Comorbidity and Clinical Trials of Disease-Modifying Therapies in Multiple Sclerosis

Lead Investigator: Amber Salter, University of Texas Southwestern Medical Center
Title of Proposal Research: Comorbidity and Clinical Trials of Disease-Modifying Therapies in Multiple Sclerosis
Vivli Data Request: 7606
Funding Source: Department of Defense
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Multiple sclerosis (MS) is a chronic disease where the immune system attacks the brain and spinal cord. It is estimated that 2.8 million people live with MS worldwide. People living with MS often have co-existing (comorbid) health conditions. Examples include depression, anxiety and high blood pressure. Prior studies suggested that these co-existing conditions may affect the severity of MS. For example, relapses may occur more often, and disability may worsen more quickly. However, findings from these studies have differed. We recently got data from a clinical trial comparing two MS treatments, the CombiRx trial. We used these data to see if we could use clinical trial data to look at how co-existing health conditions affect disease activity in MS. We found that the clinical trial worked very well to answer this question. Also, we found that high cholesterol and anxiety were associated with an increased risk of relapse. In this study we will look at data from multiple, completed clinical trials to look at how co-existing health conditions affect disease activity and progression in MS. By using consistent methods and combining the results across studies we can much more confident about our findings.

The study will use existing data collected from multiple clinical trials designed to test how well disease-modifying therapies (DMT) work in MS. In clinical trials, data are collected carefully, at regular intervals, and in large numbers of people. We will use these data to find out if co-existing conditions affect how likely it is for someone with MS to have a relapse, develop worsening disability or new lesions on brain magnetic resonance imaging (MRI), all considered measures of disease activity. We will also use these data to find out if having a comorbid condition affects how well a DMT therapy works. For example, does having diabetes in addition to MS make a DMT work less well? We hope that this information will help people with MS and their clinicians make more informed and personalized decisions about treatment.

The information gained from this study has the potential to greatly advance MS care. Our findings will provide a better understanding of the effect of specific comorbid conditions on disease activity, and how well DMTs work in MS persons with these conditions. When we finish this study, this information could help clinicians and people with relapsing MS to make better decisions about their care by helping them to consider all of their health conditions in their decisions. The study will raise awareness and encourage clinicians to take a more holistic approach to treating MS and these other conditions.

Statistical Analysis Plan:

We propose to conduct a two-stage individual patient data meta-analysis. This will involve conducting analyses in a series of clinical trials, then pooling the effect measures across clinical trials using random-effects meta-analysis. The criteria for studies included were that the studies be randomized, controlled, Phase III clinical trials used to establish the efficacy of several DMTs in MS. We aim to perform these analyses including additional studies beyond those requested in this proposal and the list of other studies are in the full Statistical Analysis Plan. Due to the differing restrictions of how these trials are accessed, we will harmonize studies and conduct standardized analyses to estimate summary statistics to then be exported and used in the meta-analysis. Data analyses will be conducted in SASv9.4 for all clinical trials and the meta-analyses.

To ensure consistency of our approach across studies, and that the findings can be meta-analyzed across studies we will follow the Maelstrom retrospective harmonization guidelines. The steps include (i) assembling the studies of interest; (ii) documenting individual study designs, methods and contents; (iii) define the variables of interest and evaluate their harmonization potential; (iv) determine potential for harmonization and study specific items needed; (v) process study-specific data items using a common format to generate harmonized datasets with the required variables as delineated in C1; (vi) assess the quality of the harmonized datasets generated (missing data, missing variables, confirmation of participant characteristics match those reported in clinical trials thereby ensuring correct interpretation of dataset); (vii) conduct the analysis.
All time points available will be used to determine the endpoints. The primary endpoint is no evidence of disease activity (NEDA) based on relapses, sustained disability worsening, MRI changes. Sustained disability worsening will be defined as a 1-point increase in the Expanded Disability Status Scale (EDSS) if the baseline EDSS was ≤5.0 and half point increase in the EDSS if the baseline EDSS was 5.5, sustained for 6 months. The secondary endpoints are annualized relapse rate, sustained disability worsening (sustained for 3 or 6 months), change in T2 lesion volume and annualized combined unique active lesions (sum of the number of new enhancing lesions, new non-enhancing T2 lesions, and enlarged non-enhancing T2 lesions observed after enrollment). Tertiary endpoints will be time to relapse and annualized number of new enhancing lesions. All subjects from placebo-controlled, Phase III clinical trials will be included in the analysis. Comorbidity will be classified in the following ways: (i) any; (ii) a count (0, 1, 2, ≥3); and as (iii) individual comorbidities with the priority conditions being depression, anxiety disorders, hypertension, dyslipidemia, diabetes, migraine, chronic lung disease.
For each clinical trial, we will report the prevalence of comorbidity at enrollment overall, at the end of years 1 and 2 (and 3 where applicable); 95% confidence intervals (95%CI) will be reported based on the binomial distribution. We will report prevalence ratios and 95%CI for the comparison of comorbidity status across groups.
The association between comorbidity and no evidence of disease activity, and the secondary outcome of sustained disability worsening will be examined using a Cox proportional hazards model and the hazard ratio and 95%CI will be reported. Negative binomial regression model with generalized estimating equations, with exchangeable correlation coefficient will be used for secondary outcomes of annualized relapse rate, annualized number of new enhancing lesions, change in T2 lesion volume and annualized number of new enhancing lesions. Univariate and multivariable models will be conducted and include the following covariates: DMT (yes vs. no), age at enrollment (continuous), gender (females as reference group), race (White as reference group), body mass index (categorized as <18.5, underweight; 18.5-24.9, normal [reference]; 25.0-29.9, overweight; ≥30, obese), smoking status. In sensitivity analyses, we will include the number of relapses in the 12 months prior to enrollment. Model assumptions will be tested using standard methods. We will be conducting multiple analyses, thus we will employ a false discovery rate correction (FDR = 0.10) for secondary analyses. We will combine findings across clinical trials using random-effects meta-analysis using the Der-Simonian and Laird estimator. The heterogeneity of findings across studies will be assessed using the I2 statistic.

Requested Studies:

A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate the Efficacy and Safety of Ocrelizumab in Comparison to Interferon Beta-1a (Rebif®) in Patients With Relapsing Multiple Sclerosis
Data Contributor: Roche
Study ID: NCT01247324
Sponsor ID: WA21092

A Randomized, Double-Blind, Double-Dummy, Parallel-Group Study To Evaluate the Efficacy and Safety of Ocrelizumab in Comparison to Interferon Beta-1a (Rebif) in Patients With Relapsing Multiple Sclerosis
Data Contributor: Roche
Study ID: NCT01412333
Sponsor ID: WA21093

A Phase III, Multicentre, Randomized, Parallel-group, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis
Data Contributor: Roche
Study ID: NCT01194570
Sponsor ID: WA25046

Public Disclosures:

A. Salter, S. Lancia, K. Kowalec, K. Fitzgerald, R. A. Marie. O107/355 Prevalence of Comorbidities in Phase III Clinical Trials for Disease-Modifying Therapies in Multiple Sclerosis. MSMilan2023 – Oral Presentations. Multiple Sclerosis Journal, vol. 29 no. 3_suppl. Pp 4-136. Page 82. Doi: 10.1177/13524585231196191