Trial Outcomes & Findings for A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction (NCT NCT00532844)

Last Updated: 2021-05-17

Results Overview

Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

52 participants

Primary outcome timeframe

At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.

Results posted on

2021-05-17

Participant Flow

This was a single-center study.

A total of 52 subjects were randomized into the study and received study drug. Of these, 4 subjects were enrolled under an earlier version of the protocol that used different eligibility criteria and were monitored according to different data collection procedures. Only the 48 subjects enrolled under the final protocol were included in the analyses.

Participant milestones

Participant milestones
Measure	Sapropterin Dihydrochloride 10mg/kg First; Then Sapropterin Dihydrochloride 10mg/kg and Vitamin C Sequence A: Sapropterin dihydrochloride as the first treatment followed by sapropterin dihydrochloride and vitamin C Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 28 The washout period of 1 day comprised between treatment regimens.	Sapropterin Dihydrochloride 10mg/kg and Vitamin C First; Then Sapropterin Dihydrochloride 10mg/kg Sequence B: Sapropterin dihydrochloride and vitamin C as the first treatment followed by sapropterin dihydrochloride. Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal Day 28. The washout period of 1 day comprised between treatment regimens.
Treatment Period - Day 1 to Day 14 STARTED	24	24
Treatment Period - Day 1 to Day 14 COMPLETED	24	23
Treatment Period - Day 1 to Day 14 NOT COMPLETED	0	1
Washout (1 Day) STARTED	24	23
Washout (1 Day) COMPLETED	24	23
Washout (1 Day) NOT COMPLETED	0	0
Treatment Period - Day 15 to Day 28 STARTED	24	23
Treatment Period - Day 15 to Day 28 COMPLETED	20	23
Treatment Period - Day 15 to Day 28 NOT COMPLETED	4	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Sapropterin Dihydrochloride 10mg/kg First; Then Sapropterin Dihydrochloride 10mg/kg and Vitamin C Sequence A: Sapropterin dihydrochloride as the first treatment followed by sapropterin dihydrochloride and vitamin C Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 28 The washout period of 1 day comprised between treatment regimens.	Sapropterin Dihydrochloride 10mg/kg and Vitamin C First; Then Sapropterin Dihydrochloride 10mg/kg Sequence B: Sapropterin dihydrochloride and vitamin C as the first treatment followed by sapropterin dihydrochloride. Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal Day 28. The washout period of 1 day comprised between treatment regimens.
Treatment Period - Day 1 to Day 14 Withdrawal of consent	0	1
Treatment Period - Day 15 to Day 28 Pregnancy	1	0
Treatment Period - Day 15 to Day 28 Personal reasons	1	0
Treatment Period - Day 15 to Day 28 Adverse Event	1	0
Treatment Period - Day 15 to Day 28 withdrawal of consent	1	0

