Clinical trial NCT06481709
Conditions: Bioavailability
Sponsor: APR Applied Pharma Research s.a.
Start date: 2024-07-30; Completion date: 2024-08-31
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a single center, Phase 1, randomized, open-label, single-dose, 4 treatment, 4-period, 4-sequence, crossover study designed to compare the pharmacokinetics (PK) of sapropterin from the Test and Reference products, and to evaluate the effect of food and the effect of water administration on the bioavailability of sapropterin from the Test product in healthy subjects.

.

Detailed description:
In each period, subjects will receive a single 10 mg/kg dose of sapropterin dihydrochloride on Day 1, under fasting or fed conditions, and with or without water, followed by 24 hours of PK sampling. The study will include a screening visit from Day -30 to Day -1. In each period, eligible subjects will be admitted to the clinical site on Day -1 and will be confined until completion of the assessments on Day 2. There will be a washout period of at least 7 days between doses.

Arms: arm 1: Where the Subject receives in this order

D is 1 x 10 mg/kg dose\* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions

C is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.

A is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.

B is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions. arm 2: Where the Subject receives in this order

A is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.

D is 1 x 10 mg/kg dose\* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions

B is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.

C is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions. arm 3: Where the Subject receives in this order

B is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.

A is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.

C is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.

D is 1 x 10 mg/kg dose\* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions arm 4: Where the Subject receives in this order

C is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered with water under fed conditions.

B is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fed conditions.

D is 1 x 10 mg/kg dose\* of Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution dissolved in water and administered under fed conditions

A is 1 x 10 mg/kg dose\* of sapropterin dihydrochloride oral suspension 100 mg/mL administered without water under fasting conditions.
Interventions: intervention 1: RLF-OD032 intervention 2: Kuvan
Intervention descriptions: intervention 1: 100 mg/mL oral suspension intervention 2: 100 mg powder for oral solution

Protocol documents:
Prot_SAP_000.pdf: 
230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 1 of 46 
PROJECT 230108 
PROTOCOL 2023-5439 
 
A PILOT, PHASE 1, RANDOMIZED, OPEN-LABEL, SINGLE-DOSE, FOUR-WAY 
CROSSOVER STUDY TO COMPARE THE PHARMACOKINETICS OF 
SAPROPTERIN DIHYDROCHLORIDE 100 mg/mL ORAL SUSPENSION (PRODUCT 
CODE: RLF-OD032) (TEST) WITH KUVAN® (SAPROPTERIN DIHYDROCHLORIDE) 
100 mg POWDER FOR ORAL SOLUTION (REFERENCE) AND TO EVALUATE THE 
EFFECT OF FOOD AND THE EFFECT OF WATER ON THE BIOAVAILABILITY OF 
SAPROPTERIN DIHYDROCHLORIDE 100 mg/mL ORAL SUSPENSION IN 
HEALTHY SUBJECTS 
 
 
Sponsor: 
APR Applied Pharma Research s.a. 
Via Giuseppe Corti 5 
6828 Balerna 
Switzerland 
Contract Research 
Organization: 
Pharma Medica Research Inc. 
6100 Belgrave Road, 
Mississauga, Ontario, L5R 0B7 
Canada 
Protocol Version: 
Final 
Date: 
10-MAY-2024 
 
CONFIDENTIAL 
 
This document is strictly confidential. It was developed for APR Applied Pharma Research s.a. by Syneos Health. 
The information in this document may be disclosed only to persons involved in the study, ethics committees, 
regulatory agencies and study audit personnel. This document is copyrighted in favor of Syneos Health and cannot 
be reproduced, modified, or adapted, in part or in total, without prior written approval by Syneos Health. 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 2 of 46 
Protocol Historical File 
Version 
Brief description/summary of changes 
Date 
Final 
Version submitted to the Independent Ethics Committee 
(IEC). 
10-MAY-2024 
IRB Reviewed - June 12, 2024






230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 5 of 46 
Table of Contents 
PROTOCOL HISTORICAL FILE ............................................................................................. 2 
SPONSOR SIGNATURE PAGE ................................................................................................. 3 
INVESTIGATOR SIGNATURE PAGE..................................................................................... 4 
TABLE OF CONTENTS ............................................................................................................. 5 
LIST OF TABLES ........................................................................................................................ 7 
LIST OF ABBREVIATIONS ...................................................................................................... 8 
SYNOPSIS OF PROTOCOL .................................................................................................... 10 
INCLUSION CRITERIA .................................................................................................................................................... 11 
EXCLUSION CRITERIA................................................................................................................................................... 12 
1. 
INTRODUCTION ............................................................................................................. 17 
1.1 
BACKGROUND INFORMATION............................................................................................................................ 17 
1.2 
STUDY RATIONALE ........................................................................................................................................... 18 
1.3 
BENEFIT/RISK ASSESSMENT .............................................................................................................................. 19 
2. 
OBJECTIVES .................................................................................................................... 21 
3. 
ENDPOINTS ...................................................................................................................... 21 
4. 
STUDY DESIGN ............................................................................................................... 21 
5. 
STUDY POPULATION .................................................................................................... 22 
5.1 
NUMBER OF SUBJECTS ...................................................................................................................................... 22 
5.2 
INCLUSION CRITERIA ........................................................................................................................................ 22 
5.3 
EXCLUSION CRITERIA ....................................................................................................................................... 23 
5.4 
SUBJECT WITHDRAWAL AND REPLACEMENT .................................................................................................... 24 
6. 
STUDY TREATMENTS .................................................................................................. 25 
6.1 
STUDY TREATMENT SUPPLIES AND ACCOUNTABILITY ...................................................................................... 25 
6.2 
INVESTIGATIONAL PRODUCTS ........................................................................................................................... 25 
6.3 
IDENTIFICATION OF TREATMENTS ..................................................................................................................... 26 
6.4 
RANDOMIZATION AND BLINDING ...................................................................................................................... 26 
6.5 
STUDY TREATMENT ADMINISTRATION ............................................................................................................. 26 
6.6 
ADMINISTRATION OF FOOD AND FLUID ............................................................................................................. 27 
7. 
STUDY RESTRICTIONS ................................................................................................ 28 
7.1 
CONTRACEPTION ............................................................................................................................................... 28 
7.2 
CONCOMITANT MEDICATIONS .......................................................................................................................... 29 
7.3 
DRUGS, NICOTINE AND ALCOHOL ..................................................................................................................... 30 
7.4 
DIET .................................................................................................................................................................. 30 
7.5 
POSTURE AND PHYSICAL ACTIVITY .................................................................................................................. 30 
8. 
STUDY PROCEDURES ................................................................................................... 30 
8.1 
SCREENING PROCEDURES (-30 TO -1) ................................................................................................................ 31 
8.2 
TEST/ PROCEDURES AT CHECK-IN ..................................................................................................................... 32 
8.3 
ON-STUDY PROCEDURES: .................................................................................................................................. 33 
8.4 
END OF STUDY PROCEDURES ............................................................................................................................. 34 
8.5 
PHARMACOKINETIC ASSESSMENTS ................................................................................................................... 35 
8.6 
SAFETY AND TOLERABILITY ASSESSMENTS ...................................................................................................... 35 
8.7 
ADVERSE EVENTS ............................................................................................................................................. 36 
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230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 6 of 46 
8.8 
PREMATURE TERMINATION OF THE STUDY ....................................................................................................... 39 
9. 
STATISTICAL ANALYSES ............................................................................................ 39 
9.1 
ANALYSIS POPULATIONS................................................................................................................................... 40 
9.2 
PHARMACOKINETIC PARAMETERS .................................................................................................................... 40 
9.3 
PHARMACOKINETIC STATISTICAL ANALYSIS .................................................................................................... 41 
9.4 
SAFETY AND TOLERABILITY ANALYSIS ............................................................................................................ 43 
10. 
DATA COLLECTION ...................................................................................................... 43 
11. 
REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE .................... 43 
11.1 
IEC APPROVAL OF PROTOCOL AND OTHER STUDY DOCUMENTS ...................................................................... 43 
11.2 
COMPLIANCE..................................................................................................................................................... 44 
11.3 
QUALITY ASSURANCE AND MONITORING ......................................................................................................... 44 
11.4 
FINANCIAL DISCLOSURE AND OBLIGATIONS ..................................................................................................... 44 
11.5 
INSURANCE ....................................................................................................................................................... 45 
11.6 
CONFIDENTIALITY AND RETENTION OF STUDY RECORDS ................................................................................. 45 
12. 
REFERENCES .................................................................................................................. 46 
 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 7 of 46 
List of Tables 
TABLE 1. 
SCHEDULE OF EVENTS ............................................................................................... 15 
TABLE 2. 
PHARMACOKINETIC PARAMETERS OF SAPROPTERIN HYDROCHLORIDE 10 MG/KG 
ADMINISTERED AS INTACT OR DISSOLVED TABLETS IN THE FASTED STATE, AND AS INTACT 
TABLETS IN THE FED OR FASTING STATES. ............................................................................ 17 
TABLE 3. 
TREATMENT SEQUENCE ............................................................................................. 26 
TABLE 4. 
HIGH-FAT, HIGH-CALORIE BREAKFAST .................................................................... 27 
TABLE 5. 
ACCEPTABLE EFFECTIVE METHODS OF CONTRACEPTION .......................................... 29 
TABLE 6. 
SCHEDULED WINDOWS OF ALLOWANCE FOR VITAL SIGNS AND ECG. ...................... 31 
TABLE 7. 
BLOOD AND URINE TESTS PERFORMED AT SCREENING ............................................. 32 
TABLE 8. 
TIME WINDOWS FOR PK BLOOD SAMPLES ................................................................ 33 
TABLE 9. 
BLOOD AND URINE TESTS PERFORMED AT END OF STUDY ........................................ 34 
TABLE 10. 
SEVERITY OF ADVERSE EVENTS ............................................................................. 37 
TABLE 11. 
ADVERSE EVENT RELATIONSHIP CATEGORIES ....................................................... 37 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 8 of 46 
List of Abbreviations 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
ANOVA 
analysis of variance 
ANCOVA 
analysis of co-variance 
AST (SGOT) 
aspartate aminotransferase 
AUC0-inf 
area under the concentration-time curve from time zero to infinity 
(extrapolated) 
AUC0-t 
area under the concentration-time curve from time zero until the last 
observed concentration 
BH4 
tetrahydrobiopterin 
-HCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDER 
Center for Drug Evaluation and Research 
CI 
confidence interval 
Cl/F 
apparent clearance 
Cmax 
maximal observed concentration 
CTA 
Clinical Trial Application 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
EOS 
end of study 
ERB/IRB 
Ethics/Institutional Review Board 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, and throat 
HIV 
human immunodeficiency virus 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 9 of 46 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
Kel 
terminal elimination rate constant 
LD 
lactate dehydrogenase 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRHD 
maximum recommended human dose 
NOL 
No Objection Letter 
OTC 
over-the-counter 
PAH 
phenylalanine hydroxylase 
PCF 
Privacy Consent Form 
PCP 
phencyclidine 
Phe 
phenylalanine 
PK 
pharmacokinetic(s) 
R2 
coefficient of determination obtained from regression analysis 
RBC 
red blood cell 
SAE 
serious adverse event 
SAS 
statistical analysis system 
SOP 
standard operation procedure 
SUSAR 
suspected, unexpected, serious adverse reaction 
T½ el 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
Tlag 
time of observation prior to the first observation with a measurable (non-
zero) concentration 
Tmax 
time when the maximal concentration is observed 
VCF 
Volunteer Consent Form 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 10 of 46 
Synopsis of Protocol 
Project Number: 
230108 
Protocol number 
2023-5439 
Title of the Study: 
A Pilot, Phase 1, Randomized, Open-Label, Single-Dose, Four-Way Crossover 
Study to Compare the Pharmacokinetics of Sapropterin Dihydrochloride 100 mg/mL 
Oral Suspension (Product Code: RLF-OD032) (Test) with Kuvan® (Sapropterin 
Dihydrochloride) 100 mg Powder for Oral Solution (Reference) and to Evaluate the 
Effect of Food and the Effect of Water on the Bioavailability of Sapropterin 
Dihydrochloride 100 mg/mL Oral Suspension in Healthy Subjects 
Clinical Research 
Facility: 
Pharma Medica Research Inc. 
4770 Sheppard Ave E, 
Toronto, Ontario, M1S 3V6 
Canada  
Biomedical Laboratory 
Facility: 
Alpha Laboratories Incorporated 
1262 Don Mills Road, 
Toronto, Ontario, M3B 2W7 
Canada 
Investigational Products: 
Test:  
Sapropterin dihydrochloride 100 mg/mL oral suspension (product 
code: RLF-OD032) (APR Applied Pharma Research s.a., Switzerland) 
Reference:  Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution 
(BioMarin Pharmaceutical Inc., USA) 
Study Phase and Type: 
Phase 1 – Comparative Pharmacokinetic (PK), Food-Effect, and Water-Effect 
Objectives: 
Primary objectives: 
 
