Clinical trial NCT03540485: Safety and Efficacy of Melatonin in Patients with Multiple Progressive Primary Sclerosis
Official title: Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Melatonin Administration in Patients with Multiple Progressive Primary Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sclerosis, Multiple
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Autoimmune Diseases
Lead sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
Sponsor class: OTHER
First posted: 2018-05-30
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase I / II randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of melatonin administration combined with ocrelizumab in patients with Progressive Multiple Primary Sclerosis.

Detailed description: 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.

Eligibility criteria: 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..
* 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.

Primary outcomes:
measure: Rates of neurological impairment
timeFrame: 2 years
measure: Rates of disability
timeFrame: 2 years
Secondary outcomes:
measure: Number of participants with treatment-related adverse events
timeFrame: monthly from date of randomization until the end of the follow-up, assessed up to 24 months
measure: Cerebral atrophy
timeFrame: In every study visit, assessed up to 24 months
measure: Fatigue
timeFrame: In every study visit, assessed up to 24 months
measure: Quality of life using the Multiple Sclerosis International Quality of Life scale
timeFrame: In every study visit, assessed up to 24 months
measure: Sleep disorders
timeFrame: In every study visit, assessed up to 24 months
measure: Spasticity
timeFrame: In every study visit, assessed up to 24 months
Other outcomes:
measure: Efficacy of neuroinflammation
timeFrame: Day 0 and after 2 years
measure: Axonal damage
timeFrame: Day 0 and after 2 years
measure: Oxidative stress
timeFrame: Day 0 and after 2 years
measure: Impact on microbiota
timeFrame: 2 years
Locations:
city: Seville
country: Spain
facility: Virgen Macarena Hospital
city: Seville
country: Spain
facility: Virgen del Rocio University Hospital
city: Seville
country: Spain
facility: Hospital Vithas Nisa Sevilla
Study officials:
affiliation: Clinical Research and Clinical Trials Unit (Virgen del Rocío University Hospital, Seville)
name: Clara M Rosso Fernández, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Biomedicine of Seville (IBiS)
name: Antonio Carrillo Vico, PhD
role: STUDY_DIRECTOR
References: