Clinical Trials Register

Summary
EudraCT Number:	2009-015768-33
Sponsor's Protocol Code Number:	EMR700773-003
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-12-16
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Portugal - INFARMED

A.2

EudraCT number

2009-015768-33

A.3

Full title of the trial

A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Safety Paediatric efficAcy phaRmacokinetic with Kuvan®

A.3.2

Name or abbreviated title of the trial where available

SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®)

A.4.1

Sponsor's protocol code number

EMR700773-003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01376908

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Serono S.A. - Geneva
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Serono S.A. - Geneva
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151 72 5200
B.5.5	Fax number	+496151 72 5200
B.5.6	E-mail	service@merck.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Kuvan
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Europe Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/199
D.3 Description of the IMP
D.3.1	Product name	Sapropterin Dihydrocholoride
D.3.2	Product code	NAP
D.3.4	Pharmaceutical form	Soluble tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SAPROPTERIN
D.3.9.1	CAS number	62989337
D.3.9.3	Other descriptive name	tetrahydrobiopterin
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Phenylketonuria

E.1.1.1

Medical condition in easily understood language

Phenylketonuria

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10034873
E.1.2	Term	Phenylketonuria (PKU)
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

1.Evaluate the efficacy after 26 weeks of Kuvan® treatment + Phe-restricted diet therapy in increasing dietary Phe tolerance, as compared to dietary therapy alone in <4 year-old infants and children with phenylketonuria (PKU). Phe tolerance will be defined as the amount of dietary Phe (mg/kg/day) ingested while maintaining blood Phe levels within the range of 120-360 μmol/L (defined as ≥120 to < 360 μmol/L).
2.Evaluate the safety after 26 weeks of Kuvan® treatment in <4 year-old infants and children with PKU.
3.Evaluate BH4 (tetrahydrobiopterin; sapropterin) blood levels via scheduled PopPK samplings.

E.2.2

Secondary objectives of the trial

1.Evaluate blood Phe levels for all subjects during the 26-week Study Period.
2.Evaluate the effectiveness of Kuvan® treatment in increasing dietary Phe tolerance, as compared to pre-Kuvan® treatment during the 26-week Study Period in <4 year-old infants and children with PKU.
3.Assess neurodevelopmental function during Kuvan® treatment, as compared to dietary treatment alone, during the 26-week Study Period in <4 year-old infants and children with PKU.
4.Assess potential effects on blood pressure during the 26-weeks Study Period and the 3-year Extension Period.
5.Assess potential effects on growth during the 26-weeks Study Period and the 3-year Extension Period.
6.Evaluate long-term safety, neurodevelopmental outcomes, dietary Phe tolerance, and blood Phe levels in the 3-year Extension Period.
7.Investigate in BH4-responsive individuals the predictive value of the phenylalanine hydroxylase (PAH) genotype.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female PKU infants and young children <4 years of age at the scheduled Day 1 visit of the 26-week Study Period (taking into consideration the maximum of 42 days in the Screening Period).
2.At least two previous blood Phe levels ≥ 400 μmol/L obtained on 2 separate occasions.
3.Previously responded, as assessed by the Investigator, to a BH4 test, if all 3 of the following criteria are satisfied:
a.The BH4 dose was 20 mg/kg/day;
b.The duration of the test was at least for 24 hours; and
c. A 30% decrease in blood Phe Levels.
Note: If a patient has not undergone a BH4 test prior to Screening, such a test must be performed, (Please refer to the note, section 7.1.1 bullet point #7)
4.Defined level of dietary Phe tolerance consistent with the diagnosis of PKU;
5.Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods.
6.Maintenance of blood Phe levels within the therapeutic target range of 120-360 μmol/L (defined as ≥120 to <360 μmol/L) over a 4-month period prior to Screening, as assessed by the Investigator. At least, the last 4 values phenylalanine (either from venous blood or dry blood spot) should be assessed, out of which 75% should be within the above therapeutic range.
7.Parent(s) and/or guardian(s) willing to comply with all study procedures, maintain strict adherence to the diet, and willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study procedures.

E.4

Principal exclusion criteria

1.Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test.
2.Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for >30 days.
3.Known hypersensitivity to Kuvan® or its excipients.
4.Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin.
5.Previous diagnosis of BH4 deficiency.
6.Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors.
7.Current use of medications that are known to affect nitric oxide synthesis, metabolism or action.
8.Current use of levodopa.
9.Current use of experimental or unregistered drugs that may affect the study outcomes.
10.Inability to comply with study procedures.
11.Inability to tolerate oral intake.
12.History of organ transplantation.
13.Concurrent disease or condition that would interfere with study participation or increase the risk for adverse events, including seizure disorders, corticosteroid administration, active malignancy, diabetes mellitus, severe congenital heart disease, renal or hepatic failure.
14.Other significant disease that in the Investigator’s opinion would exclude the subject from the trial.
15.Any condition that, in the view of the Principal Investigator renders the subject at high risk for failure to comply with treatment or to complete the study.

E.5 End points

E.5.1

Primary end point(s)

Dietary Phe tolerance after 26 weeks (6 months) of treatment with Kuvan® + a Phe-restricted diet, as compared to just a Phe-restricted diet alone.

E.5.1.1

Timepoint(s) of evaluation of this end point

26 weeks (6 months)

E.5.2

Secondary end point(s)

-Levels of blood Phe during the 26-week Study Period and the 3-year Extension Period.
-Change from Baseline (prior to enrolment) in dietary Phe tolerance after 26 weeks (6 months)
-treatment with Kuvan® + a Phe-restricted diet vs. just a Phe-restricted diet.
-Dietary Phe tolerance during the 3-year Extension Period.
-Blood pressure during the 26-week Study Period and the 3-year Extension Period.
-Growth parameters (length or height, weight, and maximum occipital-frontal head
circumference) during the 26-week Study Period and the 3-year Extension Period.
-Neuromotor developmental milestones and standardized neurodevelopment test results during the 26-week Study Period and the 3-year Extension Period.
-Safety, including attention to age group-specific safety concerns:
-Nature, incidence, and severity of adverse events;
-Long-term safety for patients enrolled into the Extension Period.
-Incidence of hypophenylalaninemia (blood Phe <120 μmol/L);
-Changes from baseline in vital signs and clinical laboratory parameters.
Population PK endpoints will include:
-CL/f (apparent clearance);
-V/f (apparent volume of distribution);
-AUC0-∞ (area under the plasma concentration curve, time 0 to infinity);
-Cmax (maximum observed plasma concentration);
-Tmax (time to maximum plasma concentration); and
-t1/2 (terminal elimination half-life).
-PAH genotype.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of study part (26 weeks) or at the end of the extension period

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

diet only

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Turkey

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

•all enrolled subjects who have received at least one dose of study drug have completed all scheduled visits
•follow-up of all subjects with ongoing adverse events at the conclusion of treatment has been addressed
•site monitoring visits to resolve any outstanding data discrepancy issues have been completed for all participating centres
•the database has been locked
•all sites have undergone a final site closure/study termination visit

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1