Safety and Tolerability of Quetiapine in Multiple Sclerosis
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|ClinicalTrials.gov Identifier: NCT02087631|
Recruitment Status : Completed
First Posted : March 14, 2014
Last Update Posted : October 9, 2019
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.
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.
|Condition or disease||Intervention/treatment||Phase|
|Multiple Sclerosis||Drug: Extended-release quetiapine fumarate||Phase 1 Phase 2|
Hide Detailed Description
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.
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
- 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.
- 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.
- Extrapyramidal Symptom Rating Scale (ESRS) Neurological assessment of four extrapyramidal abnormalities: dystonia, dyskinesia, parkinsonism, akathisia, as well as subjective extrapyramidal symptoms
- 9-hole Peg Test (9-HPT) Timed test of arm/hand function
- Timed 25-Foot Walk (T25-FW) Timed test of ambulation
- Symbol Digit Modalities Test (SDMT) Timed test of cognitive processing speed and working memory
- Epworth Sleepiness Scale (ESS) 8 self-report items measuring sleepiness
- Modified Fatigue Impact Scale (MFIS) 21 self-report items measuring fatigue
- Athens Insomnia Scale (AIS) 8 self-report items measuring insomnia
- Center for Epidemiologic Studies Depression Scale (CES-D) 20 self-report items measuring depression
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||14 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Dose-finding, Safety and Tolerability Trial of Extended-release Quetiapine in Relapsing-remitting and Progressive Multiple Sclerosis|
|Actual Study Start Date :||December 2014|
|Actual Primary Completion Date :||July 2019|
|Actual Study Completion Date :||July 2019|
Extended-release quetiapine fumarate up to 300mg once daily for 4 weeks
Drug: Extended-release quetiapine fumarate
Dosing schedule for RRMS: Group 1: 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: 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: 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 Dosing schedule for progressive MS: Group 1: Day 1-14: 50 mg Day 15-28: 100 mg Day 29-30: 50mg; Group 2: 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: 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
Other Name: Seroquel XR
- Dose-limiting toxicity [ Time Frame: 4 weeks ]The primary outcome is the occurrence of dose-limiting toxicity (DLT). Dose-limiting toxicity for any patient in this study is defined as early discontinuation of quetiapine XR due to an adverse event (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 by the week 4 visit.
- Adverse events [ Time Frame: 4 weeks ]Secondary objectives are to determine treatment safety and tolerance. This will be determined by adverse event reporting; by measuring the impact of treatment on sleep, fatigue, and depression using validated patient report scales; by determining the occurrence of extrapyramidal function by using the extrapyramidal symptom rating scale; and by measuring the impact on cognition by means of the symbol digit modality test.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02087631
|MS Clinic, Foothills Medical Centre|
|Calgary, Alberta, Canada, T2N 2T9|
|Principal Investigator:||Luanne M Metz, MD,FRCPC||University of Calgary|