Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients' and parents' quality of life: the phenylketonuria - quality of life (PKU-QOL) questionnaires

BACKGROUND: The aim of our study was to develop and validate the first set of PKU-specific Health-related Quality of Life (HRQoL) questionnaires that: 1) were developed for patients with PKU and their parents, 2) cover the physical, emotional, and social impacts of PKU and its treatment on patients' lives, 3) are age specific (Child PKU-QOL, Adolescent PKU-QOL, Adult PKU-QOL), 4) enable the evaluation of the HRQoL of children by their parents (Parent PKU-QOL), and 5) have been cross-culturally adapted for use in seven countries (i.e. France, Germany, Italy, The Netherlands, Spain, Turkey and the UK). METHODS: The PKU-QOL questionnaires were developed according to reference methods including patients', parents' and healthcare professionals' interviews; testing in a pilot study (qualitative step in six countries), and linguistic validation of the finalised pilot versions in Turkish. For finalisation and psychometric validation, the pilot versions were included in a multicentre, prospective, non-interventional, observational study conducted in 34 sites in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Iterative multi-trait analyses were conducted. Psychometric properties were assessed (concurrent and clinical validity, internal consistency reliability and test-retest reliability). RESULTS: Data from 559 subjects (306 patients, 253 parents) were analysed. After finalisation, the PKU-QOL questionnaires included 40 items (Child PKU-QOL), 58 items (Adolescent PKU-QOL), 65 items (Adult PKU-QOL) and 54 items (Parent PKU-QOL), distributed in four modules: PKU symptoms, PKU in general, administration of Phe-free protein supplements and dietary protein restriction. The measurement properties of the Adolescent, Adult and Parent PKU-QOL questionnaires were overall fairly satisfactory, but weaker for the Child questionnaire. CONCLUSIONS: The four PKU-QOL questionnaires developed for different ages (Child PKU-QOL, Adolescent PKU-QOL, Adult PKU-QOL), and for parents of children with PKU (Parent PKU-QOL) are valid and reliable instruments for assessing the multifaceted impact of PKU on patients of different age groups (children, adolescents and adults) and their parents, and are available for use in seven countries. They are very promising tools to explore how patients' perceptions evolve with age, to increase knowledge of the impact of PKU on patients and parents in different countries, and to help monitor the effect of therapeutic strategies

Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries

The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL

Additional file 3: Table S3. of Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries

Comparisons of PKU-QOL scores according to BH4 intake. This file includes four tables presenting in the child, adolescent, adult and parent samples the comparison of PKU-QOL scores according to BH4 intake (BH4 intake; no BH4 intake)

Additional file 2: Table S2. of Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries

Comparisons of PKU-QOL scores according to the overall health status as assessed by the clinicians. This file includes four tables presenting in the child, adolescent, adult and parent samples the comparison of PKU-QOL scores according to the overall assessment of health status made by the clinicians (poor; fair; good; very good; excellent)

Additional file 1: Table S1. of Assessment of the impact of phenylketonuria and its treatment on quality of life of patients and parents from seven European countries

Comparisons of PKU-QOL scores according to the severity of PKU. This file includes four tables presenting in the child, adolescent, adult and parent samples the comparison of PKU-QOL scores according to the severity of PKU (mild-moderate PKU: Phe level 600–1200 μmol/L; Classical PKU: Phe level >1200 μmol/L)

Additional file 1: Figure S1. of Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Summary of neuromotor developmental milestones – ITT population. Data show (a) the proportion of patients with normal development in the area of assessment at baseline, (b) Week 12, and (c) Week 26 treated with sapropterin plus the Phe-restricted diet, or Phe-restricted diet alone. P-values show comparison of results between treatment groups at Week 26 using the chi-squared test. Table S1. PAH genotypes of sapropterin responders (n=37). (DOCX 180 kb

Efficacy, Safety And Population Pharmacokinetics Of Sapropterin In Pku Patients < 4 Years: Results From The Spark Open-Label, Multicentre, Randomized Phase Iiib Trial

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients >= 4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan r) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children = 1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using nonlinear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children < 4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients < 4 years with BH4-responsive phenylketonuria.WoSScopu