Safety and Tolerability of Quetiapine in Multiple Sclerosis
Safety and Tolerability of Quetiapine in Multiple Sclerosis
Study Purpose:

 The purpose of this clinical trial is to determine if extended-release quetiapine in a dose
 of 300 mg daily is tolerable to people with relapsing remitting and progressive MS. The
 investigators will also determine if the investigators can increase the dose up to 300 mg
 daily within 3 days in people with relapsing remitting MS and within 2 weeks in people with
 progressive MS. The investigators will determine if at least two thirds of study participants
 tolerate the drug well enough to continue it for 4 weeks. Tolerance will be determined
 separately for people with relapsing remitting and progressive MS. People with progressive MS
 may be less tolerant of side effects because of greater underlying brain injury from MS.
 Alternatively, people with progressive MS may gain more benefit from the improved sleep that
 usually occurs with use of quetiapine or they may be more willing to tolerate some side
 effects. This clinical trial will determine the maximally tolerated dose for future trials of
 this drug.

 The number of participants in this study will depend on the tolerability at each dose tested.
 A maximum of 18 people with relapsing remitting MS and 18 people with primary or secondary
 progressive MS will be included.

 Study Design:

 The cohort expansion design (3+3) is used to determine toxicity-based dosing. This design is
 used in oncology phase I trials as it is guided by patient safety and minimizes the number of
 participants exposed to toxicity (Ivy et al. 2010). Maximum toxicity is defined as 33% or
 less. In this model, three patients will comprise the initial cohort. In the absence of DLT
 treatment may be escalated to the next higher dose in the next group of three patients.
 However, if one of three patients reaches DLT the cohort is expanded to six patients to
 verify that the toxicity rate has not exceeded or reached 33%. When the toxicity rate exceeds
 or reaches 33% in a cohort, this dose is deemed the maximum administered dose and a lower
 dose will be used in the next group of three patients. Patients with RRMS and progressive MS
 will be evaluated in separate groups using different dose schedules.
Background:

 Multiple sclerosis causes episodes of inflammation that injure or kill nerve cells and the
 cells that coat them with myelin. These episodes of inflammation may cause a relapse (attack)
 or the inflammation may only be detectable with brain MRI. Inflammatory episodes are the main
 feature of relapsing-remitting MS (RRMS). Most relapses can be prevented by current
 treatments for RRMS. This remains important because dead nerve cells cannot be replaced.

 Fortunately, there are also repair processes that can rescue injured nerve and myelin cells.
 An important aspect of repair is regeneration of the myelin forming cells. If the myelin can
 be protected or even replaced the nerves have a better chance of survival. However if injured
 myelin is not repaired or replaced the nerve cell is not protected and will likely later also
 die; this may be the underlying process that causes the progression. The investigators
 obviously need therapies in MS that do more than just reduce the frequency of relapses and
 the silent episodes of inflammation. The investigators need treatments that help repair.

 Quetiapine is a medication which has been shown to stimulate the myelin forming cells (called
 oligodendrocytes) to improve myelin repair in mice. It therefore may also improve myelin
 repair in people with MS. However, before testing the effects of quetiapine on myelin repair,
 the investigators must first determine if the medication is safe and if the dose is tolerated
 in people with MS in short-term treatment trials.

 Quetiapine is currently approved in Canada to treat several psychiatric conditions including
 depression and psychosis. It has also been shown to be useful to treat anxiety and insomnia.
 Quetiapine is available as an extended release pill that can be taken once daily. Doses up to
 800 mg per day may be used to treat some of these conditions but the investigators estimate
 that a dose of only 300 mg daily will be needed to stimulate myelin repair. It is not clear
 if the dose of 300 mg will be well tolerated by people with MS who may not need a medication
 to treat these conditions.

 Visit schedule:

 Screen period, baseline, week 1 [telephone], week 2 [telephone], week 3 [telephone], week 4,
 and week 8. Treatment with quetiapine XR will last for 4 weeks or until day 28. On day 29,
 the dose of quetiapine will be tapered by 50 mg every two days to avoid development of
 withdrawal syndrome and insomnia.

 Treatment and Dose schedule:

 Quetiapine XR dosing schedule for relapsing-remitting MS Group 1 Dose schedule Day 1-3: 50 mg
 Day 4-6: 100 mg Day 7-28: 150 mg Day 29-30: 100mg Day 31-32: 50mg Group 2 Dose schedule Day
 1-2: 50 mg Day 3-4: 150 mg Day 5-6: 200 mg Day 7-28: 300 mg Day 29-30: 250mg Day 31-32: 200mg
 Day 33-34: 150mg Day 35-36: 100mg Day 37-38: 50mg Group 3 Dose Schedule Day 1: 50 mg Day 2:
 100 mg Day 3: 200 mg Day 4-28: 300 mg Day 29-30: 250mg Day 31-32: 200mg Day 33-34: 150mg Day
 35-36: 100mg Day 37-38: 50mg Quetiapine XR dosing schedule for progressive MS Group 1 Dose
 schedule Day 1-14: 50 mg Day 15-28: 100 mg Day 29-30: 50mg Group 2 Dose schedule Day 1-5: 50
 mg Day 6-10: 100 mg Day 11-15: 150 mg Day 16-28: 200 mg Day 29-30: 150mg Day 31-32: 100mg Day
 33-34: 50mg Group 3 Dose Schedule Day 1-5: 50 mg Day 6-10: 100 mg Day 11-15: 200 mg Day
 16-28: 300 mg Day 29-30: 250mg Day 31-32: 200mg Day 33-34: 150mg Day 35-36: 100mg Day 37-38:
 50mg

 Measures:

 1. Determination of dose-limiting toxicity Dose-limiting toxicity for any patient in this
 study is defined as early discontinuation of quetiapine XR due to an AE that is
 possibly, probably or definitely due to use of study drug. Patients who discontinue
 medication due to an AE will still be kept in the trial for safety assessment at weeks 4
 and 8. Because of the small number of treated participants anyone who discontinues study
 drug for a reason or adverse event unrelated to use of the study drug will be excluded
 from the analysis and replaced. The dose-limiting toxicity will be determined for each
 group of patients: RRMS and progressive MS. The maximally tolerated dose and dose
 escalation schedule for future trials is the dose where fewer than 33% of participants
 reached dose-limiting toxicity. This will differ for each group of patients, RRMS and
 progressive MS.

 2. Scales

 1. Functional Systems (FS) and Expanded Disability Status Scale (EDSS) A score based
 on a standardized neurological examination, observation of ambulation distance (up
 to 500 metres), and questions regarding bladder, bowel and sexual function.

 2. Extrapyramidal Symptom Rating Scale (ESRS) Neurological assessment of four
 extrapyramidal abnormalities: dystonia, dyskinesia, parkinsonism, akathisia, as
 well as subjective extrapyramidal symptoms

 3. 9-hole Peg Test (9-HPT) Timed test of arm/hand function

 4. Timed 25-Foot Walk (T25-FW) Timed test of ambulation

 5. Symbol Digit Modalities Test (SDMT) Timed test of cognitive processing speed and
 working memory

 6. Epworth Sleepiness Scale (ESS) 8 self-report items measuring sleepiness

 7. Modified Fatigue Impact Scale (MFIS) 21 self-report items measuring fatigue

 8. Athens Insomnia Scale (AIS) 8 self-report items measuring insomnia

 9. Center for Epidemiologic Studies Depression Scale (CES-D) 20 self-report items
 measuring depression
Inclusion Criteria:

 -  Age 18 to 65 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 quetiapine treatment and for one
 month after stopping treatment.

 -  MS defined according to the McDonald criteria (2010; Polman et al. 2011)

 -  Progressive MS (primary progressive course, secondary progressive course, or
 progressive relapsing course) course according to Lublin and Reingold (1996).

 NOTE: No longer recruiting RRMS patients

 -  Patients currently on glatiramer acetate, interferon-beta, fingolimod (treatment
 longer than 3 months), or dimethyl fumarate as well as those on no treatment.

 -  Written informed consent

 Exclusion Criteria:

 Patients are to be excluded from enrolment if they display any of the following (current
 treatment reflects use at the time of screening and 14 days before screening):

 -  Clinically significant depression, renal, hepatic, cardiovascular, respiratory,
 metabolic, ophthalmologic, cerebrovascular, or other serious physical disease

 -  Inability to perform the 9 hole peg test and the oral SDMT at baseline

 -  Diagnosis of dementia, diabetes, or cataracts

 -  History of seizures, tardive dyskinesia, or symptomatic hypotension.

 -  Clinically significant gastrointestinal or endocrine disorder, such as pancreatitis,
 gastrointestinal obstruction, and hypothyroidism

 -  Poorly managed constipation, defined as a bowel routine that does not result in a
 bowel movement at least every other day.

 -  The presence of any circumstances that may increase the risk of occurrence of torsade
 de pointes and/or sudden death including (1) a history of cardiac arrhythmias such as
 bradycardia; (2) hypokalemia or hypomagnesaemia; (3) concomitant use of other drugs
 that prolong the QTc interval; (4) prolonged QTc at screening; and (5) presence of
 congenital prolongation of the QT interval

 -  Body Mass Index > 30 (obesity)

 -  Clinically significant abnormal laboratory values, electrocardiogram, or vital signs
 at screening or any elevation of fasting glucose

 -  Pregnant or breastfeeding women

 -  Current treatment with natalizumab

 -  Current treatment with immunosuppressive medications other than: steroids for relapses
 and the MS disease-modifying therapies mentioned in the inclusion criteria. Initiation
 of fingolimod within the previous 3 months

 -  Substances that are not permitted include current treatment with: potent CYP3A4
 inhibitors (e.g. ketoconazole, ritonavir) or potent CYP3A4 inducers (e.g. phenytoin,
 rifampin, St. John's Wort), pro- or anti-dopaminergic medications, or medications that
 produce clinically significant alterations of QTc interval.

 -  Previous or current treatment with quetiapine or any other antipsychotic

 -  Known hypersensitivity to any of the ingredients in quetiapine including lactose

 -  Inability to swallow pills without chewing or crushing

 -  Use, within the previous three months, of any experimental MS treatment

 -  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

 -  Concurrent participation in any therapeutic clinical trial