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Mitochondrial Complex I Dysfunction in PWS

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ClinicalTrials.gov Identifier: NCT03831425
Recruitment Status : Not yet recruiting
First Posted : February 5, 2019
Last Update Posted : August 18, 2021
Sponsor:
Collaborator:
Foundation for Prader-Willi Research
Information provided by (Responsible Party):
Ingrid Tein, The Hospital for Sick Children

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.

Condition or disease Intervention/treatment Phase
Prader-Willi Syndrome Dietary Supplement: Coenzyme Q10 Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: prospective, randomized, double-blind, controlled, cross-over study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The Sick Kids research pharmacist will be responsible for dispensing the CoQ10 capsules which will be of highest grade, purity and safety from Webber Natural Pharmaceuticals Limited. A placebo will be prepared by the Sick Kids research pharmacy and will consist of lactose-filled capsules. The CoQ10 and placebo capsules will not be identical in colour, shape or taste. However, as stated above, researchers, participants and families will be blinded to the treatment phase. They will know they are receiving one capsule for one part of the study and another capsule for the next part. No one (except the pharmacist and an unblinded study team member, who will only distribute and collect the medication given to the family (will not conduct any testing)) will know which capsule contains CoQ10 and which contains the placebo
Primary Purpose: Treatment
Official Title: Mitochondrial Complex I Dysfunction in Prader Willi Syndrome: A New Therapeutic Target
Estimated Study Start Date : September 15, 2021
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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).
Dietary Supplement: Coenzyme Q10
6 week trial of either treatment with CoenzymeQ.

Placebo Comparator: 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).
Other: Placebo
6 week trial of either treatment with Placebo




Primary Outcome Measures :
  1. Three minute step test [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in the baseline number of steps in 3 minutes of testing


Secondary Outcome Measures :
  1. Vertical Jump Test [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in the baseline jumping height (centimetres)

  2. Hand Grip Test [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in the baseline hand grip strength (kg)

  3. 6 Minute walk test [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in baseline number of metres walked in 6 minutes

  4. Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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).

  5. Three Day Physical Activity Record (3DPAR) [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in the baseline three day recall of time (number of minutes) spent at rest, and in light, moderate and vigorous activity

  6. SWAN Rating Scale for Attention Deficit Hyperactivity Disorder (ADHD) [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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.

  7. Montreal Cognitive Assessment (MOCA) [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in the baseline total cognitive score out of 30 points (range 0 to 30). The higher the number, the better the cognition.

  8. Childhood Health Assessment Questionnaire (CHAQ) [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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.

  9. Pediatric Quality of Life Index (PedQL) [ Time Frame: Baseline, week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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.


Other Outcome Measures:
  1. Maximal Work (measured in watts ) from incremental cycle ergometry [ Time Frame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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.

  2. 31-phosphorus magnetic resonance spectroscopy (MRS) ergometry [ Time Frame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    Change in muscular phosphocreatine ((PCr) measured by 31P-Magnetic Resonance Spectroscopy) while performing bicycle exercise in the Magnetic Resonance scanner.

  3. Maximal Aerobic Capacity (Oxygen Uptake (VO2) in milliliters per kilogram body weight per minute)from incremental cycle ergometry [ Time Frame: week 8 (after 6 weeks on study drug or placebo), [6 week washout], week 20 (after 6 weeks study drug or placebo) ]
    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).



Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03831425


Contacts
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Contact: Ingrid Tein, MD 4168137654 ext 205668 ingrid.tein@sickkids.ca

Sponsors and Collaborators
The Hospital for Sick Children
Foundation for Prader-Willi Research
Investigators
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Principal Investigator: Ingrid Tein, MD The Hospital for Sick Children
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Responsible Party: Ingrid Tein, Director, Neurometabolic Clinic, Staff Neurologist, Division of Neurology, Principal Investigator, Senior Associate Scientist, Genetics and Genome Biology Program, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT03831425    
Other Study ID Numbers: 1000053066
First Posted: February 5, 2019    Key Record Dates
Last Update Posted: August 18, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ingrid Tein, The Hospital for Sick Children:
CoQ10
muscle function
attention span
quality of life
Additional relevant MeSH terms:
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Prader-Willi Syndrome
Syndrome
Disease
Pathologic Processes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn
Obesity
Overnutrition
Nutrition Disorders
Ubiquinone
Coenzyme Q10
Micronutrients
Physiological Effects of Drugs
Vitamins