PolG, Primary Mitochondrial MyopathyPIONEERNCT07775872
Prospective Natural History Study of POLG Disease
An observational study of PolG, Primary Mitochondrial Myopathy, run by The POLG Foundation at 21 sites in 9 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- PolG, Primary Mitochondrial Myopathy
- How many people
- 300 participants
- Where
- 21 sitesin 9 countries
- Study dates
- 17 Jun 2026to 17 Jun 2031
- How long will I take part?
- 3 Years
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Target Population: Patients of all ages with genetically confirmed POLG disease (autosomal recessive or dominant).
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
21 sites in 9 countries. Contact the study team or a site near you to ask about taking part.
21 sites in 9 countries
United States7 sites, 7 recruiting
- Not yet recruiting
Akron Children's Hospital
Akron, Ohio, 44308
Bruce Bruce Cohen, 330-543-4734, Htonni@akronchildrens.org
Danielle Black, 412-744-1068, danielle.black@umdf.org
- Not yet recruiting
Children's Hospital Colorado
Aurora, Colorado, 80045
Austin Austin Larson, 303-724-2338, austin.larson@childrenscolorado.org
Danielle Black, 412-744-1068, danielle.black@umdf.org
- Not yet recruiting
Baylor Hospital
Dallas, Texas, 75246
Fernado Fernado Scaglia, 713-798-4265, fscaglia@bcm.edu
Danielle Black, 412-744-1068, danielle.black@umdf.org
- Not yet recruiting
UTHealth Houston
Houston, Texas, 77030
Mary Kay Mary Kay Koeing, 713-500-7201, dane.r.weinig@uth.tmc.edu
Danielle Black, 412-744-1068, danielle.black@umdf.org
- Not yet recruiting
Columbia University Irving Medical Center
New York, New York, 10032
Michio Michio Hirano, 212-342-5767, ke4@cumc.columbia.edu
Danielle Black, 412-744-1068, danielle.black@umdf.org
- Not yet recruiting
Children's Hospital of Philadelphia-Philadelphia
Philadelphia, Pennsylvania, 19104
pioneer@polgfoundation.org
- Not yet recruiting
University of California San Diego
San Diego, California, 92121
Jennifer Jennifer Yang, 858-246-2288, jcrowhurst@health.ucsd.edu
Danielle Black, 412-744-1068, danielle.black@umdf.org
Norway4 sites, 4 recruiting
- Recruiting
Haukeland University Hospital-Bergen
Bergen, Vestland, 5009
pioneer@polgfoundation.org
- Not yet recruiting
Oslo University Hospital
Oslo, Oslo, 0424
pioneer@polgfoundation.org
- Not yet recruiting
University Hospital of North Norway - Tromsø
Tromsø, Troms, 9019
pioneer@polgfoundation.org
- Not yet recruiting
St. Olav's Hospital-Trondheim
Trondheim, Trøndelag, 7030
pioneer@polgfoundation.org
Finland2 sites, 2 recruiting
- Not yet recruiting
Children's Hospital, Helsinki University Hospital-Helsinki
Helsinki, Uusimaa, 00290
pioneer@polgfoundation.org
- Not yet recruiting
Oulu University Hospital-Oulu
Helsinki, Uusimaa, 00290
pioneer@polgfoundation.org
Sweden2 sites, 2 recruiting
- Not yet recruiting
The Queen Silvia Children's Hospital, University of Gothenburg
Gothenburg, Västra Götaland County, 416 50
pioneer@polgfoundation.org
- Not yet recruiting
Karolinska University Hospital
Solna, Stockholm County, 171 76
Karin Næs, pioneer@polgfoundation.org
United Kingdom2 sites, 2 recruiting
- Not yet recruiting
Addenbrooke's Hospital, Cambridge University Hospitals
Cambridge, Cambridgeshire, CB2 0QQ
pioneer@polgfoundation.org
- Not yet recruiting
Great Ormond Street Hospital
London, Central London, WC1N 1EH
pioneer@polgfoundation.org
Australia1 site, 1 recruiting
- Not yet recruiting
Prince of Wales Hospital, Sydney
Sydney, New South Wales, 2031
pioneer@polgfoundation.org
Denmark1 site, 1 recruiting
- Not yet recruiting
Copenhagen University Hospital- Copenhagen
Copenhagen, Capital Region of Denmark, 2100
pioneer@polgfoundation.org
Netherlands1 site, 1 recruiting
- Not yet recruiting
Maastricht University-Maastricht
Maastricht, Limburg, 6200 MD Maastricht
pioneer@polgfoundation.org
Spain1 site, 1 recruiting
- Recruiting
Hospital 12 de Octubre- Madrid
Madrid, Madrid, 28041
pioneer@polgfoundation.org
About this study
Official title: Global 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
Read the detailed description
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.
