Mitochondrial Complex I Dysfunction in PWS

Prader-Willi Syndrome Clinical Trial

Official title:

Mitochondrial Complex I Dysfunction in Prader Willi Syndrome: A New Therapeutic Target

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03831425
• Other study ID #: 1000053066
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 1, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: April 2023
• Source: The Hospital for Sick Children
• Contact: Bushra Momtaz
• Phone: 4168137654
• Email: bushra.momtaz[@]sickkids.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 14
• Est. completion date: December 31, 2024
• Est. primary completion date: June 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Prader-Willi Syndrome
• Syndrome

Intervention

Dietary Supplement:
• Coenzyme Q10
6 week trial of either treatment with CoenzymeQ.

Other:
• Placebo
6 week trial of either treatment with Placebo

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
The Hospital for Sick Children	Foundation for Prader-Willi Research

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Maximal Work (measured in watts ) from incremental cycle ergometry	Change in the amount of work (measured in watts) in a bicycle ride to exhaustion. Participants will ride a stationary bicycle (cycle ergometer) until unable to continue. Workloads will progressively increase every minute from 'easy to pedal' to 'very hard to pedal' until participants are unable to sustain the pedalling for 1 minute. The higher the watts, the more work the participant is able to do.	week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Other	31-phosphorus magnetic resonance spectroscopy (MRS) ergometry	Change in muscular phosphocreatine ((PCr) measured by 31P-Magnetic Resonance Spectroscopy) while performing bicycle exercise in the Magnetic Resonance scanner.	week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Other	Maximal Aerobic Capacity (Oxygen Uptake (VO2) in milliliters per kilogram body weight per minute)from incremental cycle ergometry	Change in aerobic capacity (oxygen uptake (VO2) ml/kg/min) will be measured in a bicycle ride to exhaustion. Workloads will progressively increase every minute from 'easy to pedal' to 'very hard to pedal' until participants are unable to sustain the pedalling for 1 minute. Participants will breathe through a low resistance breathing valve and inspired and expired concentrations of oxygen and carbon dioxide will be measured to determine VO2. The higher the VO2, the higher the aerobic capacity (physical fitness).	week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Primary	Three minute step test	Change in the baseline number of steps in 3 minutes of testing	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Vertical Jump Test	Change in the baseline jumping height (centimetres)	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Hand Grip Test	Change in the baseline hand grip strength (kg)	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	6 Minute walk test	Change in baseline number of metres walked in 6 minutes	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale	Change in the baseline multi-dimensional fatigue scale; total score is reported. The higher the number, the greater the fatigue (range from 0 to 72).	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Three Day Physical Activity Record (3DPAR)	Change in the baseline three day recall of time (number of minutes) spent at rest, and in light, moderate and vigorous activity	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	SWAN Rating Scale for Attention Deficit Hyperactivity Disorder (ADHD)	Change in the baseline total reported score (out of 18 items). If the sum of items 1-9 is 6 or greater, the child is likely ADHD-Inattentive type. If the sum of items 10-18 is 6 or greater, the child is likely ADHD-Hyperactive/Impulsive type. If both the sums of 1-9 and 10-18 are 6 or greater, the child is likely ADHD combined type.	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Montreal Cognitive Assessment (MOCA)	Change in the baseline total cognitive score out of 30 points (range 0 to 30). The higher the number, the better the cognition.	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Childhood Health Assessment Questionnaire (CHAQ)	Change in the baseline CHAQ score. Assessment of how an illness or condition affects child's ability to function in daily life. There are individual items in each of 8 sections (Arising, Eating, Dressing, Walking, Hygiene, Reach, Grip, Activities). Scoring of individual items ranges from 0-3 (0=from no difficulty to 3= unable to do). The higher the score, the more difficult is the task to a maximum of 3 points for each section. For each of the 8 sections, whatever the highest individual score was becomes the score of the section (max 3 points). Points are added to the section score if devices or aids are used for that section (to a maximum of 3 points). The CHAQ score is the total of the 8 sections, divided by 8 with a range from 0 points (no impact on quality of life) to 3 (large impact on quality of life) . The higher the score, the greater the impact of the illness on function.	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)
Secondary	Pediatric Quality of Life Index (PedQL)	Change in baseline child quality of life using pictorial scales and comparators. The lower the score, the worse the quality of life. This is scored out of 10 cm.	Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo)