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NCT Number: NCT07775872

Prospective Natural History Study of POLG Disease

The PIONEER study is a prospective, natural history study dedicated to characterizing the clinical progression of POLG-related disorders. The research aims to bridge the gap between genetic diagnosis and drug development by mapping how these rare mitochondrial conditions evolve over time. By observing the disease's natural trajectory through a multi-center approach, The study identifies critical clinical milestones that serve as a foundation for evaluating therapeutic efficacy and future therapeutic interventions

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Key information

Conditions

PolG, Primary Mitochondrial Myopathy Ataxia Brain Diseases Central Nervous System Diseases Chronic Disease Cranial Nerve Diseases Disease Attributes Dyskinesias Epilepsy Eye Diseases Metabolic Diseases Mitochondrial Diseases Mitochondrial Myopathies Muscular Diseases Musculoskeletal Diseases Nervous System Diseases Neurologic Manifestations Neuromuscular Diseases Nutritional and Metabolic Diseases Ocular Motility Disorders Ophthalmoplegia Ophthalmoplegia, Chronic Progressive External Paralysis Pathologic Processes Pathological Conditions, Signs and Symptoms Seizures Signs and Symptoms

Age range

Up to 75 year

Sex eligibility

All sexes

Study type

Observational

Primary location

University of California San Diego, San Diego, California, United States

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About this study

This is a multi-centre, Multi-country Prospective Observational Natural History study designed to bridge the gap between genetic diagnosis and therapeutic development for POLG-related disorders. These mitochondrial conditions are rare. This study utilizes a prospective, longitudinal design which allows researchers to track the "phenotypic evolution" of the disease over several years, providing the high-quality baseline data that regulatory agencies like the FDA require to evaluate the success of future drug interventions.

clinical parameters such as the Newcastle Mitochondrial Disease Scale (NMDAS) for multi-system involvement, the SARA scale for ataxia, and functional tests like the Nine-Hole Peg Test for motor dexterity, alongside fluid biomarkers including GDF-15 and FGF-21 are conducted to validate clinical endpoints throughout the study duration. inclusion criteria require participants of any age to have a genetically confirmed POLG-related disorder with documented pathogenic variants, as well as the ability to comply with longitudinal follow-up assessments over 3 years. This rigorous framework allows researchers to correlate specific genetic mutations with objective clinical milestones, providing the necessary baseline data to evaluate the efficacy of future therapeutic interventions.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • male & female from age 0 to 75.
  • A genetically confirmed POLG -associated disorder based on both phenotype and genotype is required.
  • Parental/guardian permission (informed consent) and if appropriate with child assent.

Exclusion criteria

  • Diagnosis of mitochondrial disorder other than POLG
  • Subject with POLG Variant of unknown significance or benign variant.
  • Parents/guardians or subjects who, in the opinion of the investigator, may be non-compliant with the study schedules or procedures.
  • Subjects unable or unwilling to provide informed consent.
  • History of or current clinically important condition other than what is related to the PMD which, in the opinion of the Investigator will confound the results of the NHS.

Treatment and study plan

Primary outcomes

  1. Scale for the Assessment and Rating of Ataxia (SARA)

    Time frame: Baseline through 36 months (every 12 months)

    The Scale for the Assessment and Rating of Ataxia (SARA) is a clinical scale that is based on a semi-quantitative assessment of cerebellar ataxia on an impairment level. Total scores range from 0 to 40. Higher scores indicate greater ataxia severity.

Secondary outcomes

  1. Newcastle Mitochondrial Disease Scale

    Time frame: Baseline through 36 months (every 12 months)

    The Newcastle Mitochondrial Disease Adult Scale (NMDAS) is a validated, semi-quantitative clinical scoring instrument used to assess disease severity and progression in adults with mitochondrial disease. Total scores range from 0 to 145, with higher scores indicating greater disease severity and functional impairment.

    The NMDAS will be administered to participants aged 18 years and older.

  2. Newcastle Paediatric Mitochondrial Disease Scale (NPMDS)

    Time frame: Baseline through 36 months (every 12 months)

    The Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) is a validated, semi-quantitative clinical scoring instrument used to assess disease severity and progression in paediatric patients with mitochondrial disease. Scores range from 0 to 82.

    Higher scores indicate greater disease severity and functional impairment. The NPMDS will be administered to participants aged 0-17 years.

  3. Patient-Reported Outcomes Measurement Information System (PROMIS) Mitochondrial Fatigue

    Time frame: Baseline through 36 months (every 6 months)

    The Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue instruments assess the impact and severity of fatigue. Age-appropriate PROMIS Fatigue instruments will be administered to participants and caregivers, as applicable. Scores are reported as standardized T-scores, typically ranging from approximately 20 to 80, with a population mean of 50 and standard deviation of 10. Higher scores indicate greater fatigue severity and worse fatigue-related burden.

  4. Research and Development 36 (RAND-36) Health Survey Quality of Life

    Time frame: Baseline through 36 months (every 12 months)

    The RAND-36 Health Survey is a self-reported measure of health-related quality of life across eight health domains. This questionnaire will be used in adult patients age 18 and older. Domain scores range from 0 to 100.

    Higher scores indicate better health-related quality of life.

  5. Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale

    Time frame: Baseline through 36 months (every 12 months)

    The Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale assesses health-related quality of life in pediatric participants using age-appropriate self-report and parent-proxy forms. Scores range from 0 to 100.

    Higher scores indicate better health-related quality of life.

  6. Gastrointestinal Symptom Rating Scale (GSRS) Total Score

    Time frame: Baseline through 36 months (every 12 months)

    The Gastrointestinal Symptom Rating Scale (GSRS) assesses gastrointestinal symptom severity like reflux, abdominal pain, indigestion, diarrhoea, and constipation. The Total scores range from 1 to 7.

    Higher scores indicate more severe gastrointestinal symptoms and worse gastrointestinal health.

  7. Paediatric (PedsQL) Gastrointestinal Symptoms Module

    Time frame: Baseline through 36 months (every 12 months)

    The Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module assesses gastrointestinal symptom-related quality of life in pediatric participants.

    Scores range from 0 to 100, with higher scores indicating better gastrointestinal health-related quality of life.

  8. Quality of Life in Epilepsy Inventory-31-P (QOLIE-31-P)

    Time frame: the questionnaire shall be reassessed on Baseline visit, 6 months, every 12 months through 36 months.

    The Quality of Life in Epilepsy Inventory-31-P (QOLIE-31-P) assesses epilepsy-specific quality of life in adults. Scores range from 0 to 100, with higher scores indicating better quality of life.

  9. Paediatric Quality of Life Inventory (PedsQL) Epilepsy Module

    Time frame: the questionnaire shall be reassessed on Baseline visit, 6 months, and every 12 months, through 36 months.

    The Paediatric Quality of Life Inventory (PedsQL) Epilepsy Module assesses epilepsy-related quality of life in pediatric participants using age-appropriate self-report and parent-proxy forms. Scores range from 0 to 100, with higher scores indicating better epilepsy-related quality of life.

  10. Patient Global Impression of Change (PGI-C)

    Time frame: Baseline through 36 months (baseline, 12 months)

    The Patient Global Impression of Change (PGI-C) is a participant-reported assessment of overall change in health status since study enrolment.

    Scores range from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse.

    Lower scores indicate improvement and higher scores indicate worsening.

  11. Overall Survival

    Time frame: Baseline through 36 months (at every visit)

    Time from enrolment to death from any cause.

  12. Number of DNA Polymerase Gamma (POLG) Disease-Related Hospitalizations

    Time frame: Baseline through 36 months (at every visit)

    Number of hospital admissions attributable to DNA Polymerase Gamma (POLG)-related disease complications during study follow-up.

  13. DNA Polymerase Gamma (POLG) Burdensome Symptom Assessment

    Time frame: Baseline through 36 months (at every visit)

    The DNA Polymerase Gamma (POLG) Burdensome Symptom Assessment is a participant- or caregiver-reported assessment designed to identify the symptom related to DNA Polymerase Gamma (POLG)-related disease that has the greatest impact on daily life. Participants identify their most burdensome symptom and rate its severity and burden using an 11-point numeric rating scale ranging from 0 to 10, where 0 indicates "Not Present" and 10 indicates "Worst Imaginable". Higher scores indicate greater symptom burden and worse disease impact.

Study contacts

Contact information is provided by the study sponsor or research team.

PIONEER

CONTACT

[email protected]

+15716094617

Sponsors and collaborators

Lead sponsor

The POLG Foundation

Other

Collaborators

  • ClinTrek Research Private Limited
  • Jeeva Clinical Trials Inc
  • United Mitochondrial Disease Foundation (UMDF)

Registry information

Official study title

Global Prospective Natural History Study of POLG Disease

Acronym: PIONEER

Important dates

Study start
2026
Primary completion
2029
Study completion
2031
First posted
Aug 20, 2026
Registry last updated
Aug 20, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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