Pilot Trial of Domperidone in Relapsing-Remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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The first major objective of this pilot trial is to demonstrate that it is possible to study myelin repair in relapsing-remitting multiple sclerosis (RRMS) patients with enhancing lesions on MRI by using advanced imaging techniques. To demonstrate that this is possible the investigators will recruit 24 RRMS patients who are being treated with standard disease modifying therapy (DMT) and have new lesions identified on clinically indicated brain MRI scans and measure myelin repair at 16 and 32 weeks using MRI measures of myelin repair. The second major objective is to determine how much repair occurs in participants treated with domperidone compared with those who are not treated. This will allow us to design larger trials to confirm that domperidone improves repair. The study will also confirm the safety and tolerability of domperidone in RRMS, determine circulating prolactin levels during dosing with domperidone 10mg three times daily in people with RRMS, and explore the impact of other clinical factors (such as age) on lesion repair. In addition, blood will be collected to test for metabolomics and the investigators will bank blood for future study of biomarkers that can help the investigators better understand MS. Metabolomics is an experimental test where changes in the pattern of the chemicals in blood cells are compared at different time points (during and after inflammation). There will be random changes but changes that are common in most study participants may help identify chemicals that signal stages in injury or repair. The investigators will also compare the pattern of change in those with the best repair to those with the worst repair. This may help identify a chemical that is associated with better or worse repair and help develop new treatment strategies. There are currently no blood tests that help in the diagnosis of MS, help determine which drug a person will respond to, or help determine a person's expected MS outcome. Any such tests would be considered biomarkers.

Detailed Description
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Primary Objectives: To demonstrate that the investigators can recruit DMT treated RRMS patients who have breakthrough enhancing lesions identified on clinically indicated monitoring brain MRI scans and measure lesion repair over 32 weeks. To obtain estimates of the magnitude and variability of lesion repair in DMT treated RRMS patients who are taking add-on domperidone, or no add-on treatment. The investigators will evaluate three MRI measures [texture analysis, diffusion tensor imaging (DTI), and magnetization transfer imaging (MTI)] for their ability to measure repair within acute enhancing lesions in RRMS. They will also evaluate repair at 16 and 32 weeks. These outcomes will aid in the development of future trials. No therapies have yet been shown to improve lesion repair, and there is no accepted trial model to evaluate lesion repair in humans. Therefore, the investigators anticipate that the data from this trial will inform the design of future phase 2 trials of therapies to promote lesion repair in MS. Secondary Objectives: To determine the safety and tolerability of domperidone in RRMS To determine serum prolactin levels during dosing with domperidone 10mg tid in this population To explore metabolomic profiling during lesion repair. To explore the impact of the following variables on lesion repair: prolactin level at 6 weeks, concurrent use of each type of DMT, Vitamin D and B12 levels at baseline, patient clinical characteristics (MS duration, EDSS), imaging characteristics (T2 lesion volume, enhancing lesion volume), patient demographics and behaviours (age, sex, smoking status).

Official Title
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Randomized, Controlled Pilot Trial of Domperidone in Relapsing-Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Domperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be between age 18 and 60 years. Sexually active men and women of child-bearing potential, defined as those who are not postmenopausal (24 consecutive months) or permanently sterilised, must agree to use adequate contraception. Adequate contraception is defined as methods of birth control which result in a low failure rate [i.e. less than 1% per year] when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), barrier contraceptives, sexual abstinence or vasectomised partner. Adequate contraception is required during domperidone treatment and for one month after stopping treatment. Participants must have MS defined according to the McDonald criteria (Polman et al. 2011). Participants must have RRMS according to Lublin et al. (2014). Participants must have been treated with a stable approved dose of glatiramer acetate, interferon-beta, fingolimod, dimethyl fumarate, or teriflunomide for at least 6 months. Participants must be scheduled to have a clinically indicated brain MRI to monitor DMT effectiveness. Participants must have at least one gadolinium enhancing lesion on their DMT monitoring MRI (screening MRI). Participants must report at least 80% adherence to their current DMT and have had no treatment discontinuation for one week or longer within the prior 6 months. Participants must be patients of the Calgary MS Clinic. Participants must provide written informed consent Exclusion Criteria: Participants who are pregnant or breastfeeding Participants in whom it is expected that their current DMT will be discontinued within 16 weeks. Indicators of likely discontinuation will include poor DMT tolerance, a wish by the participant to discontinue the DMT, or a history of poor clinical response to the current DMT (such as a relapse within the previous year while on the current DMT) Participants who have a long QT interval, defined as corrected QT interval of more than 470 msec in men and more than 450 msec in women, on screening ECG. Participants with known long-QT syndrome or known cardiac arrhythmia. Participants who currently or previously have been treated with natalizumab. Participants who are currently treated with domperidone or have taken it within the previous 3 months. Participants who are taking drugs which prolong QT intervals or who are treated with drugs that inhibit cytochrome P450 3A4. Participants who are concurrently treated with drugs that may increase serum prolactin levels. Participants who have a prolactinoma Participants who use systemic corticosteroids within the 8 weeks prior to the screening MRI or who use concurrent immunosuppressive medications including systemic corticosteroids. Participants who have a history of breast cancer or breast carcinoma in situ or who have clinically significant depression, renal, hepatic, cardiovascular, respiratory, metabolic, ophthalmologic, cerebrovascular, or other serious physical disease. Participants in whom gastrointestinal stimulation might be dangerous, i.e. gastrointestinal hemorrhage or mechanical obstruction or perforation Participants who have a known allergy or other intolerability to domperidone. Participants with serum potassium, sodium, magnesium or calcium levels outside the normal range, serum creatinine > 6 mg/100 ml or > 0.6 mmol/l), or who have any other condition or situation that in the opinion of the investigator would either put the patient at risk of worsening health if enrolled in the trial or would prevent completion of the trial. Participants who are concurrently participating in any therapeutic clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Domperidone<br>Add on oral Domperidone 10 mg, three times daily. Target dose:30mg daily. Duration: 16 weeks | Drug: Domperidone<br>* Addition of Domperidone to current Disease Modifying Therapy.<br>* Other names: domperidone maleate;|
| No Intervention: No add on treatment<br>No add on treatment. Control group | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measures of repair within enhancing T1 MRI lesions | Texture analysis, Diffusion Tensor Imaging (DTI) and Magnetization Transfer Imaging (MTI) will be used. This is a pilot study so the investigators are measuring repair at 2 time points and with 3 imaging methods to aid in the design of future studies. | up to 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of adverse events over the 16 week treatment period. | Adverse events will be collected at all visits and by telephone if an encounter occurs. Clinical outcomes are not sufficiently sensitive or specific to stand as measures of repair in phase 2 clinical trials that aim to screen therapies for their potential to provide neuroprotection or enhance repair. Therefore the investigators will only use clinical measures at the baseline visit to describe participants with regards to level of clinical impairment. The investigators will use the standard measure of clinical impairment, the EDSS. The baseline neurological examination and EDSS will also be used to confirm the occurrence of a relapse. A relapse that occurs during the treatment period in a participant on domperidone will be considered an adverse event. Enhancing lesions on MRI after baseline will also be considered adverse events. | at 6 and 16 weeks | 
| Serum Prolactin Levels at both 6 and 16 weeks | To determine how much domperidone 10mg three times daily increases serum prolactin levels in this MS population over time. The investigators will also explore the relationship between prolactin level and repair. | at 6 and 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Domperidone, Relapsing-Remitting MS, Demyelinating disease, Remyelination