Sapropterin dihydrochloride for phenylketonuria
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and safety of sapropterin dihydrochloride in decreasing blood Phe levels in people with PKU.
Background
Description of the condition
Phenylketonuria (PKU) is an autosomal recessive mendelian disorder (OMIM 261600) characterized by an increase of phenylalanine (Phe) in blood and body fluids (Scriver 2001).
Phenylketonuria manifests itself as increased Phe concentration in blood (hyperphenylalaninemia (HPA)). Ninety‐eight per cent of HPA is due to mutations in the gene coding for phenylalanine hydroxylase (PAH) enzyme (E.C.1.14.16.1). Two percent of HPA is due to a defect in tetrahydrobiopterin (BH4) metabolism which is an essential co‐factor for the activity of PAH (Baulny 2007).
The incidence of PKU due to mutations in the PAH gene is about 1 in 10,000 in individuals of European and Oriental Asian origin (Scriver 2007).
On the basis of blood Phe concentration, HPA due to PAH deficiency can be classified into classic PKU (Phe >1200 μmol/L); mild PKU (Phe 600 ‐1200 μmol/L); and mild HPA (Phe < 600 μmol/L but more than the upper reference limit) (Williams 2008).
In untreated PKU, the infant appears normal for the first few months of life, but later on shows features of progressive encephalopathy. Other features include growth failure, microcephaly, seizures, intellectual impairment, eczema, lightly pigmented skin and musty odour (Scriver 2001; Baulny 2007; Williams 2008).
Metabolic derangement in PKU
Phenylalanine is an essential amino acid provided by protein in the diet. A small amount of this is used for protein synthesis and the rest is hydroxylated to tyrosine and further metabolized. The Phe hydroxylation requires PAH, dihydropteridine reductase (DHPR) and BH4. When conversion to tyrosine is blocked, Phe accumulates in the body fluids (Scriver 2001). Above a threshold level (1300 μmol) the high Phe level is thought to result in neurotoxicity and lead to mental retardation. (Williams 2008).
Description of the intervention
The mainstay of treatment for PKU is a Phe‐restricted diet and the goal is to keep the Phe concentration in body fluids to < 360 μmol/L which prevents the neuropsychological changes. The treatment is to be instituted by 20 days of age, should be aggressive with regular monitoring of blood Phe levels. Ideally the strict dietary restriction should continue into adult life (MRC (UK) 1993; Cockburn 1996; NIH Consensus Development Panel 2001).
The Phe‐restricted diet is designed in a way that allows a decrease in blood Phe concentration, provides sufficient tyrosine (now an essential amino acid) and other nutrients required for optimal growth and development of the child (Baulny 2007). This involves exclusion from diet of almost all natural protein with the exception of that occurring in vegetables and fruits. Commercially available supplements of amino acids that lack Phe are to be taken on a daily basis. (Baulny 2007; Williams 2008).
A strict compliance with such a diet has been shown to be compatible with better cognitive and motor function, behavioral temperament and executive function. An early termination of treatment affects IQ scores and there may be abnormal neurological features later in life (Scriver 2001). Non‐compliance in teenagers and adults was associated with an increase in the rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity (Koch 2002).
Compliance with diet does not necessarily lead to a normal overall IQ. Subtle cognitive impairments are present (Griffiths 2000; Channon 2007). The diet itself is very restrictive in nature, the supplements used have an unpleasant taste and odour and there is always the risk of nutritional deficiencies. Some progress has been achieved in recent years in these aspects with newer and better formulations (Giovanni 2007). In spite of these advances, there is still potential for severe compromise of quality of life (Wappner 1999; Scriver 2007). As a result of this, by late adolescence and adulthood at least 75% of people with PKU are non‐compliant (Koch 2002). Therefore, other methods of treatment have been actively sought.
BH4 supplementation
Sapropterin dihydrochloride is an orally active synthetic form of BH4. There are several reports in the literature of people with PKU who responded to pharmacological doses of BH4 loading with a reduction in blood phenylalanine levels. All these individuals had mutations in the PAH gene. Defects in BH4 synthesis or regeneration (primary BH4 defect) had been ruled out (Kure 1999; Lindner 2001; Nuoffer 2001; Spaapen 2001; Trefz 2001; Matalon 2002; Muntau 2002; Steinfeld 2002; Shintaku 2004).
Individuals responsive to BH4 are identified initially by performing a BH4 loading test. A positive response to BH4 is arbitrarily considered as a decrease of 30% or more of blood phenylalanine concentration 24 hours after administration of BH4 (Michals‐Matalon 2007). The protocol for the BH4 loading test is variable (Blau 2004; Shintaku 2004).
How the intervention might work
Prevalence of BH4 responsiveness was variable in different studies (Bernegger 2002; Muntau 2002; Fiege 2005; Fiori 2005; Matalon 2005; Boveda 2007; Fiege 2007). There was variation in the intensity of response which was independent of the severity of the PKU, dose of BH4 used in the loading test, duration of the test and genotype. Even people with the same genotype showed differences in the intensity of response (Lindner 2001; Steinfeld 2003; Leuzzi 2006). There are a few reports of long‐term use of BH4 that show that BH4 allows relaxation of the dietary restrictions in people with PKU without any adverse effects (Cerone 2004; Shintaku 2004; Steinfeld 2004; Belanger‐Quintana 2005; Fiori 2005; Burlina 2009). Some authors have reported beneficial effects in a few people with severe classic PKU (Hennermann 2005; Matalon 2005) .Most of the individuals who respond have mild to moderate PKU. All the people with PKU who respond positively to BH4 have at least some residual PAH enzyme activity. Sapropterin, by enhancing the activity of residual PAH enzyme, may increase tolerance to phenylalanine and allow a less restrictive diet (Erlandsen 2004; Blau 2004).