To compare the PK of sapropterin dihydrochloride 100 mg/mL oral suspension 
(Test) with Kuvan 100 mg powder for oral solution (Reference) following a 10 
mg/kg dose in healthy subjects. 
 
To evaluate the effect of a high-fat, high-calorie meal on the bioavailability of 
sapropterin dihydrochloride 100 mg/mL oral suspension following a 10 mg/kg 
dose in healthy subjects. 
 
To evaluate the effect of water administration on the bioavailability of 
sapropterin dihydrochloride 100 mg/mL oral suspension following a 10 mg/kg 
dose in healthy subjects. 
Secondary objective: 
 
To evaluate the safety and tolerability of sapropterin dihydrochloride when 
administered to healthy subjects. 
Endpoints: 
Primary endpoints: 
 
PK 
o 
Uncorrected and baseline-corrected sapropterin AUC0-t, AUC0-inf, and Cmax 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 11 of 46 
Secondary endpoints: 
 
PK 
o 
Uncorrected and baseline-corrected sapropterin Tmax and Tlag 
o 
Uncorrected and baseline-corrected sapropterin T½ el, Residual area, Kel, 
Cl/F, and Vz/F 
 
Safety 
o 
Adverse events (AEs), vital signs measurements (blood pressure, pulse 
rate, respiratory rate, and temperature), 12-lead electrocardiogram (ECG) 
recordings, physical examinations, and clinical laboratory test results, 
including hematology, biochemistry, and urinalysis. 
Study Design: 
This is a single center, Phase 1, randomized, open-label, single-dose, 4-treatment, 
4-period, 4-sequence, crossover study designed to compare the PK of sapropterin 
from the Test and Reference products, and to evaluate the effect of food and the effect 
of water administration on the bioavailability of sapropterin from the Test product in 
healthy subjects. 
In each period, subjects will receive a single 10 mg/kg dose of sapropterin 
dihydrochloride on Day 1, under fasting or fed conditions, and with or without water, 
followed by 24 hours of PK sampling. 
The study will include a screening visit from Day -30 to Day -1. In each period, 
eligible subjects will be admitted to the clinical site on Day -1 and will be confined 
until completion of the assessments on Day 2. There will be a washout period of at 
least 7 days between doses. 
Study Population: 
It is planned to enroll 16 healthy adult males and females for participation in this 
study. All attempts will be made to have an equal number of males and females. 
Inclusion/Exclusion 
Criteria: 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in the study: 
1. Male or female, light smoker (no more than 10 cigarettes daily) or non-smoker, 
 body mass index 
18.5 
2 
 
