Treatment of hyperphenylalaninemia with Sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) and its influence on the amino acids and fatty acids patterns from childhood to adulthood (Tratamiento de la hiperfenilalaninemia con dihidrocloruro de Sapropterina [tetrahidrobiopterina, 6r-bh4] y su influencia en el patrón de aminoácidos y ácidos grasos desde la infancia hasta la edad adulta)

ISRCTN	ISRCTN77098312
DOI	https://doi.org/10.1186/ISRCTN77098312
Protocol serial number	EC81/00474
Sponsor	Aragon Institute of Health Sciences [Instituto Aragonés de Ciencias de la Salud] (Spain)
Funder	Aragon Institute of Health Sciences [Instituto Aragonés de Ciencias de la Salud] (Spain)

Submission date: 31/01/2011
Registration date: 18/04/2011
Last edited: 18/04/2011

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Maria Concepción García Jiménez
Scientific

Servicio de Pediatría. Unidad de Metabolismo. Hospital Universitario Miguel Servet.
Paseo Isabel La Católica 1-3.
Zaragoza
50009
Spain

Phone	+34 607224828
Email	igarciaji@salud.aragon.es

Study information

Primary study design	Interventional
Study design	Phase IV longitudinal retrospective and prospective unblinded controlled single-centre clinical study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Treatment of hyperphenylalaninemia with Sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) and its influence on the amino acids and fatty acids patterns from childhood to adulthood, a Phase IV, longitudinal, unblinded, controlled, single-centre, retrospective and prospective clinical study
Study objectives	The aim of this study is to compare the response to dietary treatment or pharmacological treatment with Sapropterin in patients with hyperphenylalaninemia secondary to phenylalanine hydroxylase deficiency and to assess the blood profile of long-chain fatty acids and amino acids and its relationship with the metabolic control and other complications such as osteopenia. Hyperphenylalaninemia (HPA) is a metabolic disorder mainly caused by a defect in the phenylalanine hydroxylase gene, which produces a deficiency of this enzyme resulting in an alteration of the metabolism of phenylalanine (Phe) and consequently its accumulation. Phe is toxic to the central nervous system, therefore an accumulation of Phe leads to an alteration in the psychomotor development. A strict diet can control the Phe blood level enough to avoid most of the serious neurological effects. However, dietary treatment presents some problems, such as difficult adherence, negative impact on the daily life of the patients or nutritional deficiencies. Sapropterin significantly reduces and maintains blood Phe concentrations with the subsequently improving quality of diet. Sapropterin allows to partially or fully liberalize the diet with limited intake of phenylalanine in certain types of hyperphenylalaninemias. This will improve the quality of life of patients, as well as their neurological / cognitive development. Furthermore, in patients who have a good response to Sapropterin, this treatment is able to maintain certain biochemical parameters (total amino acids and essential fatty acids) equally or better controlled than the dietary treatment.
Ethics approval(s)	Clinical Research Ethics Committee of Aragon [Comité Ético de Investigación Clínica de Aragón] Ref: C.I. EC09/055, 02/09/2009
Health condition(s) or problem(s) studied	Hyperphenylalaninemia (HPA)
Intervention	1. Male and female patients with hyperphenylalaninemia secondary to phenylalanine hydroxylase deficiency, controlled in the Metabolism Unit at Children's Hospital Miguel Servet, who respond to treatment with Sapropterin being able to leave the phenylalanine free diet completely or partially 2. The drug administered is Kuvan® (tablets of 100 mg) at a dose of 5-20 mg/kg/day orally (PO), in a single dose. Calculated dose will be rounded to the nearest 100 mg 3. Tablets should be dissolved in water (120 ml for children and 240 ml for adults), and solution should be drunk within 15-20 minutes after preparation 4. Control group: patients of both sexes, from birth, diagnosed with classic hyperphenylalaninemia, controlled in the Metabolism Unit at Children's Hospital Miguel Servet, who have not responded to treatment with Sapropterin and are only under dietary treatment. 5. Every four months the following information will be collected: 5.1. Anthropometric variables (weight, height), phenylalanine tolerance by a nutrition survey which collects intakes for the previous three days. F 5.2. In subjects taking Sapropterin, daily dose, adherence to treatment, and adverse effects will also be collected 5.3. Biochemical parameters will be assessed every 4 months during the year following the beginning of the study, they will include: total amino acids, essential (AA) amino acids (phenylalanine, methionine, tryptophan, valine, leucine, isoleucine, histidine, lysine, tyrosine) and essential fatty acids 5.5. An estimation will be made of the ratios total AA/AA essential and Phe/Tyr before and after treatment with Sapropterin. 6. Total duration of treatment: 1 year 7. Total duration of follow-up: 28 days
Intervention type	Drug
Phase	Phase IV
Drug / device / biological / vaccine name(s)	1. Sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) 2. Kuvan®
Primary outcome measure(s)	1. Every four months biochemical analysis of total amino acids and essential fatty acids as indicators of quality 2. Amino acids levels were analyzed by HPLC (cation-exchange high performance liquid chromatography) 3. The levels of essential fatty acids were determined by gas-liquid chromatography
Key secondary outcome measure(s)	1. Prevalence in our population of patients with hyperphenylalaninemia who respond to Sapropterin 2. Correlation between a type of mutation and the response to Sapropterin 3. Relationship in our population between the response to Sapropterin and the severity of biochemical phenotype and genotype 4. Profile of total and essential amino acids and fatty acids on patients treated with Sapropterin versus patients treated with diet. Liberalization of phenylalanine-free diet as much as possible 5. Diet liberalization will be assessed by increasing the amounts of Phe on the daily diet and controlling at the same time the Phe blood level is within the appropriate limits (less than 240 nmol/ml in children under 6 year-old, less than 360 nmol/ml in children of 6-10 year-old, and less than 500 nmol/ml in older than 10)
Completion date	25/11/2011

Eligibility

Participant type(s)	Patient
Age group	Other
Sex	All
Target sample size at registration	30
Key inclusion criteria	1. Patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency, who respond to treatment with Sapropterin 2. Childbearing women who should have a negative pregnancy test within 7 days prior to start of treatment with Sapropterin and should use reliable contraception during the whole study 3. The control group will include patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency that are metabolically well controlled without Sapropterin
Key exclusion criteria	1. Liver impairment or other underlying chronic disease that may require regular treatment 2. Pregnancy and breastfeeding
Date of first enrolment	12/03/2009
Date of final enrolment	25/11/2011

Locations

Countries of recruitment

Spain

Study participating centre

Servicio de Pediatría. Unidad de Metabolismo. Hospital Universitario Miguel Servet.

Zaragoza
50009
Spain

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes