Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria

• ClinicalTrials.gov Identifier: NCT01732471
• Recruitment Status: Completed
• First Posted: November 22, 2012
• Results First Posted: July 28, 2014
• Last Update Posted: July 28, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Phenylketonuria
• Intervention: Drug: Kuvan®
• Enrollment: 90

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Kuvan®
Arm/Group Description	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Period Title: Overall Study
Started	90
Completed	89
Not Completed	1
Reason Not Completed
Withdrawal by Subject	1

Baseline Characteristics

Arm/Group Title		Kuvan®
Arm/Group Description		Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Overall Number of Baseline Participants		90
Baseline Analysis Population Description		Intention to Treat (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	90 participants
		9.59 (4.09)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	90 participants
	Female	41 45.6%
	Male	49 54.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment
Description	Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.

Arm/Group Title	Kuvan®
Arm/Group Description:	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Overall Number of Participants Analyzed	90
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	33.3; (23.7 to 44.1)

2. Secondary Outcome

Title	Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population
Description	Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.
Time Frame	Baseline, Day 8

Outcome Measure Data

Analysis Population Description

Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.

Arm/Group Title	Kuvan®
Arm/Group Description:	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Overall Number of Participants Analyzed	90
Mean (Standard Deviation); Unit of Measure: percent change
	-14.14 (28.35)

3. Secondary Outcome

Title	Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders
Description	Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.
Time Frame	Baseline, Day 8

Outcome Measure Data

Analysis Population Description

Sub-population of responders included participants with reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.

Arm/Group Title	Kuvan®
Arm/Group Description:	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Overall Number of Participants Analyzed	30
Mean (Standard Deviation); Unit of Measure: percent change
	-44.25 (15.13)

4. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population
Description	An adverse event (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.
Time Frame	Baseline up to Week 11

Outcome Measure Data

Analysis Population Description

Overall safety population included all participants who received at least 1 dose of investigational medicinal product.

Arm/Group Title	Kuvan®
Arm/Group Description:	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
Overall Number of Participants Analyzed	90
Measure Type: Number; Unit of Measure: participants
AEs	24
SAEs	1

Adverse Events

Time Frame	Baseline up to Week 11
Adverse Event Reporting Description	An AE is any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE is an AE resulting in any of following outcomes:death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Arm/Group Title	Kuvan®
Arm/Group Description	Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.
All-Cause Mortality
	Kuvan®
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Kuvan®
	Affected / at Risk (%)
Total	1/90 (1.11%)
Injury, poisoning and procedural complications
Upper limb fracture * 1	1/90 (1.11%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Kuvan®
	Affected / at Risk (%)
Total	23/90 (25.56%)
Blood and lymphatic system disorders
Anaemia * 1	1/90 (1.11%)
Eye disorders
Myopia * 1	1/90 (1.11%)
Gastrointestinal disorders
Diarrhoea * 1	1/90 (1.11%)
Faeces pale * 1	1/90 (1.11%)
Gastroduodenitis * 1	1/90 (1.11%)
Infections and infestations
Oral herpes * 1	1/90 (1.11%)
Injury, poisoning and procedural complications
Heat stroke * 1	1/90 (1.11%)
Metabolism and nutrition disorders
Iodine deficiency * 1	1/90 (1.11%)
Renal and urinary disorders
Haematuria * 1	1/90 (1.11%)
Leukocyturia * 1	1/90 (1.11%)
Phenylketonuria * 1	2/90 (2.22%)
Reproductive system and breast disorders
Dysmenorrhoea * 1	1/90 (1.11%)
Genital labial adhesions * 1	1/90 (1.11%)
Respiratory, thoracic and mediastinal disorders
Bronchitis * 1	1/90 (1.11%)
Respiratory tract infection * 1	2/90 (2.22%)
Respiratory tract infection viral * 1	9/90 (10.00%)
Skin and subcutaneous tissue disorders
Skin odour abnormal * 1	1/90 (1.11%)
Vascular disorders
Retinal vascular disorder * 1	2/90 (2.22%)
Syncope * 1	1/90 (1.11%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

All written or oral publications and/or information related to Study and/or results of Study should be submitted at first in writing to Sponsor at least 30 working days for publication and 15 working days for brief review, abstract before planned date of submission. If Sponsor is filing a patent application on Study results, Sponsor can delay its authorization for publication/communication of Study results to Investigator and/or Research Centre until date of international registration of patent.

Results Point of Contact

• Name/Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA
• Phone: +49-6151-72-5200
• EMail: service@merckgroup.com

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01732471
• Other Study ID Numbers: EMR 700773_510
• First Submitted: November 19, 2012
• First Posted: November 22, 2012
• Results First Submitted: June 24, 2014
• Results First Posted: July 28, 2014
• Last Update Posted: July 28, 2014