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

NCT01082328 | Completed Phase 4 Results

• 1 other identifier: EMR 700773-503
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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.

Conditions

Phenylketonuria

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With at Least 30 Percent Reduction From Baseline in Blood Phenylalanine (Phe) Level

  Response to treatment was defined as 30 percent reduction from Baseline in blood phenylalanine (Phe) Level during the 28 +/- 1 days.

  Baseline up to Day 28 +/- 1

Secondary Outcomes (5)

• Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal

  Baseline up to Day 42 +/- 3

• Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®

  Baseline up to Day 28 +/- 1

• 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

  Baseline up to Day 28 +/- 1

• Percentage of Early-, Late- and Partial-Responders According to Phenotype

  Baseline up to Day 28 +/- 1

• Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio

  Baseline, Day 28

Study Arms (1)

Kuvan®

EXPERIMENTAL

Drug: Kuvan®

Interventions

Kuvan® DRUG

Kuvan® (sapropterin dihydrochloride) oral solution 20 milligram per kilogram (mg/kg) will be given once daily for 28 +/- 1 days.

Also known as: Sapropterin dihydrochloride

Kuvan®

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead
• Merck Serono Norway: collaborator
• Smerud Medical Research International AS: collaborator

Study Sites (1)

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

Oslo, Norway

Location

Related Publications (25)

• 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

  BACKGROUND

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

  PMID: 11757784 BACKGROUND

• 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.

  PMID: 2014802 BACKGROUND

• 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. doi: 10.1007/BF00197152.

  PMID: 1679029 BACKGROUND

• Kaufman S. An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr. 1989 May;114(5):895-900. doi: 10.1016/s0022-3476(89)80161-1. No abstract available.

  PMID: 2654351 BACKGROUND

• Huttenlocher PR. The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr. 2000 Oct;159 Suppl 2:S102-6. doi: 10.1007/pl00014371.

  PMID: 11043154 BACKGROUND

• 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. doi: 10.1016/s0140-6736(02)09334-0.

  PMID: 12114043 BACKGROUND

• 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. doi: 10.1007/BF01805813.

  PMID: 6434835 BACKGROUND

• 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. doi: 10.1023/b:boli.0000042985.02049.ff.

  PMID: 15669671 BACKGROUND

• 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. doi: 10.1016/s0022-3476(99)70138-1.

  PMID: 10484807 BACKGROUND

• Muntau AC, Roschinger 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. doi: 10.1056/NEJMoa021654.

  PMID: 12501224 BACKGROUND

• 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. doi: 10.1016/j.ymgme.2005.06.026. Epub 2005 Oct 20.

  PMID: 16242984 BACKGROUND

• 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. doi: 10.1203/01.PDR.0000111283.91564.7E. Epub 2003 Dec 17.

  PMID: 14681498 BACKGROUND

• Hennermann JB, Buhrer C, Blau N, Vetter B, Monch 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. doi: 10.1016/j.ymgme.2005.05.013. Epub 2005 Jul 26.

  PMID: 16051511 BACKGROUND

• Belanger-Quintana A, Garcia MJ, Castro M, Desviat LR, Perez B, Mejia B, Ugarte M, Martinez-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. doi: 10.1016/j.ymgme.2005.07.024. Epub 2005 Sep 13.

  PMID: 16165389 BACKGROUND

• Lambruschini N, Perez-Duenas B, Vilaseca MA, Mas A, Artuch R, Gassio R, Gomez L, Gutierrez A, Campistol J. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab. 2005 Dec;86 Suppl 1:S54-60. doi: 10.1016/j.ymgme.2005.05.014. Epub 2005 Jul 22.

  PMID: 16040265 BACKGROUND

• Kuvan® Package Insert. BioMarin. 2007

  BACKGROUND

• 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. No abstract available.

  PMID: 18327672 BACKGROUND

• Fiege B, Blau N. Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr. 2007 Jun;150(6):627-30. doi: 10.1016/j.jpeds.2007.02.017.

  PMID: 17517248 BACKGROUND

• 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. doi: 10.1016/j.ymgme.2007.09.017.

  PMID: 18036498 BACKGROUND

• Zurfluh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thony B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008 Jan;29(1):167-75. doi: 10.1002/humu.20637.

  PMID: 17935162 BACKGROUND

• 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.

  BACKGROUND

• 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. doi: 10.1016/S0140-6736(07)61234-3.

  PMID: 17693179 BACKGROUND

• 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.

  PMID: 19261295 BACKGROUND

• 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. doi: 10.1111/1467-8624.00370.

  PMID: 11768137 BACKGROUND

Related Links

• Arnold GL. Phenylketonuria, Publication Link

MeSH Terms

Conditions

Phenylketonurias

Interventions

sapropterin

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Serono S.A., an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2010
• First Posted: March 8, 2010
• Study Start: May 1, 2010
• Primary Completion: May 1, 2012
• Study Completion: May 1, 2012
• Last Updated: February 27, 2014
• Results First Posted: August 1, 2013

Record last verified: 2014-01

Locations

NO (1)