Clinical trial NCT03831425: Mitochondrial Complex I Dysfunction in PWS
Official title: Mitochondrial Complex I Dysfunction in Prader Willi Syndrome: A New Therapeutic Target
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Prader-Willi Syndrome
Keywords: CoQ10
muscle function
attention span
quality of life
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Foundation for Prader-Willi Research
First posted: 2019-02-05
Enrollment: 0
Sex: ALL
Minimum age (years): 13
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: prospective, randomized, double-blind, controlled, cross-over study with CoQ10 and placebo arms
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Three minute step test
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary outcomes:
measure: Vertical Jump Test
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Hand Grip Test
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: 6 Minute walk test
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Three Day Physical Activity Record (3DPAR)
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: SWAN Rating Scale for Attention Deficit Hyperactivity Disorder (ADHD)
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Montreal Cognitive Assessment (MOCA)
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Childhood Health Assessment Questionnaire (CHAQ)
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Pediatric Quality of Life Index (PedQL)
timeFrame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Other outcomes:
measure: Maximal Work (measured in watts ) from incremental cycle ergometry
timeFrame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: 31-phosphorus magnetic resonance spectroscopy (MRS) ergometry
timeFrame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
measure: Maximal Aerobic Capacity (Oxygen Uptake (VO2) in milliliters per kilogram body weight per minute)from incremental cycle ergometry
timeFrame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Ingrid Tein, MD
role: PRINCIPAL_INVESTIGATOR
References: