Dataset Information

The Kuvan(®) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin.

ABSTRACT: INTRODUCTION:Sapropterin dihydrochloride (Kuvan(®)), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ?4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency. AIMS/METHODS:KAMPER is an ongoing, observational, multicentre registry with the primary objective of providing information over 15 years on long-term safety of sapropterin dihydrochloride treatment in patients with HPA. Here we report initial data on characteristics from patients recruited by the time of the third interim analysis and results at 1 year. RESULTS:Overall, 325 patients from 55 sites in seven European countries were included in the analysis: 296 (91.1%) patients with PAH deficiency (median [Q1, Q3] age, 10.3 [7.2, 15.0] years) and 29 (8.9%) with BH4 deficiency (12.8 [6.6, 18.9] years). Fifty-nine patients (18.2%) were aged ?18 years; 4 patients were pregnant. No elderly patients (aged ?65 years) or patients with renal or hepatic insufficiency were enroled in the study. Twelve-month data were available for 164 patients with PAH deficiency and 16 with BH4 deficiency. No new safety concerns were identified as of May 2013. CONCLUSIONS:Initial data from KAMPER show that sapropterin dihydrochloride has a favourable safety profile. Registry data collected over time will provide insight into the management and outcomes of patients with PAH deficiency and BH4 deficiency, including long-term safety, impact on growth and neurocognitive outcomes and the effect of sapropterin dihydrochloride treatment on populations of special interest.

SUBMITTER: Trefz FK

PROVIDER: S-EPMC4484899 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The Kuvan(®) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin.

Trefz Friedrich K FK Muntau Ania C AC Lagler Florian B FB Moreau Flavie F Alm Jan J Burlina Alberto A Rutsch Frank F Bélanger-Quintana Amaya A Feillet François F

JIMD reports 20150331

<h4>Introduction</h4>Sapropterin dihydrochloride (Kuvan(®)), a synthetic 6R-diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged ≥4 years with hyperphenylalaninaemia (HPA) due to BH4-responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency.<h4>Aims/methods</h4>KAMPER is an ongoing, observational, multicentre registry with the primary obje ...[more]

PMID: 25822821

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Project description:BackgroundPhenylketonuria results from a deficiency of the enzyme phenylalanine hydroxylase. Dietary restriction of phenylalanine keeps blood phenylalanine concentration low. Most natural foods are excluded from diet and supplements are used to supply other nutrients. Recent publications report a decrease in blood phenylalanine concentration in some patients treated with sapropterin dihydrochloride. We examined the evidence for the use of sapropterin dihydrochloride to treat phenylketonuria. This is an update of a previously published Cochrane Review. ObjectivesTo assess the safety and efficacy of sapropterin dihydrochloride in lowering blood phenylalanine concentration in people with phenylketonuria.Search methodsWe identified relevant trials from the Group's Inborn Errors of Metabolism Trials Register. Date of last search: 11 August 2014.We also searched ClinicalTrials.gov and Current controlled trials. Last search: 4 September 2014We contacted the manufacturers of the drug (BioMarin Pharmaceutical Inc.) for information regarding any unpublished trials.Selection criteriaRandomized controlled trials comparing sapropterin with no supplementation or placebo in people with phenylketonuria due to phenylalanine hydroxylase deficiency.Data collection and analysisTwo authors independently assessed trials and extracted outcome data.Main resultsTwo placebo-controlled trials were included. One trial administered 10 mg/kg/day sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to saproterin.This trial measured change in blood phenylalanine concentration. The second trial screened 90 children (4 to 12 years) with phenylketonuria whose diet was restricted, for responsiveness to sapropterin. Forty-six responders entered the placebo-controlled part of the trial and received 20 mg/kg/day sapropterin. This trial measured change in both phenylalanine concentration and protein tolerance. Both trials reported adverse events. The trials showed an overall low risk of bias; but both are Biomarin-sponsored. One trial showed a significant lowering in blood phenylalanine concentration in the sapropterin group (10 mg/kg/day), mean difference -238.80 μmol/L (95% confidence interval -343.09 to -134.51); a second trial (20 mg/kg/day sapropterin) showed a non-significant difference, mean difference -51.90 μmol/L (95% confidence interval -197.27 to 93.47). The second trial also reported a significant increase in phenylalanine tolerance, mean difference18.00 mg/kg/day (95% confidence interval 12.28 to 23.72) in the 20 mg/kg/day sapropterin group.Authors' conclusionsThere is evidence of short-term benefit from using sapropterin in some people with sapropterin-responsive forms of phenylketonuria; blood phenylalanine concentration is lowered and protein tolerance increased. There are no serious adverse events associated with using sapropterin in the short term.There is no evidence on the long-term effects of sapropterin and no clear evidence of effectiveness in severe phenylketonuria.

