Sapropterin on Cognitive Abilities in Young Adults With Phenylketonuria (SIGNAL)

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. Read our disclaimer for details. Identifier: NCT01977820
Recruitment Status : Terminated (Recruitment challenges)
First Posted : November 7, 2013
Results First Posted : February 12, 2016
Last Update Posted : February 22, 2018
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
This is a Phase 2a multicenter, double-blind, placebo-controlled, randomized, 2-arm pilot trial designed to assess the effect of sapropterin on cognitive abilities in young adults with Phenylketonuria (PKU) over a 26-week treatment period.

Condition or disease Intervention/treatment Phase
Phenylketonuria Drug: Sapropterin Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Double-Blind, Placebo-Controlled, Randomized, 2-Arm Phase IIa Pilot Trial Assessing the Effect of Sapropterin on Cognitive Abilities in Young Adults With Phenylketonuria
Study Start Date : February 2014
Actual Primary Completion Date : November 2014
Actual Study Completion Date : November 2014

Arm Intervention/treatment
Experimental: Sapropterin Drug: Sapropterin
Sapropterin tablets will be administered orally once daily at a dose of 20 milligram per kilogram (mg/kg) during both the 2-Week response test period and 24-Week study period.
Other Name: Kuvan®

Placebo Comparator: Placebo Drug: Placebo
Sapropterin tablets will be administered orally once daily at a dose of 20 milligram per kilogram (mg/kg) during both the 2-Week response test period and Placebo tablets matching to sapropterin will be administered orally once daily during the 24-Week study period.

Primary Outcome Measures :
  1. Number of Subjects With Adverse Events (AEs), Serious AEs (SAEs), AEs Leading to Death and AEs Leading to Discontinuation [ Time Frame: Screening up to 24 weeks + 4-week follow-up ]
    An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

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Ages Eligible for Study:   18 Years to 29 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Written informed consent given before any trial-related activities are carried out
  • Women or men with documented PKU diagnosed by at least two phenylalanine levels equal or greater than 600 micromole per liter (mcmol/L)
  • For women of childbearing potential: a negative urine pregnancy test is required at screening and willingness to use a highly effective method of contraception is required during the study and follow-up periods
  • Aged greater than or equal to (>=) 18 to 29 years, inclusive
  • Mean blood phenylalanine levels 600 to 1000 mcmol/L during 12 months preceding inclusion in the study. The mean should be calculated from at least 3 blood phenylalanine values over the last 12 months. Screening blood phenylalanine level can be one of these values. There should be at least one value dated between Month -12 and -6 before Screening and at least one value dated between Month -6 and Screening
  • An intelligence quotient (IQ) score greater than or equal to 85, assessed a maximum of 2 years before screening with an age-appropriate Wechsler scale. If no IQ test result is available, IQ testing must be performed as part of Screening using an age-appropriate Wechsler scale before the subject can be included
  • Subjects willing to comply with all study procedures, including willingness to continue current dietary recommendations during the whole trial duration

Exclusion Criteria:

  • Subjects with tetrahydrobiopterin (BH4) deficiency
  • Previous exposure to sapropterin or BH4 for greater than 30 days (or exposure to sapropterin or BH4 for less than or equal to 30 days but within the previous 6 months prior to Screening visit)
  • Subjects who, according to the Investigator, will not be able to comply with study procedures and computerized neuropsychological testing
  • Any significant illness which, according to the Investigator, might preclude participation in the study (including neurological disease, cardio-vascular disease, history of seizure, predisposition to convulsions, renal or hepatic insufficiency, and active malignancy)
  • Any significant illness, medication or substance abuse which, according to the Investigator, might affect cognitive function and cognitive testing (for example, significant visual or motor impairment, history of major head trauma, history of stroke, alcoholism, drug dependency, psychological disorder requiring chronic use of psychotropic medications such as anxiolytics, antidepressants, antipsychotic medication, mood stabilizers, and hypnotics)
  • Concomitant forbidden medication as described in the Kuvan® Summary of Product Characteristics, namely, inhibitors of dihydrofolate reductase (for example, methotrexate, trimethoprim), medications that are known to affect nitric oxide synthesis (for example, glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, molsidomin, phosphodiesterase type 5 inhibitors, and minoxidil), and levodopa, as it may cause increased excitability and irritability
  • Known hypersensitivity to sapropterin or any ingredients in the product's formulation, or to other approved or non-approved formulations of BH4
  • Subjects who have undergone cognitive neuropsychological testing similar to that to be performed as part of this trial with the following time limits: tasks with limited practice effect performed in the last 6 months, and tasks with important practice effect (such as tasks involving development of strategies) performed in the year preceding inclusion in the trial. Whether a task falls into one or the other category is left to Investigator judgment
  • Female subjects who are pregnant or in the lactation period
  • Subjects currently participating to another clinical trial or who participated in a previous clinical trial within 30 days prior to screening
  • Legal incapacity or limited legal capacity

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 identifier (NCT number): NCT01977820

Research Site
Bologna, Italy
Research site
Lausanne, Switzerland
Sponsors and Collaborators
BioMarin Pharmaceutical
Study Director: Medical Responsible BioMarin Pharmaceutical

Responsible Party: BioMarin Pharmaceutical Identifier: NCT01977820     History of Changes
Other Study ID Numbers: EMR 700773-004
2010-024311-13 ( EudraCT Number )
First Posted: November 7, 2013    Key Record Dates
Results First Posted: February 12, 2016
Last Update Posted: February 22, 2018
Last Verified: January 2018

Keywords provided by BioMarin Pharmaceutical:
Cognitive Abilities

Additional relevant MeSH terms:
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
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents