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The Effectiveness of Kuvan in Amish PKU Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02677870
Recruitment Status : Recruiting
First Posted : February 9, 2016
Last Update Posted : December 4, 2017
Sponsor:
Collaborator:
BioMarin Pharmaceutical
Information provided by (Responsible Party):
Lori-Anne Schillaci, University Hospitals Cleveland Medical Center

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.


Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: saproterin dihydrochloride Other: Diet treatment Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effectiveness of High-Dose Synthetic BH4 (Saproterin Dihydrochloride or "Kuvan") in Amish PKU Patients
Estimated Study Start Date : January 2018
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : August 2018


Arm Intervention/treatment
Diet treatment
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
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.

Active Comparator: Standard dose saproterin dihydrochloride
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
The drug will be given as described in the arm/group descriptions.
Other Name: Kuvan treatment

Other: Diet treatment
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.

Experimental: High dose saproterin dihydrochloride
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
The drug will be given as described in the arm/group descriptions.
Other Name: Kuvan treatment

Other: Diet treatment
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.




Primary Outcome Measures :
  1. Change in plasma phenylalanine levels (Measured units: umol/L) [ Time Frame: Weekly for 8 weeks (weeks 1 through 8). Then skipping two weeks for a washout period. Continuing weekly for 4 more weeks until the end of the trial (Weeks 10 through 14). ]
    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 response.

  2. Change in phenylalanine tolerance (Measured units: mg of Phe per day) [ Time Frame: Weekly for 14 weeks (weeks 1 through 14 of the trial) ]
    All patients will complete a 3-day diet diary weekly to be submitted to us on weeks 4, 8, 10 and 14 (conclusion of the study). Dietary intake will be calculated and analyzed by our metabolic dietician. An increase of Phe tolerance from baseline by 20% will be considered a response.


Secondary Outcome Measures :
  1. Executive function [ Time Frame: Measured at week 1, 4, 8, 10 and 14 ]
    Appropriate version of the BRIEF survey will be completed at each of the above visits. Caretakers will fill out surveys for any children too young to do so themselves.

  2. Quality of life [ Time Frame: Measured at week 1, 4, 8, 10 and 14 ]
    The PKU-QOL survey will be completed at each of the above visits. Caretakers will fill out surveys for any children too young to do so themselves.



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Ages Eligible for Study:   2 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02677870


Contacts
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Contact: Lori-Anne P Schillaci, MD 216-844-3936 lori-anne.schillaci@uhhospitals.org
Contact: Shawn McCandless, MD 216-844-7944 shawn.mccandless@uhhospitals.org

Locations
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United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Lori P Schillaci, MD    216-844-3936    lori-anne.schillaci@uhhospitals.org   
Sponsors and Collaborators
University Hospitals Cleveland Medical Center
BioMarin Pharmaceutical
Investigators
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Principal Investigator: Lori-Anne P Schillaci, MD University Hospitals Cleveland Medical Center
Additional Information:
Publications:

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Responsible Party: Lori-Anne Schillaci, Pediatric-Genetics Resident Physician, University Hospitals Cleveland Medical Center
ClinicalTrials.gov Identifier: NCT02677870    
Other Study ID Numbers: UHCMC IRB#
First Posted: February 9, 2016    Key Record Dates
Last Update Posted: December 4, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Lori-Anne Schillaci, University Hospitals Cleveland Medical Center:
Saproterin dihydrochloride
Kuvan
Amish
Additional relevant MeSH terms:
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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