The Effectiveness of Kuvan in Amish PKU Patients

NCT02677870 | Completed Phase 4 Results FDA Drug

• 1 other identifier: UHCMC IRB#
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine if Amish patients with PKU show responsiveness after a high dose, prolonged Saproterin trial. The population of interest has a high frequency of a specific splice site mutation, the 1066-11G\>A mutation. This splice site mutation activates a cryptic splice site resulting in an in frame insertion of 9 nucleotides preceding exon 11. This leads to protein conformational changes and abrogation of function. Previous studies of this genotype have indicated \<1% residual activity of the PAH enzyme and an insignificant responsiveness to Saproterin. However, in this specific study Phe levels were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of 20mg/kg. Based on new clinical information, the investigators hypothesize that if given a prolonged trial of Saproterin at a higher dose, Amish patients with PKU, specifically those homozygous for the c.1066-11G\>A mutation, will have a significant reduction in Phe levels or an increase in Phe tolerance and/or improvement in executive functioning and quality of life.

Conditions

Phenylketonuria

Keywords

Saproterin dihydrochloride; Kuvan; Amish

Outcome Measures

Primary Outcomes (1)

• Number of Participants With 20% Decrease in Phenylalanine Levels From Baseline (Positive Response)

  Subjects will be assessed for plasma Phe concentration by dried blood spot cards during their initial visit (day 1) and every week thereafter. Except during the two week wash-out period where no plasma Phe will be collected. A decrease of plasma Phe levels from baseline by 20% will be considered a positive response.

  Baseline, weekly for 4 weeks during diet arm, weekly for 4 weeks during both high and standard dose arms

Study Arms (3)

Diet treatment

OTHER

In part 1 of the study, patients will not receive any medication. Each patient will DIET treatment alone. They will maintain a stable, Phe restricted diet (including formula) that is consistent with their diet at the time of enrollment. This will be monitored by food diaries kept for 3 days of each week. Based on these diaries, average weekly Phe intake and Phe tolerance will be calculated and recorded.

Other: Diet treatment

Standard dose saproterin dihydrochloride

ACTIVE COMPARATOR

Study numbers will be randomized into "standard-dose saproterin dihydrochloride (Kuvan)" or "high-dose saproterin dihydrochloride (Kuvan) " groups (treatment group A or treatment group B). Both groups will receive a trial of both standard and high dose saproterin dihydrochloride before the end of the study. Standard-dose saproterin dihydrochloride will be 20mg/kg (rounded up to the nearest 100mg) provided in the form of 100mg tablets. Dosing of the tablets will be unidentifiable to patients. Medication will be given orally once daily.

Drug: saproterin dihydrochloride; Other: Diet treatment

High dose saproterin dihydrochloride

EXPERIMENTAL

Study numbers will be randomized into "standard-dose saproterin" or "high-dose saproterin" groups (treatment group A or treatment group B). Both groups will receive a trial of both standard and high dose saproterin dihydrochloride before the end of the study. Goal high-dose saproterin dihydrochloride dosing will be 40mg/kg (rounded up to the nearest 500mg), provided in the form of pre-packaged 500mg packets of powder. Labeled dosing on these packets will be covered by the investigational drug pharmacy and unidentifiable to patients. Dosing of the tablets will be unidentifiable to patients. Medication will be given orally once daily.

Drug: saproterin dihydrochloride; Other: Diet treatment

Interventions

saproterin dihydrochloride DRUG

The drug will be given as described in the arm/group descriptions.

Also known as: Kuvan treatment

High dose saproterin dihydrochloride; Standard dose saproterin dihydrochloride

Diet treatment OTHER

Patients will maintain a stable, Phe restricted diet (including formula) that is consistent with their diet at the time of enrollment. This will be monitored by food diaries kept for 3 days of each week.

