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
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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|
|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.
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|Ages Eligible for Study:||18 Years to 65 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
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
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|
|Responsible Party:||Dr. Luanne Metz, Professor, University of Calgary|
|Other Study ID Numbers:||
|First Posted:||March 14, 2014 Key Record Dates|
|Last Update Posted:||October 9, 2019|
|Last Verified:||October 2019|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Plan Description:||consent was not obtained from subjects so data can not be shared|
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