Table 1.

Outcome measures to be employed for evaluating the effect of sonlicromanol on the study objectives

Objective	Outcome measure	Comments	Reference
Primary outcome measure
Gross motor symptoms of the genetic PMD in children	Gross Motor Function Measure −88 (GMFM-88)	• 88 items, 5 categories: lying and rolling; sitting; crawling and kneeling; standing; walking, running, and jumping. • 4-point Likert scale.	[25]
Secondary outcome measures
Fine manual dexterity	9-Hole Peg Test (NHPT)	• Practice session at the screening visit.	[26]
The physical ability of the patient	10 Meter Walk Test (10MWT)	• 7-point scale ranging from total assistance to no assistance for walking/running.	[27, 28]
Muscle spasticity	Modified Tardieu Scale for Spasticity (MTS)	• Quality (on a 5-grade scale) and angle of muscle reaction.	[29]
Dystonia	Barry-Albright Dystonia Scale (BAD)	• 8 body parts will be evaluated: eyes, mouth, neck, trunk, and four limbs. • 5-point ordinal scale.	[30]
Ataxia	Scale for the Assessment and Rating of Ataxia (SARA)	• 8 items: gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test.	[31]
Disability	Paediatric Evaluation of Disability Inventory (PEDI-CAT)	• Interview-based • 3 main domains: responsibility (51 items, 5-point scale), mobility (75 items), and social/cognitive ability (60 items, 4-point scale).	[32]
PMD signs and symptoms	International Paediatric Mitochondria Disease Scale (IPMDS)	• 3 domains of the disease: complaints and symptoms (23 items), physical examination (21 items), and functional tests (13 items, some are only for children ≥6 years).	[33]
Caregiver’s burden	ZARIT-12 Burden Scale	• Ranges from ‘not at all’ to ‘extremely’.	[34]
Quality of life	Neuro Quality of life Fatigue-Short Form (NeuroQL-SF) Paediatric version	• Physical, mental, and social effects. • 8-item self-assessment questionnaire recommended for children of 8–17 years.	[35, 36]
Clinician’s perception or improvement or worsening of the PMD	Clinician-scored Global Impression of Change (CGIC)	• 7-point Likert scale.	[36, 37]
Patient’s perception of change due to intervention	Patient/Caregiver scored Global Impression of Change (PGIC)	• 7-point Likert scale. • Will be completed by 12–18-year-old children. • For children younger than 12 years or cognitively disabled, parents/caregivers will be completing the test.	[36, 38]
Patient/Caregiver scored impression of change on patient-identified 3 most bothersome symptoms caused by PMD	Most Bothersome Symptom Assessment (MBSA)	• 7-point Likert scale. • Will be completed by 12–18-year-old children. • For children younger than 12 years or cognitively disabled, parents/caregivers will be completing the test.	[36]
Growth	Growth	• Overall body growth will be measured (height, weight, head circumference, and weight-for-height).
Additional outcome measures
Health Economics and Outcomes Research	EQ-5D-Y (Proxy 1)	• HRQoL via 5 dimensions: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression. • Each dimension will have 5 levels: no, slight, moderate, severe, and extreme problems.	[39, 40]
	Health Utilities Index (HUI)	• Comprehensive health status and HRQoL.	[41, 42]
Acceptability of sonlicromanol	Entry in the diary by the parent/caregiver	• Evaluation will be based on whether the patient has swallowed the complete dose, spat out part of the dose, or refused to take the dose.	[43]
Palatability of sonlicromanol	Facial Hedonic Scale/Visual Analogue Scale-5 (FHS/VAS-5)		[43]

PMD Primary Mitochondrial Diseases, GMFM-88 Gross Motor Function Measure −88, NHPT 9-Hole Peg Test, 10MWT 10 Meter Walk Test, MTS Modified Tardieu Scale for Spasticity, BAD Barry-Albright Dystonia Scale, SARA Scale for the Assessment and Rating of Ataxia, PEDI-CAT Paediatric Evaluation of Disability Inventory, IPMDS International Paediatric Mitochondria Disease Scale, NeuroQL-SF Neuro Quality of life Fatigue-Short Form, HRQoL health-related quality of life, CGIC Clinician-scored Global Impression of Change, PGIC Patient/Caregiver scored Global Impression of Change, MBSA Most Bothersome Symptom Assessment, HUI Health Utilities Index, FHS/VAS-5 Facial Hedonic Scale/Visual Analogue Scale-5, EQ-5D-Y EuroQol 5D youth version proxy version 1