Hydroxychloroquine Administration for Reduction of Pexophagy (HARP)

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.

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.

Liquid suspension compounded to mimic the taste, appearance and texture of the investigational agent.

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.

Optical coherence tomography is an imaging study of the retina. OCT is routinely performed in clinical management of patients with peroxisomal disease.

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.

The PIP is a validated measure of parental stress related to the care for children with chronic illness.

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.