Mitochondrial Complex I Dysfunction in PWS

NCT ID: NCT03831425

Last Updated: 2024-06-18

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-01
• Study Completion Date: 2024-06-30

Brief Summary

Prader-Willi Syndrome (PWS) is characterized by profound infantile hypotonia, growth delay, cognitive impairment, muscle weakness and exercise intolerance. Studies have suggested that a defect in energy metabolism, yet to be clarified, may be involved in its pathogenesis. Many PWS patients have received Coenzyme Q10, but the rationale for this and objective impact on cellular metabolism has not been clarified.

Detailed Description

Investigators will determine the clinical efficacy of CoQ10 in a prospective, randomized, double-blind, controlled, cross-over study. Primary outcome will include determination of muscle function based on a 3 minute step test which showed good sensitivity in the investigators' pilot study. Secondary outcomes will determine effects on muscle power (maximal vertical jump), strength (hand grip), endurance (6 Minute Walk Test), fatigue (PedsQL quality of life scale), physical activity level (3DPAR), attention (ADHDT), cognition (MOCA), and physical function (CHAQ). The investigators' subaim is to elucidate the pathophysiologic mechanisms by which clinical improvements are mediated through interrogation of underlying mitochondrial dysfunction to optimize therapies. This will include determination of total aerobic capacity (maximal graded cycle ergometry), muscle metabolic function (31P-magnetic resonance spectroscopy (MRS) of muscle to evaluate high energy phosphagen, anaerobic and aerobic exercise metabolism), mitochondrial function (serum lactate, carnitine, acylcarnitines, lactate/pyruvate ratio), and blood and urine oxidative stress markers of lipid, protein and DNA peroxidation. Investigators hypothesize that CoQ10 will lead to a clinically significant improvement in motor function, power, fatigue, habitual activity, attention span & thereby quality of life in PWS.

Conditions

Prader-Willi Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Coenzyme Q

Each patient will be asked to take part in a 6 wk trial of pharmaceutical grade CoQ10 and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk CoQ10 trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).

Group Type: EXPERIMENTAL

Coenzyme Q10

Intervention Type: DIETARY_SUPPLEMENT

6 week trial of either treatment with CoenzymeQ.

Placebo

Each patient will be asked to take part in a 6 wk trial of placebo and will be randomly assigned to a start time. There will be a 6 wk washout period between treatment and placebo arms. At baseline, if this is the first arm, testing will include determination of muscle function based on our 3 min step test, muscle power (maximal jump, handgrip), strength (Queens' Square), endurance (6MWT), fatigue (PedsQL fatigue scale), physical activity level (3DPAR), attention (ADHDT scale), cognition (MoCA), physical function (CHAQ).and quality of life (PedQL). Following the 6 wk placebo trial, testing will include repeat determination of all of the above as well as determination of total aerobic capacity (maximum cycle ergometry) and muscle metabolism (31P-MRS ergometry).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

6 week trial of either treatment with Placebo

Interventions

Coenzyme Q10

6 week trial of either treatment with CoenzymeQ.

Intervention Type: DIETARY_SUPPLEMENT

Placebo

6 week trial of either treatment with Placebo

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Consent provided

2. patients with genetically confirmed PWS aged 13 to 18 years (n=14)

3. ability to cooperate with exercise testing

4. weight > 35.0 kg

5. in good general health as evidenced by medical history

6. able to take oral medications

7. for females of reproductive potential, use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 8 weeks after the end of study intervention administration

8. for males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during study participation and for an additional 8 weeks after the end of study intervention administration

Exclusion Criteria

1. unable to perform exercise tests,

2. already taking CoQ10

3. having liver disease or bile duct blockage,

4. having thyroid disease or taking thyroid medications

5. presence of diabetes

6. taking antiarrhythmics or antihypertensives or anti-failure medications

7. presence of gastric disorders

8. presence of skin disorders

9. pregnancy or lactation

10. lactose intolerance

11. known allergic reaction to CoQ10 or components of preparation.

12. treatment with another investigational drug or other intervention

13. current smoker or tobacco use within 6 months

14. current cannabis user or use within 6 months

15. presence of chronic respiratory disease other than asthma

16. presence of cardiac disease with cardiac insufficiency/CHF

17. presence of MR-incompatible metal in body, metal devices or tattoos

18. presence of a bleeding disorder

19. gelatin intolerance

20. clinically significant findings in laboratory tests at screening

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Foundation for Prader-Willi Research

OTHER

Sponsor Role: collaborator

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Ingrid Tein

Director, Neurometabolic Clinic, Staff Neurologist, Division of Neurology, Principal Investigator, Senior Associate Scientist, Genetics and Genome Biology Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ingrid Tein, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

Other Identifiers

1000053066

Identifier Type: -

Identifier Source: org_study_id