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Hydroxychloroquine Administration for Reduction of Pexophagy (HARP)

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ClinicalTrials.gov Identifier: NCT03856866
Recruitment Status : Recruiting
First Posted : February 27, 2019
Last Update Posted : February 27, 2019
Sponsor:
Information provided by (Responsible Party):
Neal Sondheimer, The Hospital for Sick Children

Brief Summary:
A series of N-of-1, crossover, randomized, placebo-controlled, double-blinded trial. Hydroxychloroquine (HCQ) and a crossover to placebo (order is randomized and blinded) will be administered in liquid suspension for 84 days (12 weeks) each with an 84 day washout in between. We hypothesize that HCQ will reduce peroxisomal turnover, which will arrest ongoing injury in PBDs caused by PEX1, PEX6 or PEX26.

Condition or disease Intervention/treatment Phase
Zellweger Syndrome Peroxisome Biogenesis Disorders Drug: Hydroxychloroquine Drug: Placebo Phase 2

Detailed Description:

HARP is a phase II/III, double-blind, placebo-controlled, randomized, crossover series N-of-1 study of the effect of hydroxychloroquine (HCQ) in patients with peroxisomal biogenesis disorders (PBD-ZSD). Patients eligible for the study must have a laboratory diagnosis of PEX1, PEX6 or PEX26 dependent PBD-ZSD from a CLIA or SCC-certified clinical laboratory, a history of abnormal VLCFA levels, and must be at least 84 days from their last HCQ dose. Patients will be excluded for known sensitivity to HCQ, known glucose-6-phosphate dehydrogenase deficiency, if they have an expected survival of less than 9 months or if they are participating in another interventional clinical trial.

HCQ will be administered at a dose of 4mg/kg/day divided into two doses, as a liquid suspension that can be given orally or through nasogastric or gastric tube. Within the study, HCQ or placebo will be given for 84 days, followed by a washout period of 84 days followed by an 84 day crossover to the alternative therapy to assess the effect the study measures.

Study measures will be completed at four intervals (initiation, end of period 1, start of period 2, end of trial). Ophthalmological monitoring of patients has three components, electroretinogram (ERG), visual acuity testing and optical coherence tomography (OCT). Plasma levels of very long-chain fatty acids (VLCFA), plasmalogen and phytanic acid will be assessed. Parents will also be administered The Pediatric Inventory for Parents (PIP), a questionnaire that was developed to evaluate the stress associated with parenting a seriously ill child, at the end of period 1 and period 2.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: A randomized, blinded, placebo controlled, crossover N of 1 trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: All parties will be masked except for research pharmacy who will do the randomization.
Primary Purpose: Treatment
Official Title: Hydroxychloroquine Administration for Reduction of Pexophagy
Actual Study Start Date : January 11, 2019
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Experimental: Hydroxychloroquine
Hydroxychloroquine: liquid suspension, 4mg/kg/day by mouth, divided bid for 84 days.
Drug: Hydroxychloroquine
Hydroxychloroquine: 4mg/kg/day, divided bid.
Other Names:
  • Apo-Hydroxyquine
  • Plaquenil

Placebo Comparator: Placebo
Liquid suspension compounded to mimic the taste, appearance and texture of the investigational agent.
Drug: Placebo
Liquid suspension compounded to mimic the active hydroxycholoquine interventional agent.




Primary Outcome Measures :
  1. Electroretinogram (ERG) voltage changes. [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Electroretinograms are a diagnostic test that measures the electric activity within cells in response to stimulus. ERG voltages are depressed in peroxisomal disease, and the quantitative evaluation of ERG voltage is another measure that has been used as an endpoint for clinical trials in peroxisomal disease. Change in b-wave voltage before and after treatment period.

  2. Change in the red blood cell levels of plasmalogen. [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Change in the red blood cell levels of plasmalogen (18:0 dimethylacetals/18:0 ratio).

  3. Change in the plasma levels of phytanic acid. [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Change in the plasma levels of phytanic acid.

  4. Change in the plasma levels of very-long chain fatty acids. [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Change in the plasma levels of very-long chain fatty acids (C26/C22).


Secondary Outcome Measures :
  1. Eye examination: Optical Coherence Tomography [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Optical coherence tomography is an imaging study of the retina. OCT is routinely performed in clinical management of patients with peroxisomal disease.

  2. Eye examination: Visual Acuity [ Time Frame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm. ]
    Visual acuity testing evaluates the visual performance of patients using the reading of a logMAR chart. Visual acuity testing is routinely performed in clinical management of patients with peroxisomal disease.

  3. Pediatric Inventory for Parents (PIP) following the treatment arms. [ Time Frame: 36 week. Measurements following each treatment arm. ]
    The PIP is a validated measure of parental stress related to the care for children with chronic illness.



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Ages Eligible for Study:   6 Months to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosed with a peroxisomal defect due to PEX1, PEX6 or PEX26 through a SCC or CLIA-certified clinical genetic testing laboratory.
  • Abnormal plasma very-long-chain fatty acid levels.
  • All therapies available in Canada have been considered and ruled out, have failed or were justified as being unsuitable for the patient. We note that there are no therapies available.
  • At least 84 days from last HCQ dose

Exclusion Criteria:

  • Known sensitivity to HCQ.
  • Known Glucose-6-phosphate dehydrogenase deficiency.
  • Expected survival is less than six months.
  • The patient does not provide informed consent.
  • The patient is participating in another interventional clinical trial.

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): NCT03856866


Contacts
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Contact: Neal Sondheimer, MD 4168137654 ext 301480 neal.sondheimer@sickkids.ca
Contact: Julie Choi, M.Sc 4168137654 ext 222838 julie.choi@sickkids.ca

Locations
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Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G1X8
Contact: Julie Choi       julie.choi@sickkids.ca   
Sponsors and Collaborators
The Hospital for Sick Children
Investigators
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Principal Investigator: Neal Sondheimer, MD The Hospital for Sick Children

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Responsible Party: Neal Sondheimer, Staff Physician - Clinical and Metabolic Genetics, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT03856866     History of Changes
Other Study ID Numbers: 1000061385
First Posted: February 27, 2019    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Neal Sondheimer, The Hospital for Sick Children:
PBD, Zellweger spectrum, PBD-ZSD

Additional relevant MeSH terms:
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Peroxisomal Disorders
Zellweger Syndrome
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Liver Diseases
Digestive System Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Kidney Diseases
Urologic Diseases
Abnormalities, Multiple
Congenital Abnormalities
Hydroxychloroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents