ENDURE: A Phase IV, prospective, open-label, uncontrolled, multi-centre cohort trial to assess the responsiveness of subjects with phenylketonuria (PKU) to treatment with Kuvan® 20 mg/kg/day for 28 days - ENDURE

• Register: EUCTR
• Last refreshed on: 6 May 2013
• Main ID: EUCTR2009-018168-81-DK
• Date of registration: 03/03/2010
• Prospective Registration: Yes
• Primary sponsor: Merck Serono Norway
• Public title: ENDURE: A Phase IV, prospective, open-label, uncontrolled, multi-centre cohort trial to assess the responsiveness of subjects with phenylketonuria (PKU) to treatment with Kuvan® 20 mg/kg/day for 28 days - ENDURE
• Scientific title: ENDURE: A Phase IV, prospective, open-label, uncontrolled, multi-centre cohort trial to assess the responsiveness of subjects with phenylketonuria (PKU) to treatment with Kuvan® 20 mg/kg/day for 28 days - ENDURE
• Date of first enrolment: 16/04/2010
• Target sample size: 70
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-018168-81
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:

Countries of recruitment

Denmark

Key inclusion & exclusion criteria

Inclusion criteria:
•aged 4 years or older at the time the informed consent is obtained
•diagnosed with PKU (subgroups defined as: classic PKU [blood Phe >1200 µmol/L], mild PKU [blood Phe 600–1200 µmol/L] or mild HPA [blood Phe 300–600 µmol/L]
•have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin)
•adherent to their normal diet and willing to adhere to the given diet for the 4 week study period
•Provide a signed (by parent if below 18 years) written informed consent.
•Documented genotyping for both PAH mutations (PKU genotype)
•PKU diagnosis should be documented with at least two historical blood Phe levels above 400 µmol/L

Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
•have documented BH4 deficiency
•have any contraindications to receive Kuvan® as outlined in the SmPC not willing or able to comply with the study procedures
•be pregnant, planning pregnancy or breastfeeding
•have been exposed to any investigational medicinal drugs or treatments within 30 days or 5 half lives, whichever is longer, prior to the screening visit
•using concomitant treatment with folate synthesis inhibiting drugs
•concurrent use of Levodopa
•concurrent use of inhibitors of dihydrofolate reductase (e.g. methotrexate, trimethoprim)
•concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodistrerase type 5 (PDE-5) inhibitors and monoxidil
•have a concurrent disease potentially interfering safety (e.g. seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus)
•have inadequate liver function, defined by alanine aminotransferase (ALT) ? 2 x upper limit of normal (ULN)
•have clinically significant renal dysfunction, defined by serum creatinine > 250 µmol/l
•Have any medical condition that, in the judgment of the investigator, would jeopardize the patient’s safety following exposure to study drug or would significantly interfere with the patient’s ability to comply with the provisions of this protocol



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Subjects diagnosed with Phenylketonuria (PKU) (classic or mild PKU, or mild hyperphenylalaninaemia (HPA)).
MedDRA version: 14.1 Level: LLT Classification code 10034873 Term: Phenylketonuria (PKU) System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Trade Name: Kuvan


Pharmaceutical Form: Soluble tablet
INN or Proposed INN: Sapropterindihydrochloride
CAS Number: 69056-38-8
Other descriptive name: SAPROPTERIN HYDROCHLORIDE
Concentration unit: mg/kg milligram(s)/kilogram
Concentration number: 100 -

Primary Outcome(s)

Secondary Objective: The secondary endpoints include:
? To assess the overall safety of a 4 weeks testing period of Kuvan® 20mg/kg/day in patients not responding early
? To evaluate the proportion of early, late, partial responders and non-responders
? To evaluate genetic PAH mutations associated with certain traits, i.e. response, adverse events,
? To identify subtypes of patients (disease severity, age) associated with the types of response (early/late/partial/non responder)
? To assess the blood phenylalanine-to-tyrosine ratio during a 4 weeks testing period of Kuvan® 20mg/kg/day

Primary end point(s): The primary endpoint of this trial is the proportion of subjects with at least 30% reduction from baseline in blood Phe level (responders) in any blood sample during the 28 +/- 1 days treatment with 20 mg/kg/day Kuvan®.

Main Objective: The primary objective of the study is to evaluate the proportion of responders (=30% reduction from baseline in blood Phe level) to 20 mg/kg/day Sapropterin dihydrochloride treatment at several time points during 28 +/- 1 days.

Secondary ID(s)

EMR-700773-503