Development of a Patient-Reported Outcome Questionnaire to Evaluate Primary Mitochondrial Myopathy Symptoms: The Primary Mitochondrial Myopathy Symptom Assessment

Gwaltney, Chad J.; Stokes, Jonathan; Aiudi, Anthony; Mazar, Iyar; Ollis, Sarah; Love, Emily; Espensen, Ashlee; Shields, Alan L.

doi:10.1097/cnd.0000000000000303

Cited by 2 publications

(3 citation statements)

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“…The PMMSA is a PRO daily diary measure that was created to evaluate treatment benefit in regulated PMM clinical trials and developed in accordance with best measurement practices and regulatory guidelines [ 21 – 23 ]. With its content validity established [ 24 ], results from the present analyses were generated to evaluate the measure’s underlying factor structure, scoring algorithm and address its psychometric performance. The CEFA results suggest that the full 10-item PMMSA is multidimensional and a composite or TSS may not be appropriate for this instrument.…”

Section: Discussionmentioning

confidence: 99%

“…The PMMSA is a ten-item daily assessment evaluating symptom severity over the past 24 h and was developed through extensive patient interviews (42 interviews were conducted) to ensure its content validity. Specifically, the symptoms assessed by the PMMSA were demonstrated to be relevant to individuals with PMM and these individuals understood the instructions, items, and response scales of the measure and were able to provide meaningful responses to the items upon administration [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease

Gwaltney¹,

Stokes

Aiudi

et al. 2022

J Patient Rep Outcomes

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Background The Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) is a 10-item patient-reported outcome (PRO) measure designed to assess the severity of mitochondrial disease symptoms. Analyses of data from a clinical trial with PMM patients were conducted to evaluate the psychometric properties of the PMMSA and to provide score interpretation guidelines for the measure. Methods The PMMSA was completed as a daily diary for approximately 14 weeks by individuals in a Phase 2 randomized, placebo-controlled crossover trial evaluating the safety, tolerability, and efficacy of subcutaneous injections of elamipretide in patents with mitochondrial disease. In addition to the PMMSA, performance-based assessments, clinician ratings, and other PRO measures were also completed. Descriptive statistics, psychometric analyses, and score interpretation guidelines were evaluated for the PMMSA. Results Participants (N = 30) had a mean age of 45.3 years, with the majority of the sample being female (n = 25, 83.3%) and non-Hispanic white (n = 29, 96.6%). The 10 PMMSA items assessing a diverse symptomology were not found to form a single underlying construct. However, four items assessing tiredness and muscle weakness were grouped into a “general fatigue” domain score. The PMMSA Fatigue 4 summary score (4FS) demonstrated stable test–retest scores, internal consistency, correlations with the scores produced by reference measures, and the ability to differentiate between different global health levels. Changes on the PMMSA 4FS were also related to change scores produced by the reference measures. PMMSA severity scores were higher for the symptom rated as “most bothersome” by each subject relative to the remaining nine PMMSA items (most bothersome symptom mean = 2.88 vs. 2.18 for other items). Distribution- and anchor-based evaluations suggested that reduction in weekly scores between 0.79 and 2.14 (scale range: 4–16) may represent a meaningful change on the PMMSA 4FS and reduction in weekly scores between 0.03 and 0.61 may represent a responder for each of the remaining six non-fatigue items, scored independently. Conclusions Upon evaluation of its psychometric properties, the PMMSA, specifically the 4FS domain, demonstrated strong reliability and construct-related validity. The PMMSA can be used to evaluate treatment benefit in clinical trials with individuals with PMM. Trial registration ClinicalTrials.gov identifier, NCT02805790; registered June 20, 2016; https://clinicaltrials.gov/ct2/show/NCT02805790.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease

Gwaltney¹,

Stokes

Aiudi

et al. 2022

J Patient Rep Outcomes

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“…Coprimary endpoints evaluated the effect of elamipretide for 24 weeks including the distance walked (in meters) on the 6MWT and the total fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA), previously described in detail. 31 The full PMMSA assesses the severity of 10 of the most common symptoms of PMM using the following 4-point scale (not at all 1 to severe 4 ; described later). PMMSA total fatigue score (TFS) focuses on myopathic symptoms most commonly associated with PMM (severity of tiredness and muscle weakness at rest and during activities, as described by participants).…”

Section: Methodsmentioning

confidence: 99%

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy

Karaa,

Bertini,

Carelli

et al. 2023

Neurology

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Background and Objectives:Primary Mitochondrial Myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely impacting physical function, exercise capacity, and quality of life (QoL). Current PMM standards-of-care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically-confirmed PMM.Methods:Following screening, eligible participants were randomized 1:1 to receive either 24weeks of elamipretide 40mg/day or placebo subcutaneously. Primary efficacy endpoints included change from baseline to Week 24 on the distance walked on the 6-minute Walk Test (6MWT), and Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included Most Bothersome Symptom Score on the PMMSA, NeuroQoL Fatigue Short Form scores, and the Patient– and Clinician–Global Impression of PMM Symptoms.Results:Participants (N=218) were randomized (n=109 elamipretide; n=109 placebo). Mean age was 45.6 year (64% women; 94% white). The majority of participants (n=162 [74%]) had mitochondrial DNA (mtDNA) mutations, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, mean distance walked on the 6MWT was 336.7±81.2 meters, mean score for Total Fatigue on the PMMSA was 10.6±2.5, and mean T-score for the Neuro-QoL Fatigue Short Form was 54.7±7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA Total Fatigue Score (TFS). Between the participants receiving elamipretide versus placebo, the difference in the Least Squares Mean (SE) from baseline to Week 24 on distance walked on the 6MWT was -3.2 (95% confidence interval,-18.7,12.3;p=0.69) meters and on the PMMSA Total Fatigue Score was -0.07 (95% confidence interval,-0.10,0.26;p=0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.Discussion:Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.Trial Registration Information:Trial registered withclinicaltrials.gov, Clinical Trials Identifier:NCT03323749; submitted on October 12, 2017;first patient enrolled October 9, 2017.https://clinicaltrials.gov/ct2/show/NCT03323749?term=elamipretide&draw=2&rank=9Classification of Evidence:This study provides Class I evidence that elamipretide does not improve the 6 minute walk test or fatigue at 24 weeks compared to placebo in patients with primary mitochondrial myopathy.

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Development of a Patient-Reported Outcome Questionnaire to Evaluate Primary Mitochondrial Myopathy Symptoms: The Primary Mitochondrial Myopathy Symptom Assessment

Cited by 2 publications

References 18 publications

Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease

Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy

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