Diet treatment; High dose saproterin dihydrochloride; Standard dose saproterin dihydrochloride

Eligibility Criteria

• Age: 2 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Current diagnosis of PKU with the following:
• Age of at least 2 years or older
• Baseline Phe level of \> 360 umol/L
• Willing to maintain a stable diet
• Patient or guardian are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures
• Are willing to comply with all study procedures
• Two identifiable mutations found on PAH gene sequencing
• Any patients already taking Saproterin (or have taken in the past), must have a treatment end date at least 14 days prior to Day 1 of the study.

You may not qualify if:

• Any patient currently taking Saproterin who has taken the medication at any point in the 14 days prior to Day 1 of the study
• Under 2 years of age
• Unwilling to maintain a stable diet
• Patients with baseline Phe levels \< 360 umol/L
• Patients unable to comply with all study procedures
• Patients unable to provide written, signed informed consent
• One (or no) identifiable mutations found on PAH gene sequencing

Sponsors & Collaborators

• University Hospitals Cleveland Medical Center: lead
• BioMarin Pharmaceutical: collaborator

Study Sites (1)

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Related Publications (8)

• Wang H, Nye L, Puffenberger E, Morton H. Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large old order Amish settlements. Am J Med Genet A. 2007 Aug 15;143A(16):1938-40. doi: 10.1002/ajmg.a.31852. No abstract available.

  PMID: 17630668 BACKGROUND

• Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, Ozer I, Gokcay G, Baykal T, Thony B, Demirkol M, Blau N. Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Mol Genet Metab. 2011 Feb;102(2):116-21. doi: 10.1016/j.ymgme.2010.11.158. Epub 2010 Nov 18.

  PMID: 21147011 BACKGROUND

• Dworniczak B, Aulehla-Scholz C, Kalaydjieva L, Bartholome K, Grudda K, Horst J. Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe. Genomics. 1991 Oct;11(2):242-6. doi: 10.1016/0888-7543(91)90129-3.

  PMID: 1769645 BACKGROUND

• Karacic I, Meili D, Sarnavka V, Heintz C, Thony B, Ramadza DP, Fumic K, Mardesic D, Baric I, Blau N. Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab. 2009 Jul;97(3):165-71. doi: 10.1016/j.ymgme.2009.03.009. Epub 2009 Apr 1.

  PMID: 19394257 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

• Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Belanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, Muntau AC, Bosch AM, Meli CA, Billette de Villemeur T, Kern I, Riva E, Giovannini M, Damaj L, Leuzzi V, Blau N. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics. 2013 Jun;131(6):e1881-8. doi: 10.1542/peds.2012-3291. Epub 2013 May 20.

  PMID: 23690520 BACKGROUND

• Waisbren S, White DA. Screening for cognitive and social-emotional problems in individuals with PKU: tools for use in the metabolic clinic. Mol Genet Metab. 2010;99 Suppl 1:S96-9. doi: 10.1016/j.ymgme.2009.10.006.

  PMID: 20123479 BACKGROUND

• Regnault A, Burlina A, Cunningham A, Bettiol E, Moreau-Stucker F, Benmedjahed K, Bosch AM. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients' and parents' quality of life: the phenylketonuria - quality of life (PKU-QOL) questionnaires. Orphanet J Rare Dis. 2015 May 10;10:59. doi: 10.1186/s13023-015-0261-6.

  PMID: 25958326 BACKGROUND

Related Links

• PKU database with known mutations and their responsiveness after Kuvan trial. Length of trial performed is also listed on website.

MeSH Terms

Conditions

Phenylketonurias

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: Dr. Lori-Anne Schillaci
• Organization: UHCMC

lori-anne.schillaci@uhhospitals.org

216-844-3936

Study Officials

• Lori-Anne P Schillaci, MD

  University Hospitals Cleveland Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2016
• First Posted: February 9, 2016
• Study Start: January 22, 2018
• Primary Completion: November 20, 2018
• Study Completion: January 1, 2019
• Last Updated: April 27, 2022
• Results First Posted: April 27, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)