid diseases, current smokers, rheumatoid arthritis patients who were diagnosed less than 1 year before the start of the study, and unwillingness to cooperate

Intervention group: 6 mg/day Melatonin (RAZAK, Iran), one hour before bedtime for 12 weeks. Control group: Placebo (Barij Essence, Iran), one hour before bedtime for 12 weeks.

Outcomes: DAS28, serum CRP and ESR (primary outcomes) and metabolic profiles, biomarkers of oxidative damage (secondary outcomes) will be quantified at study baseline and end-of-trial.

The updating process was done before publishing the paper to correct the registration information. After the initial registration of IRCT and before the start of the study and before patients recruitment, according to the project investigators, it was decided that criteria such as smoking or thyroid disease that can play a role in the rate of metabolism or exacerbation of rheumatoid arthritis should be added to exclusion criteria. Also, given that it is difficult to differentiate rheumatoid arthritis from other similar diseases at the onset of the RA because the initial manifestations may not be typical (polyarticular involvement), it was decided to exclude patients who have been diagnosed over the past year before the start of the study. In addition, since a large proportion of patients with rheumatoid arthritis mention the use of anti-inflammatory drugs such as NSAIDs in their history and the removal of a drug from the patient's drugs is not ethically correct. Also, if the patients currently using NSAIDs were excluded from the study, we lost a large part of the available samples. To solve the mentioned issue it was decided that patients in the two arms of the study be compared statistically at the end of the study in terms of drugs associated with RA to find out that is it a significant differences between the two groups or not. Regarding updating of some outcomes, before the patients entered the study, it was decided that since the clinical signs in patients with rheumatoid arthritis are very important in the diagnosis, a criterion for the severity of the disease, which includes clinical examinations of 28 important joints in this disease (DAS28-ESR) should also be included in the main outcomes, and since the ESR was required to calculate it, this variable was also added. Unfortunately, in the case of CRP, the goal was to measure quantitatively (hs-CRP) at first, but due to an error and lack of coordination with the laboratory, patients' CRP was measured qualitatively and when the investigators realized this error, it was not possible to correct it. As a result, CRP of all patients was measured qualitatively. Also in the case of LDL, since other items in the patients' lipid profile were to be measured, LDL, which was omitted in the initial recording, was added.

Patients will be randomly assigned into two groups. A randomization list will be generated from 1 to 66 by a random number generator (https://stattrek.com/statistics/random-number-generator.aspx) and patients were randomly assigned into each intervention group by their numbers. The block randomization technique with 1:1 ratio will be used to achieve balanced group sizes. Supplements and placebos are in the same packaging at the Pharmaceutical company. Only the code is written on the packages. Patients and researchers do not know the type of intervention and after analyzing the data, packet codes are decoded.

Participants, investigators or the assessors of the outcomes are unaware of the study groups.