Project description:IntroductionLambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder affecting the neuromuscular junction, clinically characterized by proximal muscle weakness and autonomic changes. LEMS is often associated with an underlying tumor (paraneoplastic form) but also occurs in the absence of cancer (idiopathic form). Treatment consists of immunomodulation (immunosuppression), anticancer treatment when carcinoma is present, and symptomatic treatment [acetylcholinesterase inhibitors and potassium channel blockers, e.g., amifampridine (3,4-diaminopyridine, i.e., 3,4-DAP), to improve neurotransmission]. Although there has long been information from case reports, several randomized controlled trials, and treatment guidelines, population data are still scarce.MethodsThe LEMS patient registry was launched in the European community in mid-2010 as a voluntary, multinational, observational, non-interventional program to collect structured empirical data on clinical course, treatment utilization, and safety and efficacy from the use of LEMS-specific treatments.ResultsSixty-nine patients have been enrolled [36 males, 32 females, 1 gender not reported; mean age 61.5 (27-84) years]. Eighteen patients (26%) were diagnosed with an associated carcinoma. At the time of enrollment, the majority of patients (65%) were receiving amifampridine [either compounded 3,4-DAP (22%) or 3,4-DAP phosphate, Firdapse(®) (43%)]. At enrollment, most patients demonstrate a profile of mild-to-moderate deficits in daily functioning but generally have good muscle strength, albeit with reduced deep tendon reflexes, frequent ataxia during walking, and signs of autonomic dysfunction including dry mouth, bladder dysfunction, and constipation.ConclusionThe LEMS European Union registry will continue to enroll patients and periodically report the accrued longitudinal data obtained on clinical assessments and laboratory findings, treatment practices, the safety and efficacy of treatment approaches, and long-term clinical outcomes.FundingBioMarin Pharmaceutical Inc., Novato, CA, USA.

Project description:Sapropterin dihydrochloride, a synthetic, stable form of the tetrahydrobiopterin cofactor of phenylalanine hydroxylase, has been shown to reduce plasma phenylalanine (Phe) levels in a significant portion of patients with phenylketonuria (PKU). When we undertook introducing this medication to our PKU clinic population, the challenges of recalling and reconnecting with a variably treated and variably compliant patient population became apparent. We offered a trial of sapropterin to all of our clinic patients with PKU. In order to determine responsiveness, we used a two tier dose escalation protocol. After diet records were taken, and baseline plasma Phe levels were established, a 7-day trial of sapropterin at 10mg/kg/day was started. At day 8, plasma phenylalanine levels were measured. Patients were considered to be responders if they had a 30% reduction in plasma Phe. If they did not respond, the dose of sapropterin was increased to 20 mg/kg/day, and levels were rechecked again in 8 days. Patients who were not responders at this time continued sapropterin for a total of 30 days and had Phe levels checked one last time. Patients who were responders and who were on a Phe-restricted diet underwent gradual liberalization of their diet to the maximum tolerated natural protein intake while still maintaining plasma levels in the acceptable treatment range of 120-360 micromol/L. In our population, 36/39 patients with hyperphenylalaninemia (HPA) who were offered a trial of sapropterin elected to start sapropterin. Five of 36 patients were non-adherent with diet records and/or medication doses and we were unable to determine if they were responders. We were unable to categorize 2 of 31 of the patients who completed the trial as responders due to dietary issues, though they were probably responders. Of the 29 patients who completed the sapropterin trial and we could categorize, 18/29 (62%) were determined to be responders. Patients were classified based on their off-diet diagnostic plasma phenylalanine levels as classical PKU (>1200 micromol/L) and variant PKU (>400 and <1200 micromol/L). The group with variant PKU had a 100% response rate, and patients with classical PKU had a 27% response rate. For the patients in the responder group who were on Phe-restricted diet, we were able to liberalize most diets, in two cases to unrestricted protein intake. We also had unexpected beneficial findings in our clinic experience, including positive behavioral improvements in an adult severely affected by untreated PKU. Even in patients who were not considered to be responders, the introduction of sapropterin provided a tool to reconnect with patients and re-introduce beneficial dietary measures.

Project description:BackgroundCurrently, there is a paucity of data concerning the long-term outcomes, educational placement and quality of life of children implanted with hearing devices from large and representative samples of the population. To address this concern, a large, prospective, multicentre, multinational patient-outcomes registry for paediatric recipients of implantable hearing devices was developed. The benefits of this registry, its approach and methodology are described.Methods/designThe Cochlear(™) Paediatric Implanted Recipient Observational Study (Cochlear P-IROS) is a prospective international patient-outcomes registry for children who are implanted in routine clinical practice with one or more hearing devices. The study aims to collect data on patient comorbidities, device use, auditory performance, quality of life and health-related utilities, across different types of implantable hearing devices from a range of manufacturers. Patients will be evaluated with a set of standardised and non-standardised questionnaires prior to initial device activation (baseline) and at six-monthly follow-up intervals up to 24 months and annually thereafter. The Cochlear P-IROS utilises a secure web interface to administer electronic case report forms to clinicians and families of implanted children. The web interface is currently available in five languages: English, Japanese, Korean, Mandarin and Russian. The interface also provides printable versions of the case report forms translated into 22 local languages for collection of data prior to entry online; additional languages may be added, as required. Participation in the Cochlear P-IROS registry is investigator-driven and voluntary. To date, the Cochlear P-IROS has recruited implant clinics across Australia, China, India, Indonesia, Turkey and Vietnam. The registry also aims to recruit multiple clinics in Cuba, Israel, Japan, Malaysia, Singapore, South Africa, South Korea and Russia.DiscussionThe use of a registry such as the Cochlear P-IROS will generate valuable data to support research interests of academics and clinicians around the globe. The data generated will be relevant for a wide range of stakeholders including regulators, payers, providers, policy makers, patients and their families, each with a different perspective for the acceptance and adoption of implantable hearing devices for the treatment of hearing loss.

Dataset Information

The Kuvan(®) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin.

Publications

The Kuvan(®) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin.

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