Clinical trial NCT04472975: Prescription Drug Safety and Effectiveness in Multiple Sclerosis
Official title: Disease-modifying Drug Safety and Effectiveness in Multiple Sclerosis [DRUMS]
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Multiple Sclerosis
Keywords: disease-modifying drugs
health administrative data
population-based
Canada
cohort studies
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: University of Manitoba
name: Dalhousie University
name: University of Saskatchewan
name: Alberta Health services
name: University of Alberta
First posted: 2020-07-16
Enrollment: 35000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: OTHER
Sampling method: PROBABILITY_SAMPLE
Study population: A MS cohort study (Studies 1, 2, 4-6) will be identified using a validated case definition of MS that will be applied to the whole-population linked administrative health data in five Canadian provinces spanning from west to east coast: British Columbia (BC; population 4.65 million \[2016\]), Alberta (AB; 4.07 million population \[2016\]), Saskatchewan (SK; population 1.10 million \[2016\]), Manitoba (MB; population 1.28 million \[2016\]) and Nova Scotia (NS; population 924,000 \[2016\]).

When MS-specific clinical data are used (British Columbia, Manitoba, Nova Scotia; Study 3), the diagnosis is neurologist confirmed, according to the prevailing international criteria.

Within each province, we anticipate finding virtually the whole population of people living with MS via the administrative data, and, in the clinical data, ≈60-80% or 100% of those seeking DMDs (the MS clinics are the sole prescribers of the DMDs).

Brief summary: The goal of our research is to find out how safe and effective the drugs used to treat multiple sclerosis (MS) are when used in the everyday, real world. To achieve these study goals, we have two main study Themes. The first Theme focuses on how effective the MS drugs are. We will examine whether the MS drugs can extend life expectancy or prolong a person's ability to stay mobile and walk. We will also look at whether the MS drugs have a beneficial effect on reducing the number of times a person with MS is admitted to a hospital or visits a physician. The second Theme focuses on side effects, including whether the MS drugs are associated with harmful effects, such as cancer, stroke or depression. We will be able to compare the different MS drugs to each other. Also, we will see if men and women or people of different ages and with other illnesses (such as having both MS and diabetes) respond to the MS drugs differently. Our findings will help people with MS and their physicians when trying to make decisions as to which MS drug might be best for them.

Detailed description: Study population:

A validated case definition of multiple sclerosis (MS) will be applied to the health administrative data to identify all MS patients in 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan and Alberta; Studies 1,2,4-6). Developed in Manitoba, the positive predictive value was 80.5% and negative predictive value (NPV) was 75.5% among a population of persons with ≥1 claim for any demyelinating disease. The NPV would be \>99% at the general population level where more than 98% of individuals have no claims for demyelinating disease. The algorithm has been successfully applied in British Columbia, Nova Scotia and Saskatchewan.

When MS-specific clinical data are used (British Columbia, Manitoba, Nova Scotia; Study 3), the diagnosis is neurologist confirmed, according to the prevailing international criteria.

Study period:

The earliest study start is Jan/1996 (the 1st full year that DMDs were available and the first year of available administrative and DMD-related data), and the latest study end is March 31, 2018; this represents \>2 decades of drug and patient-related follow-up.

Study entry:

Most recent of 1-Jan-1996, an individual's 18th birthday, date of 1st MS-related claim or date of 1st MS clinic visit (when clinical data are accessed \[Study 3\]).

Study end:

Earliest of death, emigration from the respective province, last MS clinic visit (when clinical data are accessed \[Study 3\]), or 31-December-2017 (British Columbia, Manitoba, Nova Scotia, Alberta) or 31-March-2018 (Saskatchewan).

DMD exposure:

DMD use, as identified using prescription data. An individual's exposure status can change over time and will be dynamically classified as: 1) no DMD, 2) any DMD, then by generation: 2a) any 1st or 2b) 2nd generation DMD. When possible, the individual drug classes will be explored (beta-interferon \[as one class\], glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, alemtuzumab).

Time perspective:

Analyses of prospectively recorded health administrative, prescription and clinical data.

Eligibility criteria: Inclusion Criteria:

* All MS patients (Studies 1, 2, 4-6) who have resided in one of the 5 Canadian provinces (British Columbia, Manitoba, Nova Scotia, Saskatchewan or Alberta) over the study period as identified using a validated case definition of MS that will be applied to health administrative data (≥ 3 records related to MS coded during physician or hospital visits, or prescription filled for a MS-specific DMDs).
* Subjects require 1 year of residency in a province before study entry to enable sufficient data to facilitate covariate creation, e.g. comorbidity, and to identify those with prior DMD use.
* All adults who visited a MS clinic in British Columbia, Manitoba or Nova Scotia (Study 3), were diagnosed with MS and had a relapsing-onset disease course and at least one EDSS score of 6.5 or less, recorded on or after: January 1st 1996 (British Columbia) or April 1st 1996 (Manitoba) or January 1st 1998 (Nova Scotia).

Primary outcomes:
measure: Study 1: All-cause hospitalizations
timeFrame: As recurrent events from study entry to study end, up to 22 years.
measure: Study 2: All-cause mortality
timeFrame: Measured using Cox proportional hazards models (time from study entry to death), up to 22 years.
measure: Study 3: Change in disability (Expanded Disability Status Scale [EDSS]) over time
timeFrame: Assessed using mixed effects model from study entry to study end, up to 22 years.
Secondary outcomes:
measure: Study 1: Physician consultation rates (overall and by physician specialty)
timeFrame: Overall numbers of physician consultations will be measured from study entry to study end, up to 22 years of follow-up.
measure: Study 3: MS disability, measured using the Expanded Disability Status Scale (EDSS) and assessed as time to sustained EDSS 6
timeFrame: Measured using Cox proportional hazards models (time from study entry to sustained EDSS 6 confirmed after at least 6 months with no subsequent improvement), up to 22 years of follow-up.
measure: Study 3: Sustained EDSS 4
timeFrame: Measured using Cox proportional hazards models (time from study entry to sustained EDSS 4), up to 22 years of follow-up.
measure: Study 4: Explore the modifying effects
timeFrame: From study entry to study end, up to 22 years of follow-up.
measure: Study 5: Potential incident adverse events
timeFrame: Time from study entry to the incident adverse event of interest will be assessed using Cox proportional hazards with time-varying DMD exposure, up to 22 years of follow-up.
measure: Study 6: Characteristics associated with risk of adverse events
timeFrame: From study entry to study end, up to 22 years of follow-up.
Other outcomes:
Locations:
Study officials:
affiliation: University of British Columbia
name: Helen Tremlett, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ng HS, Zhu F, Kingwell E, Zhao Y, Yao S, Ekuma O, Svenson LW, Evans C, Fisk JD, Marrie RA, Tremlett H. Disease-modifying drugs for multiple sclerosis and subsequent health service use. Mult Scler. 2022 Apr;28(4):583-596. doi: 10.1177/13524585211063403. Epub 2021 Dec 24.