Why it is important to do this review
Following the restrictive diet for PKU is beneficial but compliance after childhood is difficult to achieve as it can severely compromise the quality of life.
Sapropterin dihydrochloride administration can potentially allow a relaxation of diet or even permit discontinuation of dietary treatment in some individuals. Even in those who respond suboptimally to its administration may allow a partial relaxation of dietary restrictions making it easier to cope with a life‐long regimen. However, most of the individuals who respond to BH4 have mild to moderate PKU and some of them may not need aggressive treatment. It is therefore very important to assess critically the safety and efficacy of sapropterin dihydrochloride in a clinical setting.
Objectives
To assess the effectiveness and safety of sapropterin dihydrochloride in decreasing blood Phe levels in people with PKU.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, published and un‐published.
Types of participants
Children and adults with PKU due to PAH deficiency, who are responsive to sapropterin dihydrochloride. Individuals with PKU due to primary defect in BH4 metabolism will be excluded.
Types of interventions
Oral supplementation of sapropterin (in any dose, frequency or duration) compared with no supplementation or placebo. This intervention can be used either in combination with, or instead of, a phenylalanine‐restricted diet.
Types of outcome measures
Primary outcomes
1. Change in blood phenylalanine concentration
Secondary outcomes
1. Adverse events which may be associated with sapropterin
2. Validated quality of life measures (e.g. Profile of Quality of Life in Chronically Ill (PLC))
3. Validated measures of Intelligence and neuro‐psychometric performance (e.g. Wechsler Intelligence Scales)
4. Measures of nutritional status and growth
5. Change in protein (phenylalanine) tolerance
Search methods for identification of studies
Electronic searches
We will identify relevant trials from the Group's Inborn Errors of Metabolism Trials Register.
The Inborn Errors of Metabolism Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE and the prospective handsearching of one journal ‐ Journal of Inherited Metabolic Disease. Unpublished work was identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
Additionally we will undertake searches of the following registers (see Appendices):
Searching other resources
We will contact the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials.
Data collection and analysis
Selection of studies
Two authors, US and MM will assess the trials independently for inclusion in the review. We plan to resolve any disagreements that may arise through discussion.
Data extraction and management
We will independently extract the data from eligible trials using a trial selection and data extraction form modified for this review.
We will group outcome data into those measured at two, four and six weeks, monthly up to one year, and every three months thereafter. If data are reported at other time periods we will also consider including these. We will also contact authors for possible measurements of outcome data at other time periods. If available we will consider including these also in the analysis.
Assessment of risk of bias in included studies
We plan to assess the risk of bias of the included trials using the domain‐based evaluation as described in Cochrane Handbook for Systematic Reviews of Intervention 5.0.1 (Higgins 2008)
We will assess the following domains as 'Yes' (i.e. low risk of bias), unclear (uncertain risk of bias), 'No' (high risk of bias):
1. Randomisation
2. Concealment of allocation
3. Blinding of participants, personnel and outcome assessors
4. Incomplete outcome data
5. Selective outcome reporting
Measures of treatment effect
For binary outcomes we plan to measure the treatment effect as risk ratios (RR) with 95% confidence intervals (95% CIs). For continuous outcomes with outcome measurements on same scale, we plan to present the results as mean differences (MDs) with 95% CIs. Where the continuous outcomes are measured using different scales, we plan to use the standardised mean difference (SMD).
Unit of analysis issues
We will include results from eligible cross‐over studies using methods recommended by Elbourne (Elbourne 2002). In order to allow an intention‐to‐treat analysis we will seek data on the number of participants by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment.
Dealing with missing data
We will request information regarding any missing data from the original investigators.
Assessment of heterogeneity
We plan to quantify the impact of statistical heterogeneity in the meta‐analysis using a measure (I2) of the degree of inconsistency in the studies' results. This measure describes the percentage of total variation across studies that is due to heterogeneity rather than chance. The values of I2 lie between 0% and 100%, and a simplified categorization of heterogeneity that we plan to use is of low (I2 value of 25%); moderate (I2 value of 50%); and high (I2 value of 75%) ( Higgins 2003).
Assessment of reporting biases
If we are able to include 10 or more studies we will use a funnel plot to assess whether the review is subject to publication bias. If asymmetry is detected we will also assess other possible causes such as selection bias, reporting bias, true heterogeneity and artefact. Where available we will compare the study protocols to published reports to assess for outcome reporting bias. Otherwise we will compare the 'Methods' section of the study to the 'Results' section of the report. If we suspect outcome reporting bias we will contact authors for data.
Data synthesis
If significant heterogeneity (I2 is 50% or more) is identified we will use the random‐effects model. If we do not identify significant heterogeneity we will compute pooled estimates of the treatment effect for each outcome under a fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
If we find sources of heterogeneity and if we are able to include 10 or more studies, we will conduct meta‐analysis by subgroups. We will stratify participants according to:
1. Severity of PKU at baseline (classic PKU ‐Phe >1200 μmol/L ; mild PKU ‐Phe 600 ‐1200 μmol/L; and mild HPA ‐Phe < 600 μmol/L but more than the upper reference limit)
2. Dosage of sapropterin dihydrochloride used (10 mg/kg or 20 mg/kg)
Sensitivity analysis
We will perform sensitivity analyses to determine the impact of study quality on outcome, including and excluding studies with inadequate methods of treatment allocation. If there are any eligible crossover trials, we will conduct sensitivity analyses including and excluding these.
