Kuvan® in Phenylketonuria Patients Less Than 4 Years Old

NCT01376908 | Completed Phase 3 Results

• 2 other identifiers: EMR 700773-0032009-015768-33
• Study Type: interventional
• Target: 56
• Locations: 9 countries
• Sites: 22

Brief Summary

This is a Phase 3b, multicenter, open-label, randomized, controlled study to evaluate efficacy, safety and population pharmacokinetics of sapropterin dihydrochloride (Kuvan®) in less than 4 year-old infants and children with phenylketonuria (PKU).

Conditions

Phenylketonuria

Keywords

Phenylketonuria (PKU); Kuvan® (Sapropterin); Phe-restricted diet; Paediatric <4 years old; responders to BH4; Phe tolerance

Outcome Measures

Primary Outcomes (1)

• Dietary Phenylalanine (Phe) Tolerance at Week 26

  Phe tolerance was defined as the amount of dietary Phe prescribed (milligram per kilogram per day \[mg/kg/day\]) while maintaining blood Phe levels within the selected therapeutic target range (defined as greater than or equal to \[\>=\] 120 to less than \[\<\] 360 micromoles per liter \[mcmol/L\]).

  Week 26

Secondary Outcomes (16)

• Mean Blood Phe Levels

  Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26

• Change From Baseline in Dietary Phe Tolerance After 26 Weeks

  Baseline and at Week 26 (last observation carried-forward [LOCF])

• Number of Subjects With Any TEAEs, AEs Related to Kuvan, Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation

  From the first dose of study drug administration up to 31 days after the last dose of study drug administration

• Number of Subjects With Normal Neuromotor Developmental Milestones Assessed Using Denver Developmental Scale (DDS)

  Baseline, Weeks 12, 26

• Neurodevelopmental Status Assessed Using Bayley III Scales of Infant and Toddler Development

  Baseline and Week 26

Study Arms (2)

Kuvan® + Phe-restricted diet

EXPERIMENTAL

Subjects will be treated with Kuvan® tablets once daily along with Phe-restricted diet therapy.

Drug: Kuvan®; Other: Phenylalanine (Phe)-restricted diet

Phe-restricted diet alone

OTHER

Subjects will follow a Phe-restricted diet alone.

Other: Phenylalanine (Phe)-restricted diet

Interventions

Kuvan® DRUG

Kuvan® (sapropterin dihydrochloride) tablets will be administered orally at the dose of 10 mg/kg/day and will be escalated to 20 mg/kg/day if after 4 weeks a subject's Phe tolerance is not increased by at least 20% versus baseline.

Also known as: Sapropterin dihydrochloride

Kuvan® + Phe-restricted diet

Phenylalanine (Phe)-restricted diet OTHER

Phe intake will be adjusted every 2 weeks, based on the mean Phe levels of the previous 2 weeks using pre-defined Phe adjustment criteria.

Kuvan® + Phe-restricted diet; Phe-restricted diet alone

Eligibility Criteria

• Age: Up to 4 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female PKU infants and young children less than (\<) 4 years of age at the scheduled Day 1 visit of the 26-week study period (taking into consideration the maximum of 21 days in the screening period)
• Confirmed clinical and biochemical PKU, including at least two previous blood Phe levels greater than or equal to (\>=) 400 micromol per liter (mcmol/L) obtained on 2 separate occasions
• Previously responded, as assessed by the Investigator, to a tetrahydrobiopterin (BH4) test, if all 3 of the following criteria are satisfied:
• The BH4 dose was 20 milligram per kilogram per day (mg/kg/day)
• The duration of the test was at least for 24 hours
• A 30% decrease in blood Phe levels.
• Defined level of dietary Phe tolerance consistent with the diagnosis of PKU
• Good adherence to dietary treatment, including prescribed dietary Phe restriction and prescribed amounts of Phe-free protein supplements and low-Phe foods
• Maintenance of blood Phe levels within the therapeutic target range of 120-360 mcmol/L (defined as \>=120 to \<360 mcmol/L) over a 4-month period prior to Screening, as assessed by the Investigator
• 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

You may not qualify if:

• Use of Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin within the previous 30 days, unless for the purposes of a BH4 responsiveness test
• Previous exposure to Kuvan®, Biopten®, or any unregistered preparation of tetrahydrobiopterin for greater than (\>)30 days
• Known hypersensitivity to Kuvan® or its excipients
• Known hypersensitivity to other approved or non-approved formulations of tetrahydrobiopterin
• Previous diagnosis of BH4 deficiency
• Current use of methotrexate, trimethoprim, or other dihydrofolate reductase inhibitors
• Current use of medications that are known to affect nitric oxide synthesis, metabolism or action
• Current use of levodopa
• Current use of experimental/other investigational or unregistered drugs that may affect the study outcomes
• Inability to comply with study procedures
• Inability to tolerate oral intake
• History of organ transplantation
• 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
• Other significant disease that in the Investigator's opinion would exclude the subject from the trial
• 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

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (22)

Research Site

Graz, Austria

Location

Research site

Innsbruck, Austria

Location

Research Site

Brussels, Belgium

Location

Research Site

Edegem, Belgium

Location

Research Site

Prague, Czechia

Location

Research site

Heidelberg, Germany

Location

Research Site

Munich, Germany

Location

Research Site

Münster, Germany

Location

Research Site

Reutlingen, Germany

Location

Research Site

Bologna, Italy

Location

Research Site

Milan, Italy

Location

Research Site

Padua, Italy

Location

Research Site

Roma, Italy

Location

Research site

Rome, Italy

Location

Research Site

Amsterdam, Netherlands

Location

Research Site

Maastricht, Netherlands

Location

Research Site

Banská Bystrica, Slovakia

Location

Research Site

Bratislava, Slovakia

Location

Research Site

Košice, Slovakia

Location

Research Site

Ankara, Turkey (Türkiye)

Location

Research Site

Birmingham, United Kingdom

Location

Research site

London, United Kingdom

Location

Related Publications (2)

• Muntau AC, Burlina A, Eyskens F, Freisinger P, Leuzzi V, Sivri HS, Gramer G, Pazdirkova R, Cleary M, Lotz-Havla AS, Lane P, Alvarez I, Rutsch F. Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial. Orphanet J Rare Dis. 2021 Aug 3;16(1):341. doi: 10.1186/s13023-021-01968-1.

  PMID: 34344399 DERIVED

• Muntau AC, Burlina A, Eyskens F, Freisinger P, De Laet C, Leuzzi V, Rutsch F, Sivri HS, Vijay S, Bal MO, Gramer G, Pazdirkova R, Cleary M, Lotz-Havla AS, Munafo A, Mould DR, Moreau-Stucker F, Rogoff D. Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients <4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial. Orphanet J Rare Dis. 2017 Mar 9;12(1):47. doi: 10.1186/s13023-017-0600-x.

  PMID: 28274234 DERIVED

MeSH Terms

Conditions

Phenylketonurias

Interventions

sapropterin; Phenylalanine

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

Intervention Hierarchy (Ancestors)

Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Medical Information Services
• Organization: BioMarin Pharmaceutical Inc.

medinfo@bmrn.com

+1-800-983-4587

Study Officials

• Ignacio Alvarez, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2011
• First Posted: June 20, 2011
• Study Start: June 1, 2011
• Primary Completion: July 1, 2014
• Study Completion: February 17, 2017
• Last Updated: September 15, 2017
• Results First Posted: May 12, 2016

Record last verified: 2017-08

Locations

GB (2); SL (3); IT (5); DE (4); TU (1); BE (2); NL (2); AU (2); CZ (1)