Baseline Characteristics

A Phase 2, Pharmacokinetic (PK) Study of 6R-BH4 Alone or 6R-BH4 With Vitamin C in Subjects With Endothelial Dysfunction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sapropterin Dihydrochloride 10mg/kg First, Then Sapropterin Dihydrochloride 10mg/kg and Vitamin C n=24 Participants Sequence A: Sapropterin dihydrochloride as the first treatment followed by sapropterin dihydrochloride and vitamin C Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 28 The washout period of 1 day comprised between treatment regimens.	Sapropterin Dihydrochloride 10mg/kg and Vitamin C First, Then Sapropterin Dihydrochloride 10mg/kg n=24 Participants Sequence B: Sapropterin dihydrochloride and vitamin C as the first treatment followed by sapropterin dihydrochloride Treatment Regimen 2: Sapropterin dihydrochloride 5 mg/kg + 500 mg vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14. Treatment Regimen 1: Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal Day 28. The washout period of 1 day comprised between treatment regimens.	Total n=48 Participants Total of all reporting groups
Age, Continuous	42.7 years STANDARD_DEVIATION 12.1 • n=5 Participants	43.2 years STANDARD_DEVIATION 14.0 • n=7 Participants	42.9 years STANDARD_DEVIATION 13.0 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Age < 65 Years	24 Participants n=5 Participants	22 Participants n=7 Participants	46 Participants n=5 Participants
Age ≥ 65 Years	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race White	10 Participants n=5 Participants	15 Participants n=7 Participants	25 Participants n=5 Participants
Race Black/African American	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Race Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity Not Hispanic or Latino	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants
Ethnicity Hispanic or Latino	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Weight	95.78 kg STANDARD_DEVIATION 18.36 • n=5 Participants	96.80 kg STANDARD_DEVIATION 16.93 • n=7 Participants	96.29 kg STANDARD_DEVIATION 17.48 • n=5 Participants
Height	170.81 cm STANDARD_DEVIATION 8.47 • n=5 Participants	172.71 cm STANDARD_DEVIATION 9.98 • n=7 Participants	171.76 cm STANDARD_DEVIATION 9.21 • n=5 Participants
Body Mass Index	32.33 kg/m^2 STANDARD_DEVIATION 5.62 • n=5 Participants	32.45 kg/m^2 STANDARD_DEVIATION 5.70 • n=7 Participants	32.39 kg/m^2 STANDARD_DEVIATION 5.60 • n=5 Participants

PRIMARY outcome

Timeframe: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.

Population: Intent-to-treat (ITT) Population

Plasma BH4 concentration area under the curve (AUC0-12 hrs) at the end of each regimen in subjects with endothelial dysfunction.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=44 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=43 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Area Under the Curve (AUC0-12hrs) of Plasma BH4 Concentration	633 nM*hr Standard Deviation 286	993 nM*hr Standard Deviation 545

SECONDARY outcome

Timeframe: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.

Population: ITT population

Plasma BH2 and B concentration area under the curve (AUC0-12hrs) at the end of each regimen in subjects with endothelial dysfunction.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=44 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=43 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration BH2	875 nM*hr Standard Deviation 455	772 nM*hr Standard Deviation 376
Area Under the Curve (AUC0-12hrs) of Plasma BH2 and B Concentration B	231 nM*hr Standard Deviation 163	185 nM*hr Standard Deviation 123

SECONDARY outcome

Timeframe: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.

Population: ITT population

Total biopterin concentration area under the curve (AUC0-12hours) at the end of each regimen in subjects with endothelial dysfunction is theoretically the sum of BH4, BH2 and B. Biopterin is the metabolite of BH4 after oxidative conversion of BH4 and BH2 to biopterin. Total biopterin concentrations represent the summation of drug and metabolites: BH4, BH2 and B. The total biopterin concentrations can be converted to BH4 concentration using the conversion factor 2.150.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=44 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=43 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Area Under the Curve (AUC0-12hours) for Calculated BH4 (From Total Biopterin)	440 nM*hr Standard Deviation 183	440 nM*hr Standard Deviation 211

SECONDARY outcome

Timeframe: At 30 minutes prior to dosing, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 hours after dosing.

Population: ITT population. AUC (0 to 12 hour) means were calculated for 44 subjects in the Sapropterin dihydrichloride and 43 subjects on Sapropterin dihydrochloride + Vitamin C

Ratio of Mean AUC (0-12 hours) for subjects receiving (Sapropterin dihydrochloride + Vitamin C)/ Mean AUC (0-12 hours) for subjects receiving Sapropterin dihydrochloride alone) for BH4, BH2, B, BH4/BH2 Ratio, and BH4 Calculated from Total Biopterin.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=44 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. Calculated BH4 (from Total Biopterin)	1.03 ratio Standard Deviation 0.33	—
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. BH2	0.998 ratio Standard Deviation 0.577	—
Ratio of BH2, B and BH4 Calculated From Total Biopterin Area Under the Curve (0-12hours) for Subjects Administered Sapropterin Dihydrochloride With Vitamin C to Subjects Administered Sapropterin Alone. B	1.04 ratio Standard Deviation 1.10	—

SECONDARY outcome

Timeframe: At Baseline, Day 13 and Day 27

Population: ITT population.

PAT measures pulse wave amplitude of the small arteries of the finger as a surrogate to assess endothelial function and arterial stiffness using a finger plethysmographic probe and 5-minute occlusion of the brachial artery. Endothelial dysfunction, a protocol inclusion criteria, is defined by an abnormal PAT of \< or = 1.70. Change is calculated as follows: end time measurement - starting time measurement.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=44 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=43 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change From Baseline in Peripheral Arterial Tonometry (PAT) Baseline	1.5113 Ratio Standard Deviation 0.1669	1.4859 Ratio Standard Deviation 0.1437
Change From Baseline in Peripheral Arterial Tonometry (PAT) Day 13	1.8509 Ratio Standard Deviation 0.4677	1.7754 Ratio Standard Deviation 0.3760
Change From Baseline in Peripheral Arterial Tonometry (PAT) Change from Baseline to Day 13	0.3467 Ratio Standard Deviation 0.4311	0.2902 Ratio Standard Deviation 0.4329
Change From Baseline in Peripheral Arterial Tonometry (PAT) Day 27	1.9047 Ratio Standard Deviation 0.4903	1.6482 Ratio Standard Deviation 0.4250
Change From Baseline in Peripheral Arterial Tonometry (PAT) Change from Day 13 to Day 27	0.1293 Ratio Standard Deviation 0.4897	-0.1641 Ratio Standard Deviation 0.4294

SECONDARY outcome

Timeframe: At Baseline, Day 13 and Day 27

Population: ITT population

Change is calculated as follows: end time measurement - starting time measurement. Mean daytime systolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=23 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=20 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change From Baseline in Systolic Blood Pressure (SBP) Baseline	125.14 mm Hg Standard Deviation 13.42	131.29 mm Hg Standard Deviation 13.05
Change From Baseline in Systolic Blood Pressure (SBP) Change from Baseline to Day 13	-3.24 mm Hg Standard Deviation 8.64	-0.10 mm Hg Standard Deviation 6.53
Change From Baseline in Systolic Blood Pressure (SBP) Change from Day 13 to Day 27	-1.67 mm Hg Standard Deviation 7.29	3.31 mm Hg Standard Deviation 6.43

SECONDARY outcome

Timeframe: At Baseline, Day 13 and Day 27

Population: ITT population

Change is calculated as follows: end time measurement - starting time measurement. Mean daytime diastolic blood pressure measured by ambulatory blood pressure monitoring (ABPM)

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=23 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=20 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change From Baseline in Diastolic Blood Pressure (DBP) Change from Baseline to Day 13	-2.31 mm Hg Standard Deviation 6.84	0.45 mm Hg Standard Deviation 5.31
Change From Baseline in Diastolic Blood Pressure (DBP) Change from Day 13 to Day 27	-2.01 mm Hg Standard Deviation 6.60	1.23 mm Hg Standard Deviation 5.21
Change From Baseline in Diastolic Blood Pressure (DBP) Baseline	77.32 mm Hg Standard Deviation 11.05	80.15 mm Hg Standard Deviation 14.05

SECONDARY outcome

Timeframe: Up to 56 ± 3 Days.

Population: ITT and Safety Population. Four subjects enrolled in the study before changing from a parallel to a cross over study not reflected in the data table in the Participant Flow module. Two subjects received sapropterin dihydrochloride only and two subjects received sapropterin dihydrichloride + vitamin C only.

A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=49 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=50 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Subjects with any Adverse Event	19 Participants	16 Participants
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Subjects with any Serious Adverse Event	0 Participants	0 Participants
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Subjects with any treatment-related Adverse Event	16 Participants	13 Participants
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Any treatment-related Serious Adverse Event	0 Participants	0 Participants
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Death	0 Participants	0 Participants
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Any AEs Leading to Study Discontinuation	1 Participants	0 Participants

SECONDARY outcome

Timeframe: At Baseline, Day 14 and Day 28

Population: ITT Population

Biomarkers of endothelial function, oxidative stress, and inflammation as measured by 8-isoprostane.

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=42 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=41 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change From Baseline in Urinary 8-isoprostane/Creatinine Baseline	898.01 pg/mg Standard Deviation 671.25	992.38 pg/mg Standard Deviation 569.80
Change From Baseline in Urinary 8-isoprostane/Creatinine Change from Baseline to Day 14	-192.13 pg/mg Standard Deviation 529.16	-31.75 pg/mg Standard Deviation 664.40
Change From Baseline in Urinary 8-isoprostane/Creatinine Change from Day 14 to Day 28	-117.61 pg/mg Standard Deviation 472.61	32.44 pg/mg Standard Deviation 364.60

SECONDARY outcome

Timeframe: At Baseline, Day 14 and Day 28.

Population: ITT Population

Biomarkers of endothelial function, oxidative stress, and inflammation as measured by cyclic guanosine monophosphate (cGMP).

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=43 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=42 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Baseline	3.7941 pmol/mL Standard Deviation 1.1839	3.8533 pmol/mL Standard Deviation 1.4658
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Change from Baseline to Day 14	0.6278 pmol/mL Standard Deviation 2.0258	0.2088 pmol/mL Standard Deviation 1.3248
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Change from Day 14 to Day 28	-0.0507 pmol/mL Standard Deviation 1.1369	-0.0078 pmol/mL Standard Deviation 1.9556

SECONDARY outcome

Timeframe: Baseline, Day 14 and Day 28

Population: ITT Population

Change in Urinary Albumin to Creatinine Ratio (mg/g) from Baseline to Day 14, Baseline to Day 28, and from Day 14 to Day 28

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=20 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=21 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Change in Urinary Albumin to Creatinine Ratio (mg/g) Baseline	13.3 mg/g Standard Deviation 35.7	12.3 mg/g Standard Deviation 19.0
Change in Urinary Albumin to Creatinine Ratio (mg/g) Change from Baseline to Day 14	-1.2 mg/g Standard Deviation 17.9	2.7 mg/g Standard Deviation 18.6
Change in Urinary Albumin to Creatinine Ratio (mg/g) Change from Day 14 to Day 28	-2.2 mg/g Standard Deviation 4.9	4.9 mg/g Standard Deviation 10.2

SECONDARY outcome

Timeframe: Baseline, Day 14 and Day 28

Population: ITT Population

Summary of Urinary Albumin to Creatinine Ratio (mg/g) by subjects with ratio \<30 mg/g and subjects with ratios \>=30 mg/g at Baseline, Day 14 and Day 28

Outcome measures

Outcome measures
Measure	Sapropterin Dihydrochloride 10 mg/kg n=27 Participants Sapropterin dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.	Sapropterin Dihydrochloride+Vitamin C 10 mg/kg n=30 Participants Sapropterin dihydrochloride 5 mg/kg and 500 mg Vitamin C twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 or Day 28.
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Baseline < 30 mg/g	13 Participants	16 Participants
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Baseline >=30 mg/g	1 Participants	2 Participants
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Day 14 < 30 mg/g	10 Participants	13 Participants
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Day 14 >=30 mg/g	2 Participants	1 Participants
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Day 28 < 30 mg/g	12 Participants	10 Participants
Number of Participants With Urinary Albumin to Creatinine Ratio <30 mg/g Day 28 >=30 mg/g	1 Participants	2 Participants

Adverse Events

Sapropterin Dihydrochloride 10mg/kg

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Sapropterin Dihydrochloride 10mg/kg and Vitamin C

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Joshua Lilienstein/Medical Director, Global Medical Affairs

BioMarin Pharmaceutical Inc.

Phone: 651.523.0310

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60