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