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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.

SUBMITTER: Schrover R

PROVIDER: S-EPMC5405472 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Schrover Rudolf R Evans Kathryn K Giugliani Roberto R Noble Ian I Bhattacharya Kaustuv K

Orphanet journal of rare diseases 20170426 1

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 differenc ...[more]

PMID: 28441951

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Project description:Background and objectivesField exercise tests (eg, 6-minute walk test [6MWT]) are important measures of functional exercise capacity in people with COPD. Shorter tests such as the 2-minute walk test (2MWT) may offer advantages in some populations but lack information about responsiveness to change. This study examined responsiveness, minimal important difference (MID), test-retest reliability, and construct validity of the 2MWT in people with stable COPD attending outpatient pulmonary rehabilitation (PR).MethodsAt pre-PR assessment, study participants completed a 2MWT twice in addition to usual measures (6MWT and Chronic Respiratory Questionnaire). At post-PR assessment following a standard PR program, measures were repeated and global rating of change scores obtained (patient and therapist). Pre-post program change scores were examined for correlations with change in 2-minute walk distance (2MWD) and used (where r≥0.3) to estimate the MID through anchor-based methods. Distribution-based estimates based on standard error of measurement were examined. Test-retest reliability (intraclass correlation coefficient [ICC] and Bland-Altman agreement) and validity (Pearson correlation with 6-minute walk distance [6MWD]) were reported.ResultsFifty-nine people (28 men) with stable COPD, mean age 68 years (SD 10 years), and percentage predicted forced expiratory volume in 1 second 48% (SD 20%) attended pre-PR assessment. Test-retest ICC for same-session 2MWD was 0.985. A mean difference of 2.4 m (95% confidence interval [CI] 0.7-4.0 m, P=0.006) occurred between the first and second trials. 2MWD and 6MWD were highly correlated (r=0.87, P<0.001). Forty-one participants completed PR and were included in responsiveness and MID analysis. Mean 2MWD improved significantly post-PR (8.8 m, 95% CI 3.6-14 m, P=0.001). The MID in 2MWD, anchored against clinically meaningful change in 6MWD, was 5.5 m (area under curve =0.81, P=0.001). Distribution-based methods estimated an MID of 4 m.ConclusionChange in 2MWD of at least 5.5 m following a PR program corresponded to a clinically meaningful change. A practice test is recommended due to learning effects.

Project description:BackgroundA minimal clinically important difference has not been established for the Abnormal Involuntary Movement Scale in patients with tardive dyskinesia. Valbenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Efficacy in randomized, double-blind, placebo-controlled trials was defined as the change from baseline in Abnormal Involuntary Movement Scale total score (sum of items 1-7).ObjectivesTo estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor-based method.MethodsData were pooled from three 6-week double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Valbenazine doses were pooled for analyses as follows: "low dose," which includes 40 or 50 mg/day; and "high dose," which includes 75 or 80 mg/day. Mean changes from baseline in Abnormal Involuntary Movement Scale total score were analyzed in all participants (valbenazine- and placebo-treated) with a Clinical Global Impression of Change-Tardive Dyskinesia or Patient Global Impression of Change score of 1 (very much improved) to 3 (minimally improved).ResultsThe least squares mean improvement from baseline to week 6 in Abnormal Involuntary Movement Scale total score was significantly greater with valbenazine (low dose: -2.4; high dose: -3.2; both, P < 0.001) versus placebo (-0.7). An minimal clinically important difference of 2 points was estimated based on least squares mean changes in Abnormal Involuntary Movement Scale total score in participants with a Clinical Global Impression of Change-Tardive Dyskinesia score ≤3 at week 6 (mean change: -2.2; median change: -2) or Patient Global Impression of Change score ≤3 at week 6 (mean change: -2.0; median change: -2).ConclusionsResults from an anchor-based method indicate that a 2-point decrease in Abnormal Involuntary Movement Scale total score may be considered clinically important. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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

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

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