The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial

Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no consensus exists on outcome measures that adequately reflect function, activities, and participation for adults with mitochondrial diseases. The Goal Attainment Scale (GAS) offers a personalized, patient-centered way to capture these outcomes. However, its validity and standardized use in trials remain unclear. This study assessed GAS construct validity in a PMD trial, including comparison with the Canadian Occupational Performance Measure (COPM), and provides guidance for future application. Data from a double-blind, randomized, placebo-controlled, exploratory Phase IIA cross-over trial on the safety and efficacy of sonlicromanol (KH176) in 18 adult m.3243 A > G patients, were retrospectively analyzed. GAS goals were categorized using the World Health Organization International Classification of Functioning, Disability and Health. Additional outcome measures with overlapping content were selected to evaluate GAS validity. Implementation quality was evaluated using 17 GAS appraisal criteria. Most goals addressed fatigue or lack of energy (85%, 22/26). GAS showed weak to moderate negative correlations with the Checklist Individual Strength (CC = -0.40) and Beck Depression Inventory-II scores (CC = -0.37), indicating higher GAS scores were associated with reductions in fatigue and depressive symptoms. Moderate correlations were observed between GAS and COPM scores (CC = 0.50–0.55). No significant correlations were found with the 6-min walk test, 36-item Short Form Health Survey or Newcastle Mitochondrial Disease Scale for Adults. Only 6 out of 17 (35%) implementation criteria were fully met. GAS demonstrated some construct validity in relation to fatigue and depressive symptoms, showed limited overlap with conventional outcome measures and suffered from suboptimal implementation. Although exploratory, these findings suggest GAS may capture patient-relevant change in individuals with PMD. To realize its potential, standardized methodology and further validation are essential for its use as a robust outcome measure in future PMD trials.