Natural History Study of Mitochondrial Myopathy

NCT05250375 | Recruiting

• 2 other identifiers: 16-0133641R01AR083552-01A1
• Study Type: observational
• Target: 1,300
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this observational study is to develop and validate tools to measure disease course in patients with primary mitochondrial myopathy (PMM). The main aims of this study are:

• Development, validation, and optimization of objective outcome measures for mitochondrial myopathy
• Defining the natural history of mitochondrial myopathy Researchers will compare data from patients with primary mitochondrial myopathy to healthy controls. Data from healthy controls will also help define normative data for future studies. Participants will perform clinical exams of muscle strength and endurance and will complete surveys.

Conditions

Primary Mitochondrial Disease

Keywords

Mitochondrial Myopathy; Mitochondrial Disease; Healthy Volunteers; Natural History; Muscle Weakness; Fatigue; Outcome Measures

Outcome Measures

Primary Outcomes (17)

• Muscle Strength of MM-COAST

  Muscle strength will be measured longitudinally by handheld dynamometry strength assessments to confirm muscle weakness in proximal and distal muscle groups.

  through study completion, an average of 5 years

• Balance of the MM-COAST

  Balance will be measured by: (1) Standing tandem with eyes closed, (2) Standing tandem with eyes open, and (3) Single leg stand with eyes closed tests.

  through study completion, an average of 5 years

• Dexterity of the MM-COAST

  Dexterity will be measured by 9 Hole Peg Test (9HPT) and Functional Dexterity Test (FDT).

  through study completion, an average of 5 years

• Mitochondrial Disease Burden for Adults

  All subjects will complete the 'gold standard' Newcastle Scale of disease burden. Newcastle Adult Scale (NMDAS): Each question in the NMDAS has a possible score from 0-5. Each of the first 3 section scores are calculated by simply summing the scores obtained for each question in that section. The higher the score the more severe the disease. The quality of life section has separate scoring.

  through study completion, an average of 5 years

• Mitochondrial Disease Burden for Children

  All subjects and their parents will complete the 'gold standard' Newcastle Scale of disease burden. Newcastle Pediatric Scale (NPMDS): NPMDS is scored by section and the final (total) score is the sum of all section scores. The section scores vary by age group (0-24 months, 2-11 years, and 12-18 years). Maximum possible total NPMDS scores are 95 for subjects under 24 months of age and 107 for those between two and 18 years of age. Higher scores indicate worse conditions.

  through study completion, an average of 5 years

• Challenges in Activities of Daily Life (ADLs)

  All subjects and their parents will complete the Karnofsky-Lansky score to assess functional abilities at each visit. Karnofsky Lansky Scale: 0-100. 0-40: Unable to care for self, requires equivalent of institutional or hospital care; disease may be progressing rapidly. 50-70: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed. 80-100: Able to carry on normal activity and to work; no special care needed.

  through study completion, an average of 5 years

• Functional Tasks of the Mitochondrial Myopathy Functional Scale (MMFS)

  The MMFS (In Person and Telemedicine Versions) will be used to quantify motor performance in NUBPL-disease in abilities to complete functional tasks such as standing, walking and gait. MMFS data will be correlated using Pearson correlation coefficient to Newcastle and Karnofsky scores, and objective measures to assess for clinical meaning. MMFS Scale: 3: Able (fully meets criteria); 2: Moderately Able (partially meets, some compensation needed); 1: Minimally Able (significant compensation needed); 0: Unable MMFS Totals: In-person Version: Total score: \*/ 66 (max score), Telemedicine Version: Total score: \*/54 (max score)

  through study completion, an average of 5 years

• Clinical Progression: Survival

  Patients will be marked as either "alive" or "deceased" at the time of a given visit date.

  through study completion, an average of 5 years

• Clinical Progression: Growth

  Patients will have their vitals recorded at the date of visit to obtain BMI (Kg/m\^2)) measurement, Height (m) and weight (kg) are required to calculate BMI.

  through study completion, an average of 5 years

• Clinical Progression: Other Illnesses

  Patients will have other illnesses not related to their mitochondrial disease recorded along with date of diagnosis and stability.

  through study completion, an average of 5 years

• Clinical Progression: Hospitalizations

  Patients will have prior hospitalizations counted and recorded. Any hospitalizations occurring within a year from the visit date will have specific information recorded including the dates of admission and discharge, and the reasons for admission and discharge.

  through study completion, an average of 5 years

• Clinical Progression: Ambulatory Status

  Patients will have their ambulatory status assessed by recording whether or not they can take 5 steps on their own. Patients' use of different kinds of wheelchairs will be recorded (manual, power assist, or power wheelchair or scooter) along with whether they are able to ambulate in the community or only in the household.

