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
Secondary identifying numbers EC81/00474
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

Study designPhase IV longitudinal retrospective and prospective unblinded controlled single-centre clinical study
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use the contact details below to request a patient information sheet
Scientific titleTreatment 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 objectivesThe 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) studiedHyperphenylalaninemia (HPA)
Intervention1. 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 typeDrug
Pharmaceutical study type(s)
PhasePhase IV
Drug / device / biological / vaccine name(s)1. Sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) 2. Kuvan®
Primary outcome measure1. 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
Secondary outcome measures1. 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)
Overall study start date12/03/2009
Completion date25/11/2011

Eligibility

Participant type(s)Patient
Age groupOther
SexBoth
Target number of participants30
Key inclusion criteria1. 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 criteria1. Liver impairment or other underlying chronic disease that may require regular treatment
2. Pregnancy and breastfeeding
Date of first enrolment12/03/2009
Date of final enrolment25/11/2011

Locations

Countries of recruitment

  • Spain

Study participating centre

Servicio de Pediatría. Unidad de Metabolismo. Hospital Universitario Miguel Servet.
Zaragoza
50009
Spain

Sponsor information

Aragon Institute of Health Sciences [Instituto Aragonés de Ciencias de la Salud] (Spain)
Government

c/o Esteban de Manuel Keenoy
Instituto Aragonés de Ciencias de la Salud
Avenida Gómez Laguna, 25.
Zaragoza
50009
Spain

Email emlopezh.iacs@aragon.es
Website http://www.aragon.es/
ROR logo "ROR" https://ror.org/05p0enq35

Funders

Funder type

Government

Aragon Institute of Health Sciences [Instituto Aragonés de Ciencias de la Salud] (Spain)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan