CogEx Trial Questions Efficacy of Cognitive Rehabilitation and Exercise for Progressive MS


A recent study conducted across 11 centers globally challenged the assumption that cognitive rehabilitation and exercise synergistically benefit patients with progressive multiple sclerosis.

Anthony Feinstein, MPhil, PhD, FRCP, a professor of psychiatry at the University of Toronto

Anthony Feinstein, MPhil, PhD, FRCP

Newly published The Lancet Neurology, findings from the randomized, sham controlled CogEx trial (NCT03679468) showed the combination of cognitive rehabilitation and exercise did not improve processing speed among patients with progressive multiple sclerosis (MS). Investigators concluded that studies comparing interventions with a nonintervention group are needed to evaluate whether clinically meaningful improvements in processing speed through this approach might be attainable in patients with progressive MS.1

Among 311 patients with progressive MS, the least squares mean group differences in Symbol Digit modalities Tests (SDMT) showed no differences between groups at 12 weeks (P = .85). In comparison with the sham cognitive rehabilitation and sham exercise group (n = 67), the observed differences were -1.30 (95% CI, -3.75 to 1.16) for the cognitive rehabilitation plus exercise group (n = 70). At the same time, differences were –2.78 (-5.23 to –0.33) for the sham cognitive rehabilitation plus exercise group (n = 71), and –0.71 (-3.11 to 1.70) for the cognitive rehabilitation plus sham exercise group (n = 76).

Clinical Takeaways

  • The CogEx trial challenges the conventional belief in the synergistic benefits of cognitive rehabilitation and exercise, highlighting the need for reevaluation and more nuanced approaches for patients with progressive MS.
  • Unexpected positive outcomes in the sham exercise group underscore the complexity of addressing cognitive decline in MS, emphasizing the importance of tailored interventions.
  • Despite challenges posed by the COVID-19 pandemic, the CogEx trial persevered, providing valuable insights into the limitations of current interventions and the necessity for individualized approaches in the realm of progressive MS research.

“The results failed to support the central hypothesis that cognitive rehabilitation and aerobic exercise would have a synergistically beneficial effect on processing speed. Indeed, the primary outcome did not differ across the 4 treatment arms, a result attributed to the sham exercise turning out to be an active intervention. Designed to avoid stressing the cardiovascular system, the stretching and balance exercises led to an unexpected improvement in the 6-minute walk test, a secondary outcome measure,“ lead author Anthony Feinstein, MPhil, PhD, FRCP, a professor of psychiatry at the University of Toronto, wrote in a supplemental editorial.2

CogEx was completed in 11 hospital clinics, universities, and rehabilitation centers in Belgium, Canada, Denmark, Italy, UK, and USA. Between December 14, 2018, and April 2, 2022, patients with progressive MS (men, n = 117 [38%] and women, n = 194 [62%]) were enrolled and 284 (91%) completed the 12-week assessment. The patients were eligible if they were between 25-65 years of age and had a score of less than 7 on the Expanded Disability Status Scale (EDSS). All participants had impaired processing speed defined as a performance of 1.282 SD or greater below normative data on the SDMT. In the study, the participants were randomly assigned 1:1:1:1 to cognitive rehabilitation plus exercise, cognitive rehabilitation plus sham exercise, exercise plus sham cognitive rehabilitation, or sham exercise plus sham cognitive rehabilitation.

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Participants completed their intervention 2 times per week during the duration of the study period. The investigators noted that cognitive rehabilitation used an individualized, computer-based, incremental approach for the improvement of processing speed and the sham cognitive rehabilitation had provided internet training individually. In addition, the exercise intervention included individualized aerobic training using a recumbent arm-leg stepper and the sham exercise involved stretching and balance tasks without inducing cardiovascular strain. The primary outcome measure was processing speed measured by SDMT at 12 weeks and the least squares mean differences in comparison between groups using linear mixed model in all participants who had completed the assessment.

“The CogEx imaging data are still being analyzed. They will hopefully provide a mechanistic understanding of why some people with advanced MS improved cognitively, whereas others did not. It is becoming clear that a ‘one size fits all’ approach to improving cognition in people with all forms of MS misses the mark. What is needed are individually tailored interventions that derive direction from specific characteristics – demographics, symptom profiles, biomarkers of disease activity – that define the potential for positive change,” Feinstein noted in the editorial.2 “These will vary between people and are yet to be clearly defined, although a study like CogEx has the potential to begin providing clues.”

All told, 11 adverse events (AEs) possibly related to the interventions were reported by participants. In the exercise plus sham cognitive rehabilitation group, 6 patients reported pain, dizziness, and falls and 2 patients reported headache and pain in the cognitive rehabilitation plus sham exercise group. In addition, 2 patients in the cognitive rehabilitation and exercise group had increased fatigue and pain, and 1 patient in the dual sham group reported fall. Investigators noted that only 5 serious AEs, unrelated to the trial, were reported and required hospitalization. These reports included 3 patients in the cognitive rehabilitation plus sham exercise group and 1 each in the cognitive rehabilitation plus exercise group and dual sham group.

“Looking back at the CogEx trial, it would be remiss not to mention the effects of the COVID pandemic on participants, investigators and the many research assistants tasked with collecting a trove of data. The study was forced to suspend enrollment and interventions multiple times according to each country’s approach to managing an unprecedented global healthcare emergency,” Feinstein noted in the editorial.2 “Nevertheless, the study endured because all involved were aware of the unique opportunity it afforded to make a difference to the lives of people with progressive MS, many of whom had despaired of what they saw as the MS therapeutic bandwagon bypassing them in favor of those with relapsing-remitting forms of the disease.”

1. Feinstein A, Amato MP, Brichetto G, et al. Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial. Lancet Neurol. 2023;22(10):912-924. doi:10.1016/S1474-4422(23)00280-6
2. Feinstein A. The CogEx trial - Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis: A randomised, blinded, sham-controlled trial. Mult Scler. 2023;29(13):1523-1525. doi:10.1177/13524585231210178
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