Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period (ENDURE)

Study Description

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Brief Summary:

The primary objective of the study is to evaluate the proportion of responders (that is, greater than or equal to [>=] 30 percent reduction from Baseline in blood phenylalanine [Phe] level) to treatment with Kuvan® (sapropterin dihydrochloride) 20 milligram per kilogram per day (mg/kg/day) for 28 days.

Condition or disease	Intervention/treatment	Phase
Phenylketonuria	Drug: Kuvan®	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	59 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official 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
Study Start Date :	May 2010
Actual Primary Completion Date :	May 2012
Actual Study Completion Date :	May 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Kuvan®	Drug: Kuvan®; Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) will be given once daily for 28 +/- 1 days.; Other Name: Sapropterin dihydrochloride

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level [ Time Frame: Baseline up to Day 28 +/- 1 ]
   Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days.

Secondary Outcome Measures :

1. Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal [ Time Frame: Baseline up to Day 42 +/- 3 ]
   An Adverse Event (AE) is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to Baseline during a clinical study with an investigational medicinal product (IMP), regardless of causal relationship and even if no IMP has been administered.
2. Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan® [ Time Frame: Baseline up to Day 28 +/- 1 ]
   Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment. Non-responders defined as percentage of participants with a Phe level reduction of less than 10 percent within 28 +/- 1 days.
3. Percentage of Participants With Greater Than or Equal to (>=) 30 Percent, 20 to 30 Percent, 10 to 20 Percent and Less Than (<) 10 Percent Reduction in Blood Phe Levels According to Phenylketonuria (PKU) Phenotypes [ Time Frame: Baseline up to Day 28 +/- 1 ]
   The Phenylketonuria (PKU) is categorized as per phenotype into classical PKU: (blood Phe levels greater than [>] 1200 micromole per liter [mcmol/l]), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild Hyperphenylalaninaemia (HPA) (blood Phe levels 300 to 600 mcmol/l).
4. Percentage of Early-, Late- and Partial-Responders According to Phenotype [ Time Frame: Baseline up to Day 28 +/- 1 ]
   The PKU is categorized as per phenotype into classical PKU: (blood Phe levels > 1200 mcmol/l), mild PKU (blood Phe levels 600 to 1200 mcmol/l), mild HPA (blood Phe levels 300 to 600 mcmol/l). Early responders defined as percentage of participants with at least 30 percent reduction in Phe levels within the first seven days of treatment. Late responders defined as percentage of participants with less than 30 percent reduction in Phe levels within first seven days of treatment, but at least 30 percent reduction in Phe levels within 28 +/- 1 days of treatment. Partial responders defined as percentage of participants with Phe levels reduction between 10 and 30 percent at any blood measurement within the 28 +/- 1 days of treatment.
5. Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio [ Time Frame: Baseline, Day 28 ]
   Phenylalanine-to-tyrosine ratio is the best indicator of dopamine availability in PKU. The change in blood phenylalanine-to-tyrosine ratio at Day 28 was calculated as blood phenylalanine-to-tyrosine ratio at Day 28 minus blood phenylalanine-to-tyrosine ratio at Baseline.

Eligibility Criteria

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Ages Eligible for Study:	4 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Subjects aged 4 years or older at the time the informed consent is obtained
• Subjects diagnosed with PKU (subgroups defined as: classic PKU [blood Phe greater than {>}1200 micromole per liter {mcmol/L}], mild PKU [blood Phe 600 to1200 mcmol/L] or mild hyperphenylalaninemia (HPA) [blood Phe 300 to 600 mcmol/L]
• Subjects who have received no previous treatment with sapropterin dihydrochloride (either Kuvan® or any other formulations of tetrahydrobiopterin [BH4])
• Subjects adherent to their normal diet and willing to adhere to the given diet for the 4 weeks study period
• Subjects who provide a signed (by parent if below 18 years) written informed consent
• Subjects with documented genotyping for both phenylalanine hydroxylase (PAH) mutations (PKU genotype)
• Phenylketonuria (PKU) diagnosis should be documented with at least two historical blood Phe levels above 400 mcmol/L
• Female subjects of childbearing potential (and, if appropriate, male subjects with female partners of childbearing potential) must be willing to avoid pregnancy by using an adequate method of contraception (defined as two barrier methods or one barrier method with spermicide, or intrauterine device or use of the oral female contraceptive) for 4 weeks prior to, during and 12 weeks after the last dose of trial medication
• Women of childbearing potential (for the purpose of this trial, women of childbearing potential are defined as "All female subjects after puberty unless they are post-menopausal for at least 2 years, are surgically sterile or are sexually inactive") must have a negative urine pregnancy test at the Baseline visit

Exclusion Criteria:

• Subjects who have documented BH4 deficiency
• Subjects who have any contraindications to receive Kuvan® as outlined in the summary of product characteristics (SmPC) not willing or able to comply with the study procedures
• Subjects who are pregnant, planning for pregnancy or breastfeeding
• Subjects who 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
• Subjects using concomitant treatment with folate synthesis inhibiting drugs
• Subjects with concurrent use of Levodopa
• Subjects with concurrent use of inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim)
• Subjects with concurrent use of agents that cause vasodilation, including those administered topically, by affecting nitric oxide (NO) metabolism or action including classical NO donors (for example, glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), sodium nitroprusside (SNP), molsidomin), phosphodiesterase type 5 (PDE-5) inhibitors and minoxidil
• Subjects who have a concurrent disease potentially interfering safety (for example, seizure disorder, oral steroid dependent asthma, other conditions requiring systemic corticosteroids, or insulin-dependent diabetes mellitus)
• Subjects who have inadequate liver function, defined by alanine aminotransferase (ALT) >= 2 times upper limit of normal (ULN)
• Subjects who have clinically significant renal dysfunction, defined by serum creatinine > 250 mcmol/L
• Have any medical condition that, in the judgment of the investigator, would jeopardize the subject's safety following exposure to study drug or would significantly interfere with the subject's ability to comply with the provisions of the protocol

Contacts and Locations

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Locations

Norway
Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet
Oslo, Norway

Sponsors and Collaborators

Merck KGaA

Merck Serono Norway

Smerud Medical Research International AS

Investigators

Study Director:	Medical Responsible	Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

PAH database, Publication Link 

Arnold GL. Phenylketonuria, Publication Link 

Publications:

Scriver CR, Kaufman S. Hyperphenylanaemia: phenylalanine hydroxylase deficiency. In: Beaudet AL, Sly WS, Valle D, editors. Metabolic and molecular bases of inherited disease. New York: McGraw-Hill 2001;1667-709

Phenylketonuria (PKU): screening and management. NIH Consens Statement. 2000 Oct 16-18;17(3):1-33. Review.

Hofman KJ, Steel G, Kazazian HH, Valle D. Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet. 1991 Apr;48(4):791-8.

Konecki DS, Lichter-Konecki U. The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations. Hum Genet. 1991 Aug;87(4):377-88. Review.

Kaufman S. An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr. 1989 May;114(5):895-900. Review.

Huttenlocher PR. The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr. 2000 Oct;159 Suppl 2:S102-6. Review.

Walter JH, White FJ, Hall SK, MacDonald A, Rylance G, Boneh A, Francis DE, Shortland GJ, Schmidt M, Vail A. How practical are recommendations for dietary control in phenylketonuria? Lancet. 2002 Jul 6;360(9326):55-7.

Koch R, Azen C, Friedman EG, Williamson ML. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis. 1984;7(2):86-90.

Brumm VL, Azen C, Moats RA, Stern AM, Broomand C, Nelson MD, Koch R. Neuropsychological outcome of subjects participating in the PKU adult collaborative study: a preliminary review. J Inherit Metab Dis. 2004;27(5):549-66.

Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N, Sakamoto O, Fujii K, Matsubara Y, Narisawa K. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr. 1999 Sep;135(3):375-8.

Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002 Dec 26;347(26):2122-32.

Trefz FK, Scheible D, Frauendienst-Egger G, Korall H, Blau N. Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Mol Genet Metab. 2005 Dec;86 Suppl 1:S75-80. Epub 2005 Oct 20.

Shintaku H, Kure S, Ohura T, Okano Y, Ohwada M, Sugiyama N, Sakura N, Yoshida I, Yoshino M, Matsubara Y, Suzuki K, Aoki K, Kitagawa T. Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res. 2004 Mar;55(3):425-30. Epub 2003 Dec 17.

Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab. 2005 Dec;86 Suppl 1:S86-90. Epub 2005 Jul 26.

Bélanger-Quintana A, García MJ, Castro M, Desviat LR, Pérez B, Mejía B, Ugarte M, Martínez-Pardo M. Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin. Mol Genet Metab. 2005 Dec;86 Suppl 1:S61-6. Epub 2005 Sep 13.

Lambruschini N, Pérez-Dueñas B, Vilaseca MA, Mas A, Artuch R, Gassió R, Gómez L, Gutiérrez A, Campistol J. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab. 2005 Dec;86 Suppl 1:S54-60. Epub 2005 Jul 22.

Kuvan® Package Insert. BioMarin. 2007

Blau N. Defining tetrahydrobiopterin (BH4)-responsiveness in PKU. J Inherit Metab Dis. 2008 Feb;31(1):2-3. doi: 10.1007/s10545-007-9979-1.

Fiege B, Blau N. Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr. 2007 Jun;150(6):627-30.

Levy H, Burton B, Cederbaum S, Scriver C. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol Genet Metab. 2007 Dec;92(4):287-91.

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008 Jan;29(1):167-75.

Fernhoff P, Burton B, Nowacka M, Hennermann J, Kakkis E, Dorenbaum PKU-008: A Long-Term, Open-Label Study of Sapropterin Dihydrochloride (Kuvan®) in PKU Subjects. Poster at the 2009 American College of Medical Genetics Annual Clinical Genetics Meeting.

Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A; Sapropterin Research Group. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet. 2007 Aug 11;370(9586):504-10.

Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, Randolph LM, Vockley J, Whitley CB, Wolff JA, Bebchuk J, Christ-Schmidt H, Hennermann JB; Sapropterin Study Group. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. 2009 May;154(5):700-7. doi: 10.1016/j.jpeds.2008.11.040. Epub 2009 Mar 4.

Luciana M, Sullivan J, Nelson CA. Associations between phenylalanine-to-tyrosine ratios and performance on tests of neuropsychological function in adolescents treated early and continuously for phenylketonuria. Child Dev. 2001 Nov-Dec;72(6):1637-52.

Responsible Party:	Merck KGaA
ClinicalTrials.gov Identifier:	NCT01082328 History of Changes
Other Study ID Numbers:	EMR 700773-503
First Posted:	March 8, 2010
Results First Posted:	August 1, 2013
Last Update Posted:	February 27, 2014
Last Verified:	January 2014

Keywords provided by Merck KGaA:

Phenylketonuria (PKU); Hyperphenylalaninemia (HPA); Kuvan®	Sapropterin dihydrochloride; Kuvan responder; Tetrahydrobiopterin (BH4)

Additional relevant MeSH terms:

Phenylketonurias; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors	Genetic Diseases, Inborn; Metabolic Diseases; Verapamil; Anti-Arrhythmia Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents