Clinical trial NCT03820804: Nutritional Status in Phenylketonuria
Official title: Trends in Nutritional Status of Patients With Phenylketonuria
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Phenylketonurias
Lead sponsor: Universidade do Porto
Sponsor class: OTHER
Collaborators: name: Centro Hospitalar do Porto
name: BioMarin Pharmaceutical
First posted: 2019-01-29
Enrollment: 94
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Centro Hospitalar do Porto is one Portuguese Reference Centre for the treatment of inborn errors of metabolism. A cohort of patients with Phenylketonuria is under follow-up with different treatment strategies implemented. All treatment strategies are fully reimbursed by the Portuguese health system and this project aims to evaluate the longitudinal impact of different treatment options on nutritional status outcome.

Brief summary: In the era of Phenylketonuria (PKU) newborn screening, early diagnosis in the neonatal period and prompt treatment institution has protected patients from developing severe and irreversible mental retardation. The main objective of the treatment is to prevent a chronic elevation of blood Phe concentrations, which together with reduced tyrosine concentrations may increase the risk of neurologic damage. In order to achieve this purpose, the mainstay of treatment is a special diet characterized by a natural protein restriction, supplemented with protein substitutes and special low protein foods.

The requirement to optimize growth and body composition, usually result in dietary prescriptions that are high in carbohydrate (\>60% of energy intake), to promote anabolism, considering the synthetic properties of this special diet. Some studies have described a high risk of developing overweight and obesity. Although there is a tendency for a higher incidence in females, it seems that the prevalence in PKU patients follows the same trend as the general population. However, there are limited studies published so far and no longitudinal studies are available describing current practice and its impact on the prevalence of overweight and obesity; neither its consequences in terms of metabolic syndrome or cardiometabolic markers.

Recently, sapropterin dihydrochloride, which is the synthetic form of Phenylalanine Hydroxylase cofactor, is available in Portugal for patients with PKU. In practice, the sapropterin treated patients increase their natural protein intake, minimizing the synthetic characteristics of the diet. While there is a need for patient re-education about the practicalities of meeting their nutritional needs, scientific evidence about the nutritional status impact of diet liberalization is inadequate.

This study aims to test the following hypothesis:

1. Global nutritional status is not significantly affected in patients with PKU under exclusive dietary treatment.
2. There is a trend for increased rates of overweight and obesity in patients with PKU from 2009 and we consider this will continue to increase.
3. The start of sapropterin treatment allows a higher natural protein intake in patients with PKU that significantly targets nutritional status in at least one of its components (anthropometry, body composition or biochemistry).

Detailed description: At the Centro Hospitalar do Porto (Reference Centre for the treatment of Inherited Metabolic Diseases) the annual nutritional status evaluation routinely generates data on anthropometry, body composition, blood pressure, nutritional intake and clinical biochemistry. Since 2009, all this information is recorded for all the patients with PKU under follow-up.

For the purpose of this project, data will be collected, from 2009 until 2018, using a minimum of 5 annual nutritional status evaluations per patient. The project will be able to compare the longitudinal evolution of nutritional status in exclusively diet treated patients (period between 2009 and 2014) with a subgroup of patients already under sapropterin treatment in the period between 2015 and 2018. Genotype is available for all patients with PKU under follow-up at Centro Hospitalar do Porto. However, the decision for starting sapropterin treatment was based on the results from a sapropterin-loading test protocol, approved in 2014 by the Portuguese Society of Metabolic Disorders (not published).

For every PKU patient under follow-up at Centro Hospitalar do Porto, the information about nutritional intake is recorded in a special file that contains all the diet details collected in every appointment. In that way, for the purpose of the annual nutritional status evaluation, every PKU patient is submitted to anthropometric and body composition evaluations, blood pressure assessment and blood samples collection for completing the hematological and biochemical measurements. Also in the same day, at the nutrition appointment, a dietary assessment is done, in order to allow further nutrition adjustments when needed. This approach allows us to know the precise nutritional ingestion in the period before all the measurements.

