Minimal clinically important difference for the 6-min walk test: literature review and application to Morquio A syndrome

Abstract

Morquio A syndrome is an ultra-rare, inherited lysosomal storage disorder associated with progressive, multi-systemic clinical impairments, causing gradual loss of functional capacity and endurance, impaired quality of life, and early mortality. Studies in Morquio A patients have used the 6-min walk test (6MWT) to assess functionality and endurance and to evaluate disease progression or efficacy of treatment. The objective of the present study was to review minimal clinically important differences (MCIDs) for the 6MWT reported for disease states that widely use the 6MWT to evaluate clinical benefit and to discuss the results in view of the challenges in estimating MCID for ultra-rare diseases, using the case of elosulfase alfa in Morquio A patients. A systematic literature search was performed using Embase and Medline to identify studies specifically estimating the MCID using either anchor-based or distribution-based methods. A total of 19 publications on 17 studies were identified; none of these included patients with Morquio A syndrome or the wider disease category of lysosomal storage disorders. Therefore, the MCIDs determined by studies in patients with respiratory, cardiovascular, or musculoskeletal disease were compared to changes in the 6MWT seen in Morquio A patients in the pivotal phase 3 clinical trial of elosulfase alfa enzyme replacement therapy. The literature review showed a mean MCID for the 6MWT of 7% change (range 3–15%) in studies using anchor-based methods and a 9% change (range 4–16%) using distribution-based methods. Results of the elosulfase alfa clinical trial and its extension showed a placebo-adjusted 14.9% improvement in the 6MWT from baseline at week 24, which was greater than the mean MCID based on the results of the systematic literature review. After 2 years, 6MWT distance increased by a mean of 20.7% from baseline in a modified per-protocol population, versus a reduction of 6.9% in comparable untreated patients from the MorCAP natural history study over the same period. Although further research is required to establish the MCID of the 6MWT in Morquio A patients, the presented data provide further evidence for the positive effect of elosulfase alfa in this patient population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0633-1) contains supplementary material, which is available to authorized users.

Effect of Robot-Assisted Gait Training in a Large Population of Children With Motor Impairment Due to Cerebral Palsy or Acquired Brain Injury

“…generally within or above the range of MCID identified by a recent systematic review in patients with respiratory, cardiovascular, and muscular diseases. 31 Progress was also obtained in global improvement of gross motor capacity. The GMFM total score improved significantly in the whole group and in the patients with ABI but not in the group of patients with CP, confirming previous research.…”

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…However, it has been objected that it should be verified whether the changes in 6MWT represent or not the "minimal clinical important difference" (MCID) for patients. There are no studies evaluating the MCID for the 6MWT in MPSs or in other LSDs, but the results obtained for MPS IVA were compared to the MCIDs determined in patients with respiratory, cardiovascular, or musculoskeletal disease (from +7 to +9 % change): the placebo-adjusted improvement in the elosulfase trial was 14.9% after 24 weeks and 20.7% after 2 years of treatment, versus a reduction of 6.9% in comparable untreated patients [160].…”

Clinically relevant differences in COPD health status: systematic review and triangulation

“…Most studies have not recently been updated, and none of these studies attempted to evaluate the quality of the MCID methodology or aim for triangulation. Outside the field of COPD, systematic reviews have emerged that summarise, quantify and make a quality assessment of the MCIDs of patient-reported outcomes and functional status tests [31,[58][59][60][61][62][63][64]. Our study is the first to do so within the field of COPD.…”