Table 3Details of Included Studies

PKU-016SPARK
Designs & PopulationsStudy DesignDB, PC, PG, phase 3b RCTOL, PG, phase 3b RCT
LocationsCanada and USEurope, Slovakia, Turkey, United Kingdom
Randomized (N)206a56d
Inclusion CriteriaPatients aged ≥ 8 years with confirmed PKU and willingness to continue their Phe-restrictive diet unchanged for the duration of the studyPatients aged < 4 years with confirmed clinical and biochemical PKU, previous response to a BH4 test, a defined level of dietary Phe tolerance, good dietary adherence, Phe levels between 120 and 360 μmol/L over the 4 months prior to screening
Exclusion CriteriaSAP within past 16 weeks, initiated or adjusted ADHD, depression or anxiety medication within ≤ 8 weeks, interfering medication or concurrent disease or conditionPrior use or exposure to SAP or any registered or unregistered preparation of BH4, previous diagnosis of BH4 deficiency, or interfering medication or concurrent disease or condition
DrugsInterventionSAP 20 mg/kg/day PO + Phe-restrictive dietSAP 10 mg/kg/day PO + Phe-restrictive diet
Comparator(s)Placebo + Phe-restrictive dietPhe-restrictive diet alone
DurationRun-in2-week screening42 days screening
DB13-week treatmentNA
OL13-week treatment26 weeks
Follow-up30 ± 7 days4 weeks
OutcomesPrimary End Points– Change in ADHD-RSbor ASRSc total score (and separate Inattention and Hyperactivity-lmpulsivity subscale scores) from BL to week 13 in Phe responders with ADHD symptoms
– Proportion of patients with CGI-I scale rating of 1 (very much improved) or 2 (much improved) at week 13 in Phe responders with or without ADHD symptoms		Dietary Phe tolerance (i.e., defined as the daily amount of Phe in mg/kg/day ingested while maintaining average Phe levels within ≥ 120 to < 360 μmol/L)
Other End PointsChange in HAM-D or HAM-A total score, BRIEF-GEC T score, BRIEF-BRI T score, BRIEF-MI T score, CGI-S scores from BL to week 13, CGI-I score of 1 or 2 at week 26, change in ADHD-RS, ASRS and above instrument scores from week 13 to week 26 and from BL to week 26Change in Phe blood levels and dietary Phe tolerance from baseline, physical growth parameters (e.g., height, weight, head circumference), age-related neuromotor developmental milestones and standardized neurodevelopment test results
NotesPublicationsBurton et al., 20159Unpublished

ADHD = attention-deficit/hyperactivity disorder; ADHD-RS = Attention Deficit Hyperactivity Disorder Rating Scale; ASRS = Adult Attention Deficit Hyperactivity Disorder Self-Report Scale; BH4 = tetrahydrobiopterin; BL = baseline; BRI = Behavioral Regulation Index; BRIEF = Behavior Rating Inventory of Executive Function; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity of Illness; DB = double-blind; GEC = Global Executive Composite; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Depression Rating Scale; NA = not applicable; OL = open-label; PC = placebo-controlled; PG = parallel-group; Phe = phenylalanine; PKU = phenylketonuria; PO = oral; RCT = randomized controlled trial; SAP = sapropterin.

a

Randomization was stratified by presence of ADHD symptoms (yes or no), age at entry (< 18 and ≥ 18 years), and use of ADHD medications (yes or no).

b

Patients aged 8 to 17 years.

c

Patients aged 18 years and older.

d

Randomization was stratified by age (< 12 months, 12 to < 24 months, and 24 to < 48 months).

Note: 6 additional reports were included (manufacturer’s submission,12 Clinical Study Report [CSR] PKU-016,10 CSR SPARK study,11 FDA Medical and Statistical reports).16,17

Source: Clinical Study Report (CSR) PKU-016,10 CSR SPARK study.11

From: 4, Results

Cover of Clinical Review Report: Sapropterin dihydrochloride (Kuvan)
Clinical Review Report: Sapropterin dihydrochloride (Kuvan) [Internet].
Copyright © 2017 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.