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

Phenylketonuria Clinical Trial

— ENDURE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01082328
• Other study ID #: EMR 700773-503
• Status: Completed
• Phase: Phase 4
• First received: March 5, 2010
• Last updated: January 26, 2014
• Start date: May 2010
• Est. completion date: May 2012

Study information

• Verified date: January 2014
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Norway: Norwegian Medicines AgencyDenmark: Danish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: May 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 4 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Phenylketonuria
• Phenylketonurias

Intervention

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

Locations

Country	Name	City	State
Norway	Department of Paediatric Research, Division of Paediatrics, Oslo University Hospital, Rikshospitalet	Oslo

Sponsors (3)

Lead Sponsor	Collaborator
Merck KGaA	Merck Serono Norway, Smerud Medical Research International AS

Country where clinical trial is conducted

Norway, 

References & Publications (25)

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. — View Citation

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. — View Citation

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. — View Citation

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.

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

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. — View Citation

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. — View Citation

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

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

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. — View Citation

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. — View Citation

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. — View Citation

Kuvan® Package Insert. BioMarin. 2007

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Number of Participants With Adverse Events (AEs), Treatment Emergent Adverse Events, Treatment Related Adverse Events and AEs Leading to Withdrawal	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.	Baseline up to Day 42 +/- 3	Yes
Secondary	Percentage of Early-, Late-, Partial-Responders and Non-responders to Treatment With Kuvan®	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.	Baseline up to Day 28 +/- 1	No
Secondary	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	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).	Baseline up to Day 28 +/- 1	No
Secondary	Percentage of Early-, Late- and Partial-Responders According to Phenotype	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.	Baseline up to Day 28 +/- 1	No
Secondary	Mean Change From Baseline in Blood Phenylalanine-to-tyrosine Ratio	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.	Baseline, Day 28	No

External Links

•   Arnold GL. Phenylketonuria, Publication Link
•   PAH database, Publication Link