Trial of Kuvan in Lesch-Nyhan Disease

Trial of Kuvan™ (Sapropterin) Treatment in Patients With Lesch Nyhan Disease

To assess the possibility that treatment with Kuvan (a form of tetrahydrobiopterin) will lessen the abnormal behavior and/or neurology commonly found in Lesch-Nyhan disease (LND); to assess biochemical changes as measured in blood and urine.

Study Overview

• Status: Withdrawn
• Conditions: Behavioral Manifestations of Lesch-Nyhan Disease
• Intervention / Treatment: Drug: sapropterin

Detailed Description

Lesch-Nyhan disease (LND) is an X-linked disorder of purine metabolism which results from mutation in the gene for the enzyme hypoxanthineguanine phosphoribosyltransferase (HPRT); patients have hyperuricemia, gout, urinary tract calculi, and nephropathy which are effectively treated with allopurinol. There is also a syndrome of dystonia, chorea and athetosis, as well as involuntary self mutilative biting and aggression toward their caretakers, for which there is no treatment.

Kuvan™ is a form of tetrahydrobiopterin (BH4), and is approved to help lower the blood levels of phenylalanine in people who have phenylketonuria (PKU). LND patients have been found to have decreased BH4 in the spinal fluid and brain; BH4 is a precursor of dopamine, which has an effect on behavior. In an earlier study Dr Nyhan found that treatment of LND with 5-hydroxytryptophan and carbidopa abolished the self-injurious behavior but was uniformly transient.

This is a single site open-label protocol for eight subjects age 4 years and older with Lesch-Nyhan Disease documented by deficiency of HPRT.

The study involves three study visits to San Diego and one study visit done locally. The first visit will last 13 days, the following visits are single day visits at week 4 and week 8, and the local study visit is a brief outpatient visit at week 6. Physical and neurological exams, videotaping of the patient's interactions with the study staff, and blood and urine collection for laboratory analyses will be performed at each San Diego visit. A family member or caregiver will be asked to complete a short assessment form and report any illness or medication changes. In addition, the study staff will have weekly telephone contact with the family to discuss any behavioral changes or study drug issues.

If the patient's self injurious behavior becomes worse after starting Kuvan the drug will be discontinued and the patient will be followed until the behavior returns to baseline.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • UCSD Mitochondrial and Metabolic Disease Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Ages 4 years and older
2. Must have documented evidence of HPRT deficiency.
3. Be on a stable treatment regimen for 30 days or more
4. Willing and able to travel to San Diego for the study visits
5. Have a local neurologist or physician familiar with the patient or experienced in managing behavioral/neuromuscular disorders and willing to assist with study procedures and adverse events if necessary

Exclusion Criteria:

1. Concurrent enrollment in an investigational drug study
2. Currently taking levodopa
3. Elevated liver enzymes
4. Renal or liver impairment or disease
5. Inability to comply with required study procedures

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: Kuvan; 10mg/kg Kuvan for 5 days followed by 20mg/kg Kuvan for a total of 60 days	Drug: sapropterin; oral 100mg tablets taken intact or dissolved in water or apple juice with morning meal for up to 60 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinical responses to be monitored will include frequency and severity of self mutilation episodes, frequency and severity of aggressive acts towards others, and any effect on involuntary movements.	Periodically during the eight weeks of treatment per patient

Secondary Outcome Measures

Outcome Measure	Time Frame
Effect of Kuvan on standard chemistries, plasma amino acids, and plasma and urinary catecholamines	Assessed periodically during treatment

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2009
• Primary Completion (ACTUAL): February 1, 2010
• Study Completion (ACTUAL): February 1, 2010

Study Registration Dates

• First Submitted: July 8, 2009
• First Submitted That Met QC Criteria: July 8, 2009
• First Posted (ESTIMATE): July 9, 2009

Study Record Updates

• Last Update Posted (ACTUAL): August 2, 2019
• Last Update Submitted That Met QC Criteria: July 31, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Lesch-Nyhan Disease; self-mutilating behavior
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Purine-Pyrimidine Metabolism, Inborn Errors; Lesch-Nyhan Syndrome
• Other Study ID Numbers: WLN01