Data will be collected from patient databases or patient records. In the period between 2009 and 2014 there are no treatments or interventions to which the patients can be randomly assigned, as no specific treatment is the focus of the project. In the period between 2015 and 2018, patients will be divided in two groups based on treatment modalities: diet-treated only or sapropterin treatment. However, their assignment in each group does not have any influence of the project itself. The inclusion in one of the two groups will be decided based on the results of the sapropterin loading test done previously within the clinical routine protocol. Patients will be identified only by a number and only medical data will be collected. No directly or indirectly nominative data will be collected and data will be anonymous.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of PKU.
* With all the clinical data available since 2009.
* Have completed the annual routine nutritional status evaluation in the periods 2009/2010, 2011/2012, 2013/2014, 2015/2016 and 2017/2018.
* Maintaining a follow-up at Centro Hospitalar do Porto.

Exclusion Criteria:

* Lost of follow-up.
* Not have completed at least one full evaluation in each time period: 2009/2010, 2011/2012, 2013/2014, 2015/2016 and 2017/2018.
* Any other chronic medical condition which may affect diet or nutritional status.

Primary outcomes:
measure: Overweight and obesity prevalence
timeFrame: 2009-2018
measure: Overweight and obesity incidence
timeFrame: 2009-2018
Secondary outcomes:
measure: Metabolic syndrome prevalence
timeFrame: 2009-2018
measure: Metabolic syndrome incidence
timeFrame: 2009-2018
measure: Body composition using bioelectrical impedance analysis
timeFrame: 2009-2018
measure: Metabolic control (blood phenylalanine concentration)
timeFrame: 2009-2018
measure: Metabolic control (blood phenylalanine concentration) and sapropterin
timeFrame: 2015-2018
measure: Phenylalanine intake and sapropterin
timeFrame: 2015-2018
Other outcomes:
Locations:
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário do Porto
Study officials:
affiliation: Centro Hospitalar do Porto
name: Júlio C Rocha, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: MacDonald A, Rocha JC, van Rijn M, Feillet F. Nutrition in phenylketonuria. Mol Genet Metab. 2011;104 Suppl:S10-8. doi: 10.1016/j.ymgme.2011.08.023. Epub 2011 Sep 2.
citation: Rocha JC, van Spronsen FJ, Almeida MF, Soares G, Quelhas D, Ramos E, Guimaraes JT, Borges N. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab. 2012 Dec;107(4):659-63. doi: 10.1016/j.ymgme.2012.10.006. Epub 2012 Oct 16.
citation: Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Ahring K, Belanger-Quintana A, MacDonald A. Optimising growth in phenylketonuria: current state of the clinical evidence base. Clin Nutr. 2012 Feb;31(1):16-21. doi: 10.1016/j.clnu.2011.09.001. Epub 2011 Sep 29.
citation: Rocha JC, MacDonald A, Trefz F. Is overweight an issue in phenylketonuria? Mol Genet Metab. 2013;110 Suppl:S18-24. doi: 10.1016/j.ymgme.2013.08.012. Epub 2013 Aug 31.
citation: MacDonald A, Ahring K, Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Belanger-Quintana A. Adjusting diet with sapropterin in phenylketonuria: what factors should be considered? Br J Nutr. 2011 Jul;106(2):175-82. doi: 10.1017/S0007114511000298.
citation: Rocha JC, van Spronsen FJ, Almeida MF, Ramos E, Guimaraes JT, Borges N. Early dietary treated patients with phenylketonuria can achieve normal growth and body composition. Mol Genet Metab. 2013;110 Suppl:S40-3. doi: 10.1016/j.ymgme.2013.10.009. Epub 2013 Oct 22.
citation: Gokmen Ozel H, Ahring K, Belanger-Quintana A, Dokoupil K, Lammardo AM, Robert M, Rocha JC, Almeida MF, van Rijn M, MacDonald A. Overweight and obesity in PKU: The results from 8 centres in Europe and Turkey. Mol Genet Metab Rep. 2014 Nov 16;1:483-486. doi: 10.1016/j.ymgmr.2014.11.003. eCollection 2014.
citation: Rocha JC, van Rijn M, van Dam E, Ahring K, Belanger-Quintana A, Dokoupil K, Gokmen Ozel H, Lammardo AM, Robert M, Heidenborg C, MacDonald A. Weight Management in Phenylketonuria: What Should Be Monitored. Ann Nutr Metab. 2016;68(1):60-5. doi: 10.1159/000442304. Epub 2015 Nov 25.