Clinical trial NCT03856866: Hydroxychloroquine Administration for Reduction of Pexophagy
Official title: Hydroxychloroquine Administration for Reduction of Pexophagy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Zellweger Syndrome
Peroxisome Biogenesis Disorders
Keywords: PBD, Zellweger spectrum, PBD-ZSD
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2019-02-27
Enrollment: 3
Sex: ALL
Minimum age (years): 6
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A randomized, blinded, placebo controlled, crossover N of 1 trial.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Electroretinogram (ERG) voltage changes.
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
measure: Change in the red blood cell levels of plasmalogen.
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
measure: Change in the plasma levels of phytanic acid.
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
measure: Change in the plasma levels of very-long chain fatty acids.
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
Secondary outcomes:
measure: Eye examination: Optical Coherence Tomography
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
measure: Eye examination: Visual Acuity
timeFrame: 12 week. Measurements at Day 0, Day 84(+/-7 days) of each treatment arm.
measure: Pediatric Inventory for Parents (PIP) following the treatment arms.
timeFrame: 36 week. Measurements following each treatment arm.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Neal Sondheimer, MD
role: PRINCIPAL_INVESTIGATOR
References: