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Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (SPARK)

Primary Purpose

Phenylketonuria

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Kuvan®

Phenylalanine (Phe)-restricted diet

About this trial

This is an interventional treatment trial for Phenylketonuria focused on measuring Phenylketonuria (PKU), Kuvan® (Sapropterin), Phe-restricted diet, Paediatric <4 years old, responders to BH4, Phe tolerance

Eligibility Criteria

undefined - 4 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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:
1. The BH4 dose was 20 milligram per kilogram per day (mg/kg/day)
2. The duration of the test was at least for 24 hours
3. 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

Exclusion Criteria:

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Kuvan® + Phe-restricted diet

Phe-restricted diet alone

Arm Description

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

Subjects will follow a Phe-restricted diet alone.

Outcomes

Primary Outcome Measures

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]).

Secondary Outcome Measures

Mean Blood Phe Levels

Mean blood phe levels were defined as the mean of blood phe levels assessed over each 2-week intervals

Change From Baseline in Dietary Phe Tolerance After 26 Weeks

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

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

An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (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. Treatment-emergent are events between first dose of study treatment and up to 31 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

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

Subjects with normal neuromotor development were assessed by standardized developmental milestones using a parent/guardian report form in the following areas: fine motor, gross motor, language, and personal-social using DDS Test. DDS Test is a widely used to examine the developmental progress of 0-6 years of children. The scale reflects what percentage of a certain age group is able to perform a certain task. Tasks are grouped into 4 categories (social contact, fine motor skill, language, and gross motor skill) and include items such as smiles spontaneously (performed by 90% of three-month-olds), knocks 2 building blocks against each other (90% of 13-month-olds), speaks 3 words other than "mom" and "dad" (90% of 21-month-olds), or hops on 1 leg (90% of 5-year-olds). The more items a child fails to perform (passed by 90% of his/her peers), the more likely the child manifests a significant developmental problems.

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

Neurodevelopmental assessments was done using the following age-dependent scales: Bayley III for subjects less than (<) 3.5 years of age and WPPSI III for subjects greater than or equal to (>=) 3.5 to <4 years of age, based on following scores: adaptive behavior composite (ABC) score, cognitive composite (CC) score, language composite (LC) score, motor composite (MC) score., and social-emotional composite (SEC) score. Composite scores ranged from 40 (very poor) to 160 (excellent) and are classified as following: >=115: accelerated performance; 85-114: development within normal limits; 70-84: mildly delayed development; less than or equal to (<=) 69: significant delayed development.

Growth Parameters Standard Deviation Scores (SDS)

Growth assessment was performed by monitoring body mass index, height (or length), weight, and maximal occipital-frontal head circumference (MOFHC). Supine length was measured up to 2 years of age thereafter standing height was measured unless subject was unable to stand upright, in which case supine length was measured. Respective parameter SDS was calculated as the value of parameter minus reference mean value of parameter divided by standard deviation of the reference population.

Number of Subjects With Hypophenylalanemia

Hypophenylalanemia is defined as the condition of blood Phe levels <120 mcmol/L.

Dietary Phe Tolerance During Extension Period

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations

The DNA samples received were quantified by using a nanophotometer, and were aliquoted to a concentration of 20 nanogram/microliter DNA and aliquots from each sample were distributed to one 96-well plate. All samples were Sanger sequenced regarding exons 1 to 13 of the PAH gene in forward direction using the DNAs in the 96-well plate. All samples showing variants were Sanger sequenced regarding the concerned exon in reverse direction using DNA from the original tube. All samples showing a homozygous mutation were analyzed by MLPA. All samples showing only 1 mutation were analyzed by MLPA. All samples showing only 1 or no mutation were resequenced completely (exons 1 to 13) in both directions.

Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)

CL/f is the rate at which a drug is removed from the body via renal, hepatic and other clearance pathways.The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Population PK Parameter: Apparent Volume of Distribution (V/f)

V/f is defined as the distribution of a medication between the plasma and the rest of the body after the dose. It is the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of the drug. The reason for pooling subjects receiving Kuvan and subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving the treatment. Ignoring this baseline endogenous value would have led to biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])

AUC [0-infinity] was estimated by determining total area under the curve of the concentration versus time curve extrapolated to infinity. Since AUC could not be obtained from non-compartmental analysis because of sparse data, AUC = Dose/(CL/F); CL/F was population apparent clearance estimated from the population PK model, & Dose the actual total dose received by the patient on one dosing interval. The reason for pooling subjects receiving Kuvan &subjects with Phe-restricted Diet was to facilitate estimation of baseline endogenous value of BH4 which can only be observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led to biased estimated of Kuvan PK parameters. This pooling assumes that the the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 were same for the 2 arms and cannot be presented per arm/per treatment group as per planned analysis.

Population PK Parameter: Terminal Elimination Half-life (t1/2)

The t1/2 was defined as the time required for plasma concentration of drug to decrease 50 percent (%) in the final stage of elimination. Since t1/2 could not be obtained from non-compartmental analysis because of sparse data, t1/2 was estimated as Log(2)*(V/F)/(CL/F), where V/F & CL/F were the population apparent central Volume & clearance, estimated from population PK model. The reason for pooling subjects receiving Kuvan & subjects with Phe-restricted Diet was to facilitate the estimation of baseline endogenous value of BH4 which can only observed in subjects not receiving treatment. Ignoring this baseline endogenous value would have led biased stimated of the Kuvan PK parameters. This pooling assumes that the addition of Kuvan does not confound the BH4 measurements in these analyses as a consequence the population PK parameters describing the PK of BH4 are the same for the 2 arms and so cannot be presented in terms of per arm/per treatment group based as per the planned analysis.

Population PK Parameter: Maximum Observed Plasma Concentration (Cmax)

Population PK Parameter: Time to Maximum Plasma Concentration (Tmax)

Full Information

NCT ID

NCT01376908

First Posted

June 17, 2011

Last Updated

August 17, 2017

Sponsor

BioMarin Pharmaceutical

1. Study Identification

Unique Protocol Identification Number

NCT01376908

Brief Title

Kuvan® in Phenylketonuria Patients Less Than 4 Years Old

Acronym

SPARK

Official Title

A Phase IIIb, Multicentre, Open-Label, Randomized, Controlled Study of the Efficacy, Safety, and Population Pharmacokinetics of Sapropterin Dihydrochloride (Kuvan®) in Phenylketonuria (PKU) Patients <4 Years Old.

Study Type

Interventional

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

June 2011 (undefined)

Primary Completion Date

July 2014 (Actual)

Study Completion Date

February 17, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

BioMarin Pharmaceutical

4. Oversight

Data Monitoring Committee

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Phenylketonuria

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

56 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Kuvan® + Phe-restricted diet

Arm Type

Experimental

Arm Description

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

Arm Title

Phe-restricted diet alone

Arm Type

Other

Arm Description

Subjects will follow a Phe-restricted diet alone.

Intervention Type

Drug

Intervention Name(s)

Kuvan®

Other Intervention Name(s)

Sapropterin dihydrochloride

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Phenylalanine (Phe)-restricted diet

Intervention Description

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.

Primary Outcome Measure Information:

Title

Dietary Phenylalanine (Phe) Tolerance at Week 26

Description

Time Frame

Week 26

Secondary Outcome Measure Information:

Title

Mean Blood Phe Levels

Description

Mean blood phe levels were defined as the mean of blood phe levels assessed over each 2-week intervals

Time Frame

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

Title

Change From Baseline in Dietary Phe Tolerance After 26 Weeks

Description

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

Baseline, Weeks 12, 26

Title

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

Description

Time Frame

Baseline and Week 26

Title

Growth Parameters Standard Deviation Scores (SDS)

Description

Time Frame

Baseline, Weeks 4, 8, 12, 16, 20, and 26

Title

Number of Subjects With Hypophenylalanemia

Description

Hypophenylalanemia is defined as the condition of blood Phe levels <120 mcmol/L.

Time Frame

Week 26

Title

Dietary Phe Tolerance During Extension Period

Description

Phe tolerance was defined as the amount of dietary Phe ingested (mg/kg/day) while maintaining blood Phe levels within the selected therapeutic target range (defined as >=120 to <360 mcmol/L).

Time Frame

Every 6 months during 3 year extension period or until product is commercially approved

Title

Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Time Frame

Baseline, Weeks 4, 8, 12, 16, 20, and 26

Title

Number of Samples With Phenylalanine Hydroxylase (PAH) Gene Mutations

Description

Time Frame

Screening (within 42 days prior to Day 1 of the 26-week study period)

Title

Population Pharmacokinetic (PK) Parameter: Apparent Clearance (CL/f)

Description

Time Frame

Weeks 5 to 12

Title

Population PK Parameter: Apparent Volume of Distribution (V/f)

Description

Time Frame

Weeks 5 to 12

Title

Population PK Parameter: Area Under the Plasma Concentration Curve, Time 0 to Infinity (AUC [0-infinity])

Description

Time Frame

Weeks 5 to 12

Title

Population PK Parameter: Terminal Elimination Half-life (t1/2)

Description

Time Frame

Weeks 5 to 12

Title

Population PK Parameter: Maximum Observed Plasma Concentration (Cmax)

Time Frame

Up to Week 26

Title

Population PK Parameter: Time to Maximum Plasma Concentration (Tmax)

Time Frame

Up to Week 26

10. Eligibility

Sex

All

Maximum Age & Unit of Time

4 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ignacio Alvarez, MD

Organizational Affiliation

BioMarin Pharmaceutical

Official's Role

Study Director

Facility Information:

Facility Name

Research Site

City

Graz

Country

Austria

Facility Name

Research site

City

Innsbruck

Country

Austria

Facility Name

Research Site

City

Bruxelles

Country

Belgium

Facility Name

Research Site

City

Edegem

Country

Belgium

Facility Name

Research Site

City

Praha 10

Country

Czechia

Facility Name

Research site

City

Heidelberg

Country

Germany

Facility Name

Research Site

City

Munich

Country

Germany

Facility Name

Research Site

City

Münster

Country

Germany

Facility Name

Research Site

City

Reutlingen

Country

Germany

Facility Name

Research Site

City

Bologna

Country

Italy

Facility Name

Research Site

City

Milano

Country

Italy

Facility Name

Research Site

City

Padova

Country

Italy

Facility Name

Research Site

City

Roma

Country

Italy

Facility Name

Research site

City

Rome

Country

Italy

Facility Name

Research Site

City

Amsterdam

Country

Netherlands

Facility Name

Research Site

City

Maastricht

Country

Netherlands

Facility Name

Research Site

City

Banska Bystrica

Country

Slovakia

Facility Name

Research Site

City

Bratislava

Country

Slovakia

Facility Name

Research Site

City

Kosice

Country

Slovakia

Facility Name

Research Site

City

Ankara

Country

Turkey

Facility Name

Research Site

City

Birmingham

Country

United Kingdom

Facility Name

Research site

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

34344399

Citation

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.

Results Reference

derived

PubMed Identifier

28274234

Citation

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.

Results Reference

derived

Learn more about this trial

Kuvan® in Phenylketonuria Patients Less Than 4 Years Old

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Kuvan® in Phenylketonuria Patients Less Than 4 Years Old (SPARK)

Phenylketonuria

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial