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 |
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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
Scientific
Servicio de Pediatría. Unidad de Metabolismo. Hospital Universitario Miguel Servet.
Paseo Isabel La Católica 1-3.
Zaragoza
50009
Spain
Phone | +34 607224828 |
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igarciaji@salud.aragon.es |
Study information
Study design | Phase IV longitudinal retrospective and prospective unblinded controlled single-centre clinical study |
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Primary study design | Interventional |
Secondary study design | Randomised controlled trial |
Study setting(s) | Hospital |
Study type | Treatment |
Participant information sheet | Not available in web format, please use the contact details below to request a patient 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 |
Pharmaceutical study type(s) | |
Phase | Phase IV |
Drug / device / biological / vaccine name(s) | 1. Sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) 2. Kuvan® |
Primary outcome measure | 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 |
Secondary outcome measures | 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) |
Overall study start date | 12/03/2009 |
Completion date | 25/11/2011 |
Eligibility
Participant type(s) | Patient |
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Age group | Other |
Sex | Both |
Target number of participants | 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
50009
Spain
Sponsor information
Aragon Institute of Health Sciences [Instituto Aragonés de Ciencias de la Salud] (Spain)
Government
Government
c/o Esteban de Manuel Keenoy
Instituto Aragonés de Ciencias de la Salud
Avenida Gómez Laguna, 25.
Zaragoza
50009
Spain
emlopezh.iacs@aragon.es | |
Website | http://www.aragon.es/ |
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 | |
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Individual participant data (IPD) Intention to share | No |
IPD sharing plan summary | Not provided at time of registration |
Publication and dissemination plan | Not provided at time of registration |
IPD sharing plan |