  through study completion, an average of 5 years

• Clinical Progression: Pacemaker Requirement

  As part of a patient's cardiopulmonary exercise test (CPET), pacemaker status will be assessed, and if a patient utilizes a pacemaker, it's make, model, and settings will be recorded.

  through study completion, an average of 5 years

• Clinical Progression: Ventilatory Support

  As part of a patient's respiratory history, ventilatory support status will be assessed by recording whether a patient uses the any of the following respiratory equipment: cough assist device, non-invasive ventilation including continuous positive airway pressure (CPAP) and Bi-pap, chest percussion, suctioning devices, other ventilation devices.

  through study completion, an average of 5 years

• Clinical Progression: Gastrostomy Status

  As part of a patient's nutritional assessment, a patient's gastrostomy status will be assessed by determining whether a patient utilizes a gastrostomy tube (or g-tube), when they had their g-tube placed and why, and whether it resulted in weight gain.

  through study completion, an average of 5 years

• Qualitative Interviews

  In-depth qualitative interviews to assess their perspective of meaningful change of individual domain assessments of the MM-COAST and MM-Function Scale.

  through study completion, an average of 5 years

• MM patient-reported outcome measure (PROM), MM-IMPACT

  Preliminary MM-IMPACT PROM, a multi-item scale which currently consists of 45 questions

  through study completion, an average of 5 years

Secondary Outcomes (4)

• Cerebellar Ataxia Outcome Measure for Primary Mitochondrial Disease (PMD)

  through study completion, an average of 5 years

• Clinical Meaningfulness of Ataxia Quantification.

  through study completion, an average of 5 years

• Evaluation of Health-Related Quality of Life by PedsQL

  through study completion, an average of 5 years

• Evaluation of daily functional activities by PEDI-CAT

  through study completion, an average of 5 years

Study Arms (2)

Primary Mitochondrial Myopathy

Patients with a mitochondrial disorder established by confirmed genetic or biochemical mutation in mtDNA or nuclear DNA or is suitable for participation in the opinion of the investigator based on clinical presentation and exhibits myopathy (exercise intolerance, muscle strength, fatigue) relating to mitochondrial disease.

Healthy Controls

Males or females age 0-100 years of age with no history of mitochondrial myopathy symptoms.

Eligibility Criteria

• Age: 0 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with primary mitochondrial myopathy and healthy volunteers

You may qualify if:

• Males or females age 0-100 years of age
• Mitochondrial disorder established by confirmed genetic or biochemical mutation in mtDNA or nuclear DNA OR is suitable for participation in the opinion of the investigator based on clinical presentation.
• Exhibits myopathy (exercise intolerance, muscle strength, fatigue) relating to Mitochondrial disease in the opinion of the investigator
• Able to provide written consent OR parental permission and child assent OR if they are an adult with diminished capacity, an LAR or healthcare representative is able to and willing to provide consent ., as approved by the appropriate Institutional Review Board (IRB) or Ethics Committee (EC)

You may not qualify if:

• Male or female fetuses
• Non English speakers
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of these criteria must be reported in accordance with IRB Policies and Procedures.
• Males or females age 0-100 years of age
• No history of mitochondrial myopathy symptoms
• Able to provide written consent or parental permission and child assent., approved by the appropriate Institutional Review Board (IRB) or Ethics Committee (EC)
• Individual is not a study staff member or a family member of a study staff member (not listed as a study staff in eIRB)
• Male or female fetuses
• Non English speakers
• Mitochondrial disorder established by confirmed genetic or biochemical mutation in mtDNA or nuclear DNA
• Exhibits myopathy (exercise intolerance, muscle strength, fatigue) relating to Mitochondrial disease
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Individual is listed as a study staff member in eIRB, OR individual is a family member of a study staff member listed in eIRB
• Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of these criteria must be reported in accordance with IRB Policies and Procedures.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead
• University of Pennsylvania: collaborator
• United Mitochondrial Disease Foundation (UMDF): collaborator
• National Institutes of Health (NIH): collaborator
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Related Publications (13)

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  PMID: 25733400 BACKGROUND

• Burstein DS, McBride MG, Min J, Paridon AA, Perelman S, Huffman EM, O'Malley S, Del Grosso J, Groepenhoff H, Paridon SM, Brothers JA. Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents. J Pediatr. 2021 Feb;229:61-69.e5. doi: 10.1016/j.jpeds.2020.09.018. Epub 2020 Sep 11.

  PMID: 32926876 BACKGROUND

• DeBrosse C, Nanga RPR, Wilson N, D'Aquilla K, Elliott M, Hariharan H, Yan F, Wade K, Nguyen S, Worsley D, Parris-Skeete C, McCormick E, Xiao R, Cunningham ZZ, Fishbein L, Nathanson KL, Lynch DR, Stallings VA, Yudkoff M, Falk MJ, Reddy R, McCormack SE. Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders. JCI Insight. 2016 Nov 3;1(18):e88207. doi: 10.1172/jci.insight.88207.

  PMID: 27812541 BACKGROUND

• Schaefer AM, Phoenix C, Elson JL, McFarland R, Chinnery PF, Turnbull DM. Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology. 2006 Jun 27;66(12):1932-4. doi: 10.1212/01.wnl.0000219759.72195.41.

  PMID: 16801664 BACKGROUND

• Phoenix C, Schaefer AM, Elson JL, Morava E, Bugiani M, Uziel G, Smeitink JA, Turnbull DM, McFarland R. A scale to monitor progression and treatment of mitochondrial disease in children. Neuromuscul Disord. 2006 Dec;16(12):814-20. doi: 10.1016/j.nmd.2006.08.006. Epub 2006 Nov 22.

  PMID: 17123819 BACKGROUND

• Kaufmann P, Engelstad K, Wei Y, Kulikova R, Oskoui M, Sproule DM, Battista V, Koenigsberger DY, Pascual JM, Shanske S, Sano M, Mao X, Hirano M, Shungu DC, Dimauro S, De Vivo DC. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology. 2011 Nov 29;77(22):1965-71. doi: 10.1212/WNL.0b013e31823a0c7f. Epub 2011 Nov 16.

  PMID: 22094475 BACKGROUND

• Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015 May;77(5):753-9. doi: 10.1002/ana.24362. Epub 2015 Mar 28.

  PMID: 25652200 BACKGROUND

• Rahman J, Rahman S. Mitochondrial medicine in the omics era. Lancet. 2018 Jun 23;391(10139):2560-2574. doi: 10.1016/S0140-6736(18)30727-X. Epub 2018 Jun 18.

  PMID: 29903433 BACKGROUND

• Friederich MW, Perez FA, Knight KM, Van Hove RA, Yang SP, Saneto RP, Van Hove JLK. Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement. Mol Genet Metab. 2020 Mar;129(3):236-242. doi: 10.1016/j.ymgme.2019.12.013. Epub 2019 Dec 30.

  PMID: 31917109 BACKGROUND

• Kimonis V, Al Dubaisi R, Maclean AE, Hall K, Weiss L, Stover AE, Schwartz PH, Berg B, Cheng C, Parikh S, Conner BR, Wu S, Hasso AN, Scott DA, Koenig MK, Karam R, Tang S, Smith M, Chao E, Balk J, Hatchwell E, Eis PS. NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum. J Med Genet. 2021 May;58(5):314-325. doi: 10.1136/jmedgenet-2020-106846. Epub 2020 Jun 9.

  PMID: 32518176 BACKGROUND

• Glanzman AM, Mazzone ES, Young SD, Gee R, Rose K, Mayhew A, Nelson L, Yun C, Alexander K, Darras BT, Zolkipli-Cunningham Z, Tennekoon G, Day JW, Finkel RS, Mercuri E, De Vivo DC, Baldwin R, Bishop KM, Montes J. Evaluator Training and Reliability for SMA Global Nusinersen Trials1. J Neuromuscul Dis. 2018;5(2):159-166. doi: 10.3233/JND-180301.

  PMID: 29865090 BACKGROUND

• Campolina-Sampaio GP, Lasmar LM, Ribeiro BS, Giannetti JG. The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil. Arq Neuropsiquiatr. 2016 Nov;74(11):909-913. doi: 10.1590/0004-282X20160137.

  PMID: 27901256 BACKGROUND

• MANUAL FOR NEWCASTLE MITOCHONDRIAL DISEASE ADULT SCALE (NMDAS). Wellcome Trust Centre Mitochondrial Research.

  BACKGROUND

MeSH Terms

Conditions

Mitochondrial Myopathies; Mitochondrial Diseases; Muscle Weakness; Fatigue

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Neuromuscular Manifestations; Neurologic Manifestations; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Officials

• Zarazuela Zolkipli-Cunningham, MBChB

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Katelynn Stanley, BS

CONTACT

267 426 4961; MitochondrialMyopathyResearch@chop.edu

Jean Flickinger, PT

CONTACT

267 426 4961; MitochondrialMyopathyResearch@chop.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 20 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2021
• First Posted: February 22, 2022
• Study Start: March 24, 2017
• Primary Completion (Estimated): March 24, 2030
• Study Completion (Estimated): March 24, 2030
• Last Updated: September 10, 2025

Record last verified: 2025-09

Locations

US (1)