Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial

Abstract

Objective: To determine whether comorbidity is associated with clinical (relapses, disability worsening) and MRI outcomes in multiple sclerosis (MS) by conducting a secondary analysis of the CombiRx clinical trial.

Methods: CombiRx compared interferon beta-1a, glatiramer acetate, and the combination of these agents. For participants eligible for evaluation of 6-month confirmed disability worsening, we used medical history, concomitant medications, and adverse events to ascertain comorbidity status. Comorbid conditions evaluated included hypertension, dyslipidemia, diabetes mellitus, depression, anxiety disorders, and migraine. Clinical outcomes included disease activity consisting of protocol-defined relapses, disability worsening, and MRI activity. We summarized the prevalence of these comorbid conditions and their association with disease activity and its components using multivariable Cox regression.

Results: Of the 1,008 participants randomized, 959 (95.1%) were eligible for assessment of 6-month disability worsening; for this subgroup, the median length of follow-up was 3.4 years (range 0.5-6.9 years). Overall, 55.1% of participants had ≥1 comorbidity at enrollment. After adjustment, anxiety (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.01-1.55) and dyslipidemia (HR 1.32, 95% CI 1.01-1.72) were associated with an increased hazard of any disease activity, while migraine (HR 0.80, 95% CI 0.67-0.97) was associated with a decreased hazard.

Conclusions: In this large trial population with rigorously obtained outcomes, comorbid conditions were common among participants and influenced disease outcomes, including relapses. The comorbidity burden of clinical trial participants with MS may be an important factor in the outcome of clinical trials. Additional investigations of the impact of comorbidity on clinical trial outcomes and response to disease-modifying therapies are warranted.

Trial registration: ClinicalTrials.gov NCT00211887.

Figure. Association of a comorbidity accounting for (A) the presence of the other comorbid conditions and (B) number of conditions with any evidence of disease activity (PD relapses) and secondary clinical outcomes

Adjusted hazard ratio for association of a comorbidity accounting for the presence of the other comorbidities (A) and number of conditions (B) with any evidence of disease activity (protocol-defined relapses) and secondary clinical outcomes. All models were adjusted for age, sex, race, body mass index, treatment status, treatment, and all comorbid conditions (in A only). When considering the number of conditions continuously, the results are consistent with the number of comorbidity categories. Hazard ratios (HRs) with 95% confidence intervals (CIs) are as follows: any disease activity (protocol defined [PD]) 1.03 (0.96–1.1), any disease activity (PD + non–protocol defined [NPD]) 1.03 (0.97–1.11), relapse (PD) 1.12 (0.99–1.27), relapse (PD + NPD) 1.15 (1.05–1.25), Expanded Disability Status Scale (EDSS) score worsening 1.00 (0.89–1.11), and combined unique activity 0.97 (0.89–1.05). LCL = lower confidence limit; UCL = upper confidence limit.