- Conditions
- PolG, Primary Mitochondrial Myopathy
- Keywords
- POLG, POLG disease, Primary Mitochondrial Disease, Mitochondrial DNA Depletion Syndrome, Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), Epilepsy, Seizures, Ataxia, Progressive External Ophthalmoplegia, Neuropathy, Mitochondrial Myopathy, Natural History Study
- Medical subject headings
- Epilepsy, Seizures, Ataxia, Ophthalmoplegia, Chronic Progressive External, Mitochondrial Myopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Single Observational Cohort | Single Observational Cohort: Individuals (Pediatric and Adults) with genetically confirmed POLG-related disorders. No intervention is administered. Participants undergo longitudinal clinical assessments, patient-reported outcomes, biomarker collection, and review of routine clinical data. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Scale for the Assessment and Rating of Ataxia (SARA)
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.
Measured: Baseline through 36 months (every 12 months)
Secondary outcomes (13)
Newcastle Mitochondrial Disease Scale
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.
Measured: Baseline through 36 months (every 12 months)
Newcastle Paediatric Mitochondrial Disease Scale (NPMDS)
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.
Measured: Baseline through 36 months (every 12 months)
Patient-Reported Outcomes Measurement Information System (PROMIS) Mitochondrial Fatigue
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.
Measured: Baseline through 36 months (every 6 months)
Research and Development 36 (RAND-36) Health Survey Quality of Life
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.
Measured: Baseline through 36 months (every 12 months)
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale
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.
Measured: Baseline through 36 months (every 12 months)
Gastrointestinal Symptom Rating Scale (GSRS) Total Score
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.
Measured: Baseline through 36 months (every 12 months)
Paediatric (PedsQL) Gastrointestinal Symptoms Module
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.
Measured: Baseline through 36 months (every 12 months)
Quality of Life in Epilepsy Inventory-31-P (QOLIE-31-P)
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.
Measured: the questionnaire shall be reassessed on Baseline visit, 6 months, every 12 months through 36 months.
Paediatric Quality of Life Inventory (PedsQL) Epilepsy Module
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.
Measured: the questionnaire shall be reassessed on Baseline visit, 6 months, and every 12 months, through 36 months.
Patient Global Impression of Change (PGI-C)
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.
Measured: Baseline through 36 months (baseline, 12 months)
Overall Survival
Time from enrolment to death from any cause.
Measured: Baseline through 36 months (at every visit)
Number of DNA Polymerase Gamma (POLG) Disease-Related Hospitalizations
Number of hospital admissions attributable to DNA Polymerase Gamma (POLG)-related disease complications during study follow-up.
Measured: Baseline through 36 months (at every visit)
DNA Polymerase Gamma (POLG) Burdensome Symptom Assessment
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.
Measured: Baseline through 36 months (at every visit)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2026
- Study start17 Jun 2026
- Primary completion17 Jun 2029 (estimated)
- Study completion17 Jun 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PolG, Primary Mitochondrial MyopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 300 participants (estimated)
- Target duration
- 3 Years
Sponsor and investigators
- Lead sponsor
- The POLG Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- Jeeva Clinical Trials Inc, ClinTrek Research Private Limited, United Mitochondrial Disease Foundation (UMDF)
- Responsible party
- Sponsor
- Investigators
- Amel Kaara, Principal investigator, Harvard Medical School & Massachusetts General HospitalOmar Hikmat, Principal investigator, Haukeland University / Bergen University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07775872
- Sponsor's protocol ID
- PIONEER-NH-2401
- Acronym
- PIONEER
- Status last verified
- Sep 2026
- First submitted
- 29 Jul 2026
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The Clinical Study Report may be shared after study completion.
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Global Prospective Natural History Study of POLG Disease
- ClinicalTrials.gov ID
- NCT07775872
- Acronym / sponsor ID
- PIONEER / PIONEER-NH-2401
- Conditions
- PolG, Primary Mitochondrial Myopathy
- Keywords
- POLG, POLG disease, Primary Mitochondrial Disease, Mitochondrial DNA Depletion Syndrome, Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), Epilepsy, Seizures
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- The POLG FoundationUniversity, hospital or other
- Collaborators
- Jeeva Clinical Trials Inc, ClinTrek Research Private Limited, United Mitochondrial Disease Foundation (UMDF)
- Study start
- 17 Jun 2026 (actual)
- Primary completion
- 17 Jun 2029 (estimated)
- Study completion
- 17 Jun 2031 (estimated)
- First posted
- 20 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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.
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Target follow-up
- 3 Years
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Observational Cohort | – | –Single Observational Cohort: Individuals (Pediatric and Adults) with genetically confirmed POLG-related disorders. No intervention is administered. Participants undergo longitudinal clinical assessments, patient-reported outcomes, biomarker collection, and review of routine clinical data. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Target Population: Patients of all ages with genetically confirmed POLG disease (autosomal recessive or dominant).
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
13 secondary outcomes
Newcastle Mitochondrial Disease Scale
Time frame: Baseline through 36 months (every 12 months)
Newcastle Paediatric Mitochondrial Disease Scale (NPMDS)
Time frame: Baseline through 36 months (every 12 months)
Patient-Reported Outcomes Measurement Information System (PROMIS) Mitochondrial Fatigue
Time frame: Baseline through 36 months (every 6 months)
Research and Development 36 (RAND-36) Health Survey Quality of Life
Time frame: Baseline through 36 months (every 12 months)
Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale
Time frame: Baseline through 36 months (every 12 months)
Gastrointestinal Symptom Rating Scale (GSRS) Total Score
Time frame: Baseline through 36 months (every 12 months)
Paediatric (PedsQL) Gastrointestinal Symptoms Module
Time frame: Baseline through 36 months (every 12 months)
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.
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.
Patient Global Impression of Change (PGI-C)
Time frame: Baseline through 36 months (baseline, 12 months)
Overall Survival
Time frame: Baseline through 36 months (at every visit)
Number of DNA Polymerase Gamma (POLG) Disease-Related Hospitalizations
Time frame: Baseline through 36 months (at every visit)
DNA Polymerase Gamma (POLG) Burdensome Symptom Assessment
Time frame: Baseline through 36 months (at every visit)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2026.
- Individual participant dataSharing planned: No. The Clinical Study Report may be shared after study completion.
Related trials for PolG, Primary Mitochondrial Myopathy
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The Precision Mito- Mito Map COMPASS Study
Mitochondrial Diseases, Myalgic Encephalomyelitis Chronic Fatigue Syndrome
RecruitingObservational study
Natural History in Primary Mitochondrial Myopathies
Primary Mitochondrial Myopathies
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Amel Kaara principal investigator
Harvard Medical School & Massachusetts General Hospital
Omar Hikmat principal investigator
Haukeland University / Bergen University
21 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of PolG, Primary Mitochondrial Myopathy, run by The POLG Foundation at 21 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 15 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in United States, Norway, Finland, Sweden, United Kingdom and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact PIONEER (+15716094617, pioneer@polgfoundation.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Scale for the Assessment and Rating of Ataxia (SARA) (time frame: Baseline through 36 months (every 12 months)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2026.