Histidine Therapy: A Project to Treat HARS Deficiency

This study evaluates the role of histidine in patients with HARS Syndrome. Children with HARS Syndrome will receive oral nutritional supplementation with histidine at a dose which will be increased in the event of acute febrile illness. Vision, hearing and plasma biomarkers will be monitored throughout the study period.

Study Overview

• Status: Active, not recruiting
• Conditions: HARS Syndrome
• Intervention / Treatment: Dietary supplement: L-Histidine

Detailed Description

HARS syndrome is a progressive degenerative disease affecting eyesight and hearing caused by a mutation in the HARS gene which codes for an enzyme involved in protein synthesis. HARS syndrome has been exclusively found in the Old Order Amish communities in Southwestern Ontario and in Pennsylvania. Children with this disorder initially have normal vision and hearing, but with a febrile illness, can have a sudden loss of vision and hearing, as well as visual hallucinations. There is some evidence that vision loss progresses, albeit at a slower rate, even without a febrile incident. In more severe cases, fluid accumulates in the lungs (acute respiratory distress syndrome or ARDS) which can cause a drop in oxygen levels and sometimes death. There is currently no specific treatment for HARS syndrome, apart from supportive care. Anecdotal evidence of an adult with HARS syndrome who was treated with the amino acid L-histidine suggests that there was an improvement in vision, however there were no baseline objective measurements of vision prior to the use of histidine. We have designed a pilot project in which histidine will be given to children with HARS for 6 months. Investigators hypothesize that the histidine will be well tolerated and easily administered, without side effects. Investigators will monitor vision, hearing and bloodwork to determine if there is any change during the course of treatment. As well, investigators plan to administer increased doses of histidine during acute illnesses, hoping to prevent deterioration in breathing due to ARDS. The results of this initial pilot project may pave the way for a longer term study of the use of histidine.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A5W9
      • London Health Sciences Centre, Department of Paediatrics, Division of Medical Genetics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Have molecularly confirmed HARS syndrome (Y454S homozygous).
2. Capable of giving informed consent or assent, or have an acceptable surrogate capable of giving consent on the participant's behalf.
3. Participant or surrogate decision maker is able to understand the study procedures and comply with them throughout the course of the study.
4. Able to take solid foods (ie applesauce) or swallow capsules (in younger children, capsule may be broken and contents mixed with applesauce).
5. At least 1 year of age or greater than 8 kg in weight (since histidine is supplied as a minimal dose of 500 mg/capsule.

Exclusion Criteria:

1. Unable or unwilling to give informed consent.
2. Unable to understand instructions or unable to attend clinic visits.
3. Children less than 1 year of age or less than ~8kg in weight (since histidine is supplied as 500 mg capsules).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; L-Histidine in 500mg capsules taken at a dose of 50mg/kg to maintain high-normal serum histidine levels	Dietary supplement: L-Histidine; L-Histidine in 500mg capsules taken at a dose of 50mg/kg to maintain high-normal serum histidine levels

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual acuity maintenance or improvement	Changes from baseline eye exam	2 years
Visual acuity maintenance or improvement	Changes from baseline electroretinography	2 years
Visual acuity maintenance or improvement	Changes from baseline ocular coherence tomography	2 years
Auditory ability maintenance or improvement	Changes from baseline auditory brainstem response	2 years
Auditory ability maintenance or improvement	Changes from baseline autoacoustic emissions	2 years
Auditory ability maintenance or improvement	Changes from baseline routine ear exam	2 years
Auditory ability maintenance or improvement	Changes from baseline audiometry	2 years
Changes in severity of acute febrile illness	Measured by length of hospital stay	2 years
Changes in severity of acute febrile illness	Measured by requirement for intensive care unit transfer	2 years
Changes in severity of acute febrile illness	Measured by number of hospitalizations	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Changes	Changes to inflammatory markers, HARS protein, HARS antibodies, Amino acid levels and biochemical markers as a result of histidine therapy	2 years
Plasma level maintenance	Does histidine supplementation result in increased plasma histidine levels	1 month

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Actual): October 31, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: September 16, 2016
• First Submitted That Met QC Criteria: October 3, 2016
• First Posted (Estimate): October 5, 2016

Study Record Updates

• Last Update Posted (Actual): June 10, 2022
• Last Update Submitted That Met QC Criteria: June 7, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: 108364

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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