Inclusion Criteria:

Patients who come to the Multiple Sclerosis Unit of the Department of Neurology of the Virgen Macarena University Hospital (Seville) or Vithas Nisa Seville Hospital or Virgen del Rocío University Hospital (Seville), and who meet the following criteria:

• - Have progressive primary multiple sclerosis according to McDonald's diagnostic criteria modified in 2010.

• - Age between 18 and 65 years old.

• - Neurological impairment measured with the Expanded Disability Status Scale (EDSS) scale between 2 and 7 (both included, without disability or only clinical symptoms up to ambulatory capacity with bilateral support).

• - Not having received any immunomodulatory, except for ocrelizumab in stable doses for at least 9 months before inclusion in this study, or immunosuppressive treatment (including cytostatic agents) during the 3 months prior to participation in the trial.

• - If there is a possibility of pregnancy (in women of childbearing age (15 to 44 years)) or paternity, accept the use of a highly effective method of birth control recommended by the Clinical Trial Facilitation Group (CTFG) during the treatment phase of the trial.

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• - Not having consumed melatonin or other dietary supplements (antioxidants or vitamins (tripling the recommended daily doses) during the month prior to participation in the trial.

• - Ability to give informed consent and comply with the visits scheduled in the study.

Exclusion Criteria:

• - Alternative diagnosis that explains both the neurological disability and the findings in nuclear magnetic resonance.

• - Clinically significant medical problems that, in the opinion of the investigators, may cause tissue damage in the central nervous system or limit its repair, or that may expose the patient to unjustified risks or damages, or cause the patient not to complete the study.

• - Clinical history of hypersensitivity reactions to melatonin.

• - Pregnancy or lactation, or planning to become pregnant or patients of childbearing age not subject to birth control methods (recommended by the Clinical Trial Facilitation Group (CTFG)).

• - Abnormal results in basal blood tests, defined as: - Serum levels of alanine transaminase or aspartate transaminase greater than 1.5 times the upper limit of normal values.

• - Total leukocyte count less than 3,000 / mm3.

• - Platelet count less than 85,000 / mm3.

• - Serum creatinine level greater than 2.0 mg / dL or glomerular filtration rate less than 30.

• - Neurological deterioration measured with the Expanded Disability Status Scale scale of less than 2 or greater than 7.

• - Be receiving any immunosuppressive therapy, except for ocrelizumab, including cytostatic agents.

Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system in young adults, has a huge social and health interest, especially the primary progressive (PP-) course, in which the disability is very fast accumulated and currently there are no available treatments in Spain. PP-MS is characterized by neuro-inflammation and, especially, by neurodegeneration, with brain atrophy as key feature. It has been proposed that PP-MS therapies should combine anti-inflammatory and neuroprotective activities. The investigators have shown that melatonin, an immunomodulatory, antioxidant and neuroprotective compound, ameliorates the disease and modulates the pathogenic/protective immune responses in a MS animal model. Moreover, melatonin caused a long-term improvement of disability on a PP-MS patient. Thus, melatonin could be of interest in the therapy of PP-MS. So far, ocrelizumab, recently authorized by the European Medicines Agency and incorporated into the portfolio of the Spanish National Health System in December 2018, is the only therapy that has shown some therapeutic efficacy on the decrease in long-term disability. The purpose of this study is to determine the feasibility of using melatonin combined with ocrelizumab to treat PP-MS. Thus, the investigators propose a randomized, single-blind, placebo-controlled study on the safety and efficacy of melatonin combined with ocrelizumab on PP-MS patients. The investigators will assess the daily administration to patients treated with ocrelizumab for at least 9 months of one oral dose of melatonin containing 100mg during 24 months on patients safety and its effects over brain atrophy progression, Expanded Disability Status Scale scores, quality of life, MS symptoms, circadian impairment and levels of markers of central nervous system inflammation, axonal damage, Blood-brain barrier disruption and oxidative stress.

Arms

Experimental: Melatonin

Daily administration of 100 mg of melatonin orally, for 24 months, single dose of melatonin between 10pm to 11pm

Placebo Comparator: Control

Daily administration of placebo orally, for 24 months between 10pm to 11pm

Interventions

Drug: - Melatonin

Daily administration of 100 mg of melatonin orally, for 24 months, single dose of melatonin between 10pm to 11pm

Other: - Placebo

Daily administration of placebo orally, for 24 months between 10pm to 11pm