Mitochondrial Complex I Dysfunction in PWS

The Hospital for Sick Children

Status and phase: Withdrawn; Phase 2

Conditions: Prader-Willi Syndrome

Treatments: Other: Placebo; Dietary Supplement: Coenzyme Q10

Study type: Interventional

Funder types: Other

Identifiers

NCT03831425

1000053066

Details and patient eligibility

About

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.

Full 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.

Sex: All

Ages: 13 to 18 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

---

0 participants in 2 patient groups, including a placebo group

Coenzyme Q

Experimental group

Description:

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).

Treatment:

Dietary Supplement: Coenzyme Q10

Placebo

Placebo Comparator group

Description:

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).

Treatment:

Other: Placebo