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.

Keywords: Endurance; Enzyme replacement therapy; MPS IVA; Minimal clinically important difference; Morquio A syndrome; Mucopolysaccharidosis IVA; Six-minute walk test.

Fig. 1

6MWT distance in untreated Morquio A patients and age-matched healthy controls. Source: [4, 14]

Fig. 2

Flow chart summary of the systematic literature search. Studies that aimed to estimate the minimal clinically important difference (MCID) for the six-minute walk test (6MWT) in diseases relevant to Morquio A syndrome including respiratory, cardiovascular, and muscular diseases were included

Fig. 3

Absolute six-minute walk test (6MWT) minimal clinically important difference (MCID) using anchor-based methods. Sources: 1 & 2 = du Bois, 2010 [29] and du Bois, 2011 [30]; 3 = Swigris, 2010 [31]; 4 = Holland, 2009 [42]; 5 = Holland, 2010 [43]; 6 = Polkey, 2013 [32]; 8 = Puhan, 2011 [44]; 9 = Redelmeier, 1997 [45]; 11 = Lee, 2014 [46]; 12 & 13 = Gremeaux, 2011 [47] and Gremeaux, 2011 [48]; 15 = Mathai, 2012 [49]; 16 = Henricson, 2013 [28]; 18 = Kwok, 2013 [50]. The green, red, blue, and orange bars represent studies conducted in patients with respiratory, cardiovascular, muscular, and ‘other’ (i.e., frail elderly) diseases, respectively. CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis; PAH: pulmonary arterial hypertension

Fig. 4

Absolute six-minute walk test (6MWT) minimal clinically important difference (MCID) using distribution-based methods. Sources: 1 & 2 = du Bois, 2010 [29] and du Bois, 2011 [30]; 3 = Swigris, 2010 [31]; 4 = Holland, 2009 [42]; 5 = Holland, 2010 [43]; 7 = Puhan, 2008 [51]; 8 = Puhan, 2011 [44]; 10 = Wise, 2005 [52]; 11 = Lee, 2014 [46]; 12 & 13 = Gremeaux, 2011 [47] and Gremeaux, 2011 [48]; 14 = Gilbert, 2009 [53]; 15 = Mathai, 2012 [49]; 17 = McDonald, 2013 [54]; 18 = Kwok, 2013 [50]. The green, red, blue, and orange bars represent studies conducted in patients with respiratory, cardiovascular, muscular, and other (i.e., frail elderly) diseases, respectively. CAD (coronary artery disease) COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis; PAH: pulmonary arterial hypertension

Fig. 5

Relative six-minute walk test (6MWT) minimal clinically important difference (MCID) using Anchor-based methods. Sources: 3 = Swigris, 2010 [31]; 4 = Holland, 2009 [42]; 5 = Holland, 2010 [43]; 6 = Polkey, 2013 [32]; 8 = Puhan, 2011 [44]; 9 = Redelmeier, 1997 [45]; 11 = Lee, 2014 [46]; 15 = Mathai, 2012 [49]; 16 = Henricson, 2013 [28]; 18 = Kwok, 2013 [50]. The green, red, blue, and orange bars represent studies conducted in patients with respiratory, cardiovascular, muscular, and other (i.e., frail elderly) diseases, respectively. COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis; PAH: pulmonary arterial hypertension

Fig. 6

Relative six-minute walk test (6MWT) minimal clinically important difference (MCID) using distribution-based methods. Sources: 1 & 2 = du Bois, 2010 [29] and du Bois, 2011 [30]; 3 = Swigris, 2010 [31]; 4 = Holland, 2009 [44]; 5 = Holland, 2010 [43]; 7 = Puhan, 2008 [51]; 8 = Puhan, 2011 [44]; 10 = Wise, 2005 [52]; 11 = Lee, 2014 [46]; 15 = Mathai, 2012 [49]; 17 = McDonald, 2013 [54]; 18 = Kwok, 2013 [50]. The green, red, blue, and orange bars represent studies conducted in patients with respiratory, cardiovascular, muscular, and other (i.e., frail elderly) diseases, respectively. COPD: chronic obstructive pulmonary disease; IPF: idiopathic pulmonary fibrosis; PAH: pulmonary arterial hypertension