 for females. 
2. Healthy as defined by: 
a. 
the absence of clinically significant illness and surgery within 30 days 
prior to dosing. 
b. the absence of clinically significant history of neurological, endocrine, 
cardiovascular, respiratory, hematological, immunological, psychiatric, 
gastrointestinal, renal, hepatic, and metabolic disease. 
3. Female subjects of non-childbearing potential must be: 
a. 
post-menopausal (no menstrual period at least 12 consecutive months 
without any other medical cause and FSH and LH values consistent with 
being menopausal); or 
b. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, 
hysterectomy or tubal ligation) at least 3 months prior to dosing. 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 12 of 46 
4. Sexually active female subjects of childbearing potential must be willing to use 
an acceptable contraceptive method throughout the study as detailed in section 
7.1. 
5. Willing to take off dentures or mouth piercing at the time of dosing. 
6. Able to understand the study procedures and provide signed informed consent 
to participate in the study. 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1. Any clinically significant abnormal finding at physical examination. 
2. Clinically significant abnormal laboratory test results (may be repeated up to 
two times) or positive serology test results for hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus 
(HIV)-1 and HIV-2 antibodies at screening. 
3. Positive pregnancy test or lactating female subject. 
4. Positive urine drug screen. 
5. Known allergic reactions to sapropterin dihydrochloride or other related drugs, 
or to any excipient in the formulation. 
6. Clinically significant ECG abnormalities or vital signs abnormalities (systolic 
blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure 
lower than 50 or over 90 mmHg, or pulse rate less than 50 or over 100 bpm) at 
screening. ECG and vitals signs may be repeated up to two times, to determine 
if the values are significantly abnormal. 
7. Recreational use of soft drugs (such as marijuana) within 1 month or hard 
drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives 
including heroin, and amphetamine derivatives) within 3 months prior to 
screening. 
8. History of alcohol addiction requiring treatment. 
9. History of abuse of medicinal product or drugs within the last 3 years. 
10. History or presence of alcoholism within the last 3 years. (>40 g ethanol/day or 
more than 10 units per week [1 unit =150 mL of wine, or 360 mL of beer, or 45 
mL of 45% alcohol]). 
11. Use of medications within the timeframes specified in section 7.2. 
12. Participation in a clinical research study involving the administration of an 
investigational or marketed drug or device within 30 days prior to dosing, 
administration of a biological product in the context of a clinical research study 
within 90 days prior to dosing, or concomitant participation in an 
investigational study involving no drug or device administration. 
13. Known predisposition to seizures. 
14. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL 
or more of whole blood within 8 weeks prior to dosing. 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 13 of 46 
15. Presence of orthodontic braces or orthodontic retention wires, or any physical 
findings in the mouth or tongue that would be likely to interfere with 
successful completion of the dosing procedure. 
16. Females who:  
a. 
Have discontinued or changed the use of implanted, intrauterine, 
intravaginal, or injected hormonal contraceptives within 6 months prior to 
study treatment administration. 
b. Have discontinued or changed the use of oral or patch hormonal 
contraceptives within 1 month prior to study treatment administration. 
17. Any reason which, in the opinion of the Investigator, would prevent the subject 
from participating in the study. 
Study Treatments: 
In each period, subjects will receive one of the following treatments, according to 
the randomization scheme: 
Treatment A: 
1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 
100 mg/mL administered without water under fasting conditions. 
Treatment B: 
1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 
100 mg/mL administered without water under fed conditions. 
Treatment C: 
1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 
100 mg/mL administered with water under fed conditions. 
Treatment D: 
1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 
100 mg powder for oral solution dissolved in water and 
administered under fed conditions. 
*The dose for each subject will be calculated by multiplying the subject’s weight 
measured on Day -1 of Period 1 by 10 mg/kg and then rounding up to the next 100 mg 
dose. For example, the weight of a 70.5 kg subject would be multiplied by 10 mg/kg, 
resulting in 705 mg and after rounding up, this subject would be assigned a dose of 
800 mg. 
For Treatment C, the administration of the suspension will be followed by a glass 
of water so that the total volume of suspension + water is 240 mL (± 5 mL). 
For Treatment D, the powder for oral solution will be dissolved in 120 mL (± 3 
mL) of water within 15 minutes before administration and the solution will be 
swallowed at the time of study treatment administration. To ensure that the entire 
dose is consumed, the dosing cup will be rinsed twice with an additional 60 mL 
(± 1 mL) of water each time (total volume of 120 mL (± 2 mL)) and the content 
will be swallowed. 
Study Procedures: 
Blood samples for PK analysis will be collected in each period at -1, -0.5, pre-dose 
(0-hour), and 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 
24 hours post-dose. 
Blood pressure, pulse rate, respiration rate, and temperature will be measured at 
screening and end-of-study (EOS). Temperature will be measured daily during 
confinement. Blood pressure and pulse rate will be measured before dosing (0-hour) 
and at 4 and 6 hours post-dose of each period. 
12-lead ECG will be measured at screening, before dosing (0-hour), at 4 and 6 hours 
post-dose of each period, and at EOS. 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 14 of 46 
Other safety procedures will be performed at pre-defined times throughout the 
study as specified in section 8.3, 8.4, 8.5, and 8.6. 
Subjects will be monitored throughout the study by the clinical staff for AEs and 
concomitant medication use. 
Statistical Analyses: 
The primary objective of this study is to evaluate the relative bioavailability of a new 
oral suspension formulation. Since this study is exploratory, no formal hypothesis 
testing is defined. 
PK analysis: 
For sapropterin, using the PROC MIXED procedure in SAS, analysis of variance 
(ANOVA) will be performed on log-transformed AUC0-t, AUC0-inf, and Cmax 
parameters at the alpha level of 0.05 on uncorreted data, ANCOVA (Analysis of Co-
Variance) will be applied for baseline corrected analysis, using the actual total dose 
included in the ANOVA statistical model as a covariate. The ratio of geometric 
means (A/D, B/D, C/D, B/C, A/C, and B/A) and 90% confidence interval (CI) for 
the ratio of geometric means, based on least-squares means from the ANOVA of the 
log-transformed data, will be calculated for AUC0-t, AUC0-inf, and Cmax. 
Uncorrected and baseline-corrected data will be presented. 
Safety and tolerability analysis: 
Safety and tolerability of sapropterin dihydrochloride will be evaluated through the 
assessment of AEs (i.e., seriousness, severity, relationship to the study treatment, 
outcome, duration, and management), vital signs, 12-lead ECGs, clinical laboratory 
tests, and physical examinations. Treatment-emergent adverse events (TEAEs) will 
be tabulated by treatment. Safety and tolerability data will be reported using 
descriptive statistics. 
 
 
IRB Reviewed - June 12, 2024


230108 Sapropterin Dihydrochloride 100 mg/mL Oral Suspension/RLF-OD032 APR Applied Pharma Research s.a. 
Comparative PK/Food-Effect/Water-Effect  
Final 10-MAY-2024 
 
Confidential 
Page 15 of 46 
Table 1. 
Schedule of Events 
Study Stage 
Screening
Admission 
(check-in-of 
Period 1) 
Admission of 
Period 2,3,4 
Treatment Periods12 
Day 
-30 to -1 
(of Period 
1) 
-1 of Period 1 or 
prior to Period 1 
dosing 
-1 of Period 2, 3, 4 
1 
2 
EOS/ET13 
Screening consent1 
X 
 
 
 
 
Informed consent2 
 
X 
 
 
 
Inclusion/exclusion criteria 
X3 
X4 
 
 
 
Demographic data 
X3 
 
 
 
 
Medical and medication 
history 
X3 
X 
X 
 
 
Confinement5 
 
X 
X 
X 
 
Discharge 
 
 
 
 
X 
Study treatment administration 
Sapropterin dihydrochloride 
oral suspension 
 
 
 
X6 
 
Kuvan powder for oral 
solution 
 
 
 
X6 
 
Pharmacokinetics 
Blood samples for PK 
analysis7 
 
 
 
X 
X 
Safety 
Physical examination8 
 
X 
 
 
X 
Body measurements (height, 
weight, BMI) 
X3 
X9 
 
 
 
Vital signs10 
X3 
X 
X 
X 
X 
12-lead ECG11 
X3 
 
 
X 
X 
Serology tests 
X3 
 
 
 
 
Biochemistry, hematology, 
and urinalysis tests 
X3 
 
 
 
X 
FSH/LH (for post-
menopausal females) 
X3 
 
 
 
 
Serum pregnancy tests 
X3 
X 
X 
 
X 
Urine pregnancy test 
 
X 
X 
 
 
Urine drugs of abuse 
X3 
X 
X 
 
 
Breath alcohol 
 
X 
X 
 
 
Monitoring and recording of 
AEs and prior/concomitant 
medication use 
 
X 
X 
X 
X 
Abbreviations: AE = adverse event; BMI = body mass index; ECG = electrocardiogram; EOS = end of study; ET = 
early termination; FSH = follicle-stimulating hormone; LH = luteinizing hormone; PK = pharmacokinetic. 
1 
Includes privacy and volunteer consent. During screening, subjects will consent to and sign privacy and 
volunteer consent forms.  
2 
An informed consent form (ICF) specific to this study will be signed by all subjects at Period 1 check-in 
(Day -1), and before any study specific procedure. 
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3 
Screening procedures can be done either at the screening visit or at Period 1 check-in (or repeated at both 
screening visit and Period 1 check-in if deemed necessary by the Investigator). 
4 
Complete outstanding procedures for inclusion/exclusion criteria confirmation. 
5 
Confinement period is at least 10.5 hours pre-dose until 24 hours post-dose. 
6 
On Day 1 of each period, subjects will receive one of the four treatments, according to the randomization 
scheme. 
7 
A total of 20 blood samples will be collected for PK analysis in each period: -1, -0.5, pre-dose (0-hour), and 
0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose. 
8 
A complete physical examination will be performed at Period 1 check-in. A brief physical examination will be 
performed at EOS. Refer to sections 8.1 and 8.4 for more details. 
9 
Weight only at check-in of Period 1. 
10 Blood pressure, pulse rate, respiration rate, and temperature will be measured at screening and EOS. 
Temperature will be measured daily during confinement. Blood pressure and pulse rate will be measured before 
dosing (0-hour) and at 4 and 6 hours post-dose of each period. 
11 12-lead ECG will be measured at screening, before dosing (0-hour), at 4 and 6 hours post-dose of each period, 
and at EOS. 
12 There are 4 treatment periods. There will be a washout period of at least 7 days between doses.   
13 EOS evaluations will be performed prior to study discharge of the last period. In case of ET, EOS procedures 
will be performed as soon as possible. 
 
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1.
Introduction
1.1
Background Information 
Sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally 
occurring tetrahydrobiopterin (BH4), the cofactor for the enzyme phenylalanine hydroxylase 
(PAH). Sapropterin dihydrochloride is indicated to reduce blood phenylalanine (Phe) levels in 
adult and pediatric patients one month of age and older with hyperphenylalaninemia due to 
BH4-responsive phenylketonuria.1,2 In patients 7 years and older, the recommended starting dose 
of sapropterin dihydrochloride is 10 to 20 mg/kg taken once daily. AEs associated with sapropterin 
dihydrochloride are listed in the Prescribing Information.1
PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with 
phenylketonuria, PAH activity is absent or deficient. Treatment with BH4 can activate residual 
PAH enzyme activity, improve the normal oxidative metabolism of Phe, and decrease Phe levels 
in some patients.1,2
When sapropterin dihydrochloride was administered in healthy subjects as intact tablets under 
fasting conditions, the calculated median Tmax for intact tablets was shorter than that for dissolved 
tablets, although the ranges were comparable. Plasma sapropterin concentrations were comparable 
at 2 hours after administration of intact tablets under fed and fasting conditions. However, 
sapropterin concentrations continued to increase under fed conditions, which was not the case 
under fasting conditions.3 Detailed pharmacokinetic parameters of sapropterin are shown in the 
table below.
Table 2.
Pharmacokinetic Parameters of Sapropterin Dihydrochloride 10 mg/kg 
Administered as Intact or Dissolved Tablets in the Fasted State, and as Intact 
Tablets in the Fed or Fasting States. 
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Based on the clinical pharmacology and biopharmaceutics review of Kuvan4, the pharmacokinetic 
parameters of sapropterin dihydrochloride 100 mg powder for oral solution are expected to be 
comparable to the 100 mg tablets based on their composition, solubility, and osmolarity. The 
powder formulation contains the same active ingredient in the same concentration, exhibits rapid 
dissolution using the dissolution method for sapropterin dihydrochloride tablets, has similar 
osmolarity in water, and its inactive ingredients are not expected to affect drug absorption and 
bioavailability.4 Absolute bioavailability or bioavailability for humans after oral administration is 
not known. In human plasma (in vitro), the protein-binding rate remained constant (22%–34%) 
within the concentration range of endogenous levels (approximately 3-10 ng/mL).2 
Sapropterin is a synthetic form of BH4 and is expected to be metabolized and recycled by the same 
endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is 
metabolized to dihydrobiopterin and biopterin. The enzymes dihydrofolate reductase and 
dihydropteridine reductase are responsible for the metabolism and recycling of BH4.1,2 
1.2 
Study Rationale 
APR Applied Pharma Research s.a. is developing an oral suspension of 100 mg/mL sapropterin 
dihydrochloride. This new formulation is intended to provide a more accurate and convenient 
mode of administration. 
This pilot study will be performed to compare the rate and extent of absorption of sapropterin from 
a sapropterin dihydrochloride oral suspension (APR Applied Pharma Research s.a. - Test) versus 
the Reference Listed Drug Kuvan 100 mg powder for oral solution (BioMarin Pharmaceutical Inc. 
- Reference), to assess variability, optimize sample collection time intervals or provide other 
information. Healthy volunteers will receive four single doses of sapropterin dihydrochloride over 
four periods under fasting or fed conditions, and with or without water. According to the label 
recommendations, Kuvan should be taken orally with a meal.1 The administration of the Reference 
drug will therefore be done under fed conditions. The evaluation of the food-effect on the new 
formulation will be performed according to FDA Guidance for Industry: Bioavailability Studies 
Submitted in NDAs or INDs - General Considerations (2022).5 The administration of the oral 
suspension (Test) with or without water will also be performed to evaluate the impact, if any, on 
drug absorption for this formulation. 
1.2.1 
Rationale for the Dose 
According to FDA Draft Guidance on Sapropterin Dihydrochloride6, a dose of 10 mg/kg will be 
administered to subjects. To account for the fact that the Reference drug is supplied as 100 mg 
powder for oral solution, the dose for each subject will be calculated by multiplying the subject’s 
weight measured on Day -1 of Period 1 by 10 mg/kg and then rounding up to the next 100 mg 
dose. This dose can be safely administered to healthy volunteers and should allow a good 
characterization of the pharmacokinetic profile of sapropterin. 
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1.2.2 
Rationale for Baseline Correction 
Sapropterin is an endogenous compound and should therefore be analyzed both with and without 
baseline correction. Therefore, for baseline correction, for each subject and treatment period, the 
baseline value will be defined as the mean of the -1 hour, -0.5 hour, and pre-dose (0) samples 
obtained before dosing, for that same subject and period. 
1.2.3 
Rationale for the Study Population 
A healthy volunteer population has been selected for the study because healthy subjects with no 
concomitant diseases and using no concomitant medications represent a homogenous population 
allowing for proper evaluation of the PK, safety, and tolerability of a drug without confounding 
factors. 
Available pregnancy registry data have not reported an association with sapropterin 
dihydrochloride and major birth defects, miscarriage, or adverse maternal or fetal outcomes when 
sapropterin dihydrochloride was used during pregnancy.1 An embryo-fetal development study with 
sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended 
human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit 
study using oral administration of sapropterin dihydrochloride during the period of organogenesis, 
a rare defect, holoprosencephaly, was noted at 10 times the MRHD.1,2 Since there have been no 
studies with pregnant women, it is uncertain whether there is human fetal risk associated with the 
use of sapropterin dihydrochloride. Therefore, only male and non-pregnant, non-lactating female 
subjects will be included in the study. 
1.3 
Benefit/Risk Assessment 
Risks to subjects in this study are related to common procedures performed (e.g., venipuncture) 
and the documented AEs listed in the current reference product information. Subjects are also at 
risk of exposure to infectious diseases, such as flu (influenza), cold (typically caused by a 
rhinovirus), or COVID-19, by being in the presence of people who may have a virus but do not 
have any symptoms. These risks are communicated to the subjects in the consent forms. In case of 
the re-emergence of COVID-19, or any other infectious disease, safety precautions such as 
masking, distancing, testing, etc. may be reinstated as deemed necessary by the study doctor and/or 
according to local public health guidelines. 
 
The inclusion and exclusion criteria have been chosen to select subjects who are known to be free 
from any significant illness, history of autoimmune diseases, and from any condition that could 
impact their safety or interfere with meeting the study objectives. The proposed safety screening 
and monitoring assessments are deemed to be sufficient to monitor potential risks of sapropterin 
dihydrochloride administration. There is no anticipated therapeutic benefit for the healthy subjects 
in this study. 
In other clinical trials, the following AEs (greater than 4%, and higher than placebo) have been 
reported by phenylketonuria patients after taking sapropterin: 1 
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 Headache (15%) 
 Rhinorrhea (11%) 
 Pharyngolaryngeal pain (10%) 
 Diarrhea (8%) 
 Vomiting (8%) 
 Cough (7%) 
 Nasal congestion (4%) 
 
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2. 
Objectives 
Primary objectives: 
 To compare the PK of sapropterin dihydrochloride 100 mg/mL oral suspension (Test) with 
Kuvan 100 mg powder for oral solution (Reference) following a 10 mg/kg dose in healthy 
subjects. 
 To evaluate the effect of a high-fat, high-calorie meal on the bioavailability of sapropterin 
dihydrochloride 100 mg/mL oral suspension following a 10 mg/kg dose in healthy subjects. 
 To evaluate the effect of water administration on the bioavailability of sapropterin 
dihydrochloride 100 mg/mL oral suspension following a 10 mg/kg dose in healthy subjects. 
Secondary objective: 
 To evaluate the safety and tolerability of sapropterin dihydrochloride when administered 
to healthy subjects. 
3. 
Endpoints 
Primary endpoints: 
 PK 
o Uncorrected and baseline-corrected sapropterin AUC0-t, AUC0-inf, and Cmax 
Secondary endpoints: 
 PK 
o Uncorrected and baseline-corrected sapropterin Tmax and Tlag 
o Uncorrected and baseline-corrected sapropterin T½ el, Residual area, Kel, Cl/F, and 
Vz/F 
 Safety 
o AEs, vital signs measurements (blood pressure, pulse rate, respiratory rate, and 
temperature), 12-lead ECG recordings, physical examinations, and clinical laboratory 
test results, including hematology, biochemistry, and urinalysis 
4. 
Study Design 
This is a single center, Phase 1, randomized, open-label, single-dose, 4-treatment, 4-period, 
4-sequence, crossover study designed to compare the PK of sapropterin from the Test and 
Reference products, and to evaluate the effect of food and the effect of water administration on the 
bioavailability of sapropterin from the Test product in healthy subjects. 
In each period, subjects will receive a single 10 mg/kg dose of sapropterin dihydrochloride on Day 
1, under fasting or fed conditions, and with or without water, followed by 24 hours of PK sampling. 
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This study will employ general screening. The study will start on the day the first subject signs 
the study’s Ethics/Institutional Review Board (ERB/IRB) approved ICF. The end date of the 
clinical trial will be the last visit of the last subject. The anticipated end of study date for most 
subjects will be their last scheduled study procedure. Unscheduled visits and AE follow-up may 
occur after the end of study procedures. The expected duration of subject participation in this 
study (from voluntary signing of the ICF to the last scheduled study procedure) will be 
approximately 24 days. 
The washout between drug administrations for each subject will be at least 7 days (±3 hours). 
The washout may be extended. The duration of subject participation will be extended by adding 
on the extra washout days. 
5. 
Study Population 
5.1 
Number of Subjects 
It is planned to enroll 16 subjects for participation in this study. All attempts will be made to 
have an equal number of males and females. The proposed number of subjects is in line with the 
sample sizes commonly used in clinical studies of this nature and is considered sufficient to 
achieve the study objectives. 
5.2 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in the study: 
1. Male or female, light smoker (no more than 10 cigarettes daily) or non-smoker
50 
years of age, with body mass index (BMI) 18.5 and 30.0 kg/m2 
 kg 
for males and 
 for females. 
2. Healthy as defined by: 
a. the absence of clinically significant illness and surgery within 30 days prior to dosing. 
b. the absence of clinically significant history of neurological, endocrine, cardiovascular, 
respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, 
and metabolic disease. 
3. Female subjects of non-childbearing potential must be: 
a. post-menopausal (no menstrual period at least 12 consecutive months without any other 
medical cause and FSH and LH values consistent with being menopausal); or 
b. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, hysterectomy or tubal 
ligation) at least 3 months prior to dosing. 
4. Sexually active female subjects of childbearing potential must be willing to use an acceptable 
contraceptive method throughout the study as detailed in section 7.1. 
5. Willing to take off dentures or mouth piercing at the time of dosing. 
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6. Able to understand the study procedures and provide signed informed consent to participate 
in the study. 
5.3 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1. Any clinically significant abnormal finding at physical examination. 
2. Clinically significant abnormal laboratory test results (may be repeated up to two times) or 
positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, or human immunodeficiency virus (HIV)-1 and HIV-2 antibodies at 
screening. 
3. Positive pregnancy test or lactating female subject. 
4. Positive urine drug screen. 
5. Known allergic reactions to sapropterin dihydrochloride or other related drugs, or to any 
excipient in the formulation. 
6. Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure 
lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, 
or pulse rate less than 50 or over 100 bpm) at screening. ECG and vitals signs may be 
repeated up to two times, to determine if the values are significantly abnormal. 
7. Recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as 
cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine 
derivatives) within 3 months prior to screening. 
8. History of alcohol addiction requiring treatment. 
9. History of abuse of medicinal product or drugs within the last 3 years. 
10. History or presence of alcoholism within the last 3 years. (>40 g ethanol/day or more than 
10 units per week [1 unit =150 mL of wine, or 360 mL of beer, or 45 mL of 45% alcohol]). 
11. Use of medications within the timeframes specified in section 7.2. 
12. Participation in a clinical research study involving the administration of an investigational or 
marketed drug or device within 30 days prior to dosing, administration of a biological 
product in the context of a clinical research study within 90 days prior to dosing, or 
concomitant participation in an investigational study involving no drug or device 
administration. 
13. Known predisposition to seizures. 
14. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of 
whole blood within 8 weeks prior to dosing. 
15. Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the 
mouth or tongue that would be likely to interfere with successful completion of the dosing 
procedure. 
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16. Females who:  
a. Have discontinued or changed the use of implanted, intrauterine, intravaginal, or injected 
hormonal contraceptives within 6 months prior to study treatment administration. 
b. Have discontinued or changed the use of oral or patch hormonal contraceptives within 
1 month prior to study treatment administration. 
17. Any reason which, in the opinion of the Investigator, would prevent the subject from 
participating in the study. 
5.4 
Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or designee may withdraw any subject from 
the study for one of the reasons described below; subject withdrawal will be done in accordance 
with the clinical site’s SOP: 
 Safety reason; 
 Non-compliance with protocol requirements; 
 Significant protocol deviation; 
 Positive pregnancy test, drug screen, or alcohol breath test. 
Subjects who experience vomiting within 10 hours after study treatment administration will be 
removed from that period of the study. Their continued participation in the study will be 
evaluated by the Investigator and PK Scientists prior to the next study treatment administration.  
Subjects who experience vomiting after this time will be assessed for their continued 
participation in the study by the Investigator. 
Subjects excluded from dosing in one period as per criteria listed above, may be invited to 
participate in subsequent periods of the study if deemed appropriate by the Investigator and 
appropriate from a statistical standpoint (i.e., would permit adequate statistical comparison). 
However, subjects with positive pregnancy test, drug screen, or alcohol breath test will be 
definitively withdrawn from the study. 
Subjects who withdraw prior to the first dosing may be replaced with a standby subject. Subjects 
who withdraw or are withdrawn from the study after the first dosing will not be replaced. 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or designee agrees that the subject is fine and can be discharged. As soon as subject 
withdrawal is confirmed, blood sampling will be stopped. A PK blood sample may be collected 
at the time of withdrawal if deemed required by the Investigator. EOS/early termination (ET) 
procedures will be performed at the time of withdrawal from the study or as soon as possible 
thereafter. 
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5.4.1 
Use of Data for Discontinued Subjects 
Data that was obtained prior to a subject’s discontinuation in this study will be maintained, used, 
and included in subsequent analyses, as applicable. If a subject withdraws from the study, the 
subject may request the destruction of samples. 
No analyses will be performed on the samples outside of the protocol requirements without the 
subject’s consent. 
6. 
Study Treatments 
6.1 
Study Treatment Supplies and Accountability 
It is the responsibility of the Sponsor to ensure that study treatments provided for this study are 
manufactured under Good Manufacturing Practice (GMP) and are suitable for human use. The 
reference product will be obtained from the US market. The Sponsor is responsible to ship a 
sufficient amount of dosage units to allow the clinical site to maintain an appropriate sampling 
for the study. 
The study treatments will be stored at the clinical site pharmacy as per applicable requirements 
in a locked, environmentally-controlled medication room with restricted access. Container(s) will 
be labeled according to applicable regulations. 
Individual doses for each subject and period will be dispensed at the clinical site pharmacy, as 
per appropriate SOP, according to the randomization scheme, and according to the subject’s 
weight measured at Period 1 check-in, in appropriate syringes/containers indicated with at least 
the project number, the period number and the subject number/spare number. Please refer to the 
pharmacy and dosing plans for detailed procedures on dispensing. 
All study treatments received at the site will be inventoried and accounted for throughout the 
study and the result recorded in the study treatment accountability record according to the 
clinical site appropriate SOP. 
At the completion of the study, unused study treatment(s) will be retained at the clinical site, 
returned to the Sponsor, or destroyed, as requested by the Sponsor. No study treatment(s) will be 
destroyed without written permission from the Sponsor. 
6.2 
Investigational Products 
Test:  
Sapropterin dihydrochloride 100 mg/mL oral suspension (product code: 
RLF-OD032) (APR Applied Pharma Research s.a., Switzerland) 
 
Reference:  Kuvan (sapropterin dihydrochloride) 100 mg powder for oral solution (BioMarin 
Pharmaceutical Inc., USA) 
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6.3 
Identification of Treatments 
Treatment A: 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL 
administered without water under fasting conditions. 
Treatment B: 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL 
administered without water under fed conditions. 
Treatment C: 1 x 10 mg/kg dose* of sapropterin dihydrochloride oral suspension 100 mg/mL 
administered with water under fed conditions. 
Treatment D 1 x 10 mg/kg dose* of Kuvan (sapropterin dihydrochloride) 100 mg powder for 
oral solution dissolved in water and administered under fed conditions. 
* The dose for each subject will be calculated by multiplying the subject’s weight measured on 
Day -1 of Period 1 by 10 mg/kg and then rounding up to the next 100 mg dose. For example, the 
weight of a 70.5 kg subject would be multiplied by 10 mg/kg, resulting in 705 mg and after 
rounding up, this subject would be assigned a dose of 800 mg. 
6.4 
Randomization and Blinding 
This study will be an open-label study due to the objective nature of the data. Subjects will be 
administered each treatment according to the block randomization scheme. A 4-sequence Williams 
design will be used (e.g.: ADBC, BACD, CBDA and DCAB):  
Table 3. 
Treatment Sequence 
 
Treatment 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
DCAB 
D 
C 
A 
B 
ADBC 
A 
D 
B 
C 
BACD 
B 
A 
C 
D 
CBDA 
C 
B 
D 
A 
 
Subjects will be assigned consecutive subject numbers in an ascending order. Each number will 
identify a subject and determine the sequence of study treatment administration according to the 
randomization scheme. 
The randomization code will not be available to the bioanalytical facility until the clinical and 
analytical phases of the study have been completed. 
6.5 
Study Treatment Administration 
Subjects will be asked to take off dentures or mouth piercing at the time of dosing. A mouth 
check will be performed to ensure study treatment and fluid (when applicable) consumption. The 
time of dosing will be set as the time the oral suspension or solution begins to be swallowed. For 
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Treatments A, B, and C, the syringe should be filled-in just before administration.  Refer to the 
pharmacy plan for detailed preparation procedures and dosing plan for administration 
procedures. 
Treatments A and B: the oral suspension will be administered from prefilled oral syringes 
directly into the subjects’ mouth. Subjects will immediately swallow all the contents of the 
syringe. A rinse of the syringe will not be required. No additional water will be given to the 
subjects. 
Treatment C: the oral suspension will be administered from prefilled oral syringes directly into 
the subjects’ mouth. Subjects will immediately swallow all the contents of the syringe followed 
by a glass of water so that the total volume of suspension + water is 240 mL (± 5 mL). A rinse of 
the syringe will not be required. 
For Treatment D, the powder for oral solution will be dissolved in 120 mL (± 3 mL) of water 
within 15 minutes before administration and the solution will be swallowed at the time of study 
treatment administration.  The powder should be placed in water and stirred until dissolved. The 
powder should dissolve completely.1,2 To ensure that the entire dose is consumed, the dosing cup 
will be rinsed twice with an additional 60 mL (± 1 mL) of water each time (total volume of 120 
mL (± 2 mL)) and the contents will be swallowed. No additional water will be given to the 
subjects. 
6.6 
Administration of Food and Fluid 
For Treatment A: 
Subjects will fast from at least 10 hours prior to study treatment administration until at least 4 
hours post-dose. 
For Treatment B, C, and D: 
After an overnight fast of at least 10 hours, subjects will consume a high-fat, high-calorie 
breakfast starting 30 minutes prior to study treatment administration. 
Table 4. 
High-Fat, High-Calorie Breakfast 
 
Calories 
(kcal) 
Total Fat 
(g) 
Carbohydrates 
(g) 
Protein 
(g) 
2 eggs 
140 
10 
0 
12 
10 g of butter for cooking eggs 
70 
8 
0 
0 
2 slices of whole wheat toast 
(approximately 64 g) 
160 
2 
31 
7 
10 g of butter for toast 
70 
8 
0 
0 
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3 triangle pieces of hash brown 
potatoes (approximately 130 g) 
218 
14 
23 
2 
250 mL of whole milk 
160 
8 
12 
8 
3 strips of chicken bacon 
(approximately 63 g) 
105 
7 
0 
9 
Total weight (g) 
 
57 
66 
38 
Total calories (kcal) 
923 
514 
262 
152 
Relative caloric content 
 
56% 
28% 
 
16% 
Note: Due to supply chain issues, some ingredients may not be available therefore, the content of the high-fat, 
high-calorie breakfast is subject to change. Any change will be notified to the Sponsor and ensured that the total 
caloric content and breakdown between fat, carbohydrate, and protein is maintained according to FDA requirements: 
high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 
calories). The meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively.7 
Subjects who do not consume the entire meal in the required time will be dismissed from that 
period of the study prior to study treatment administration. Their continued participation in the 
remainder of the study will be determined by the Investigator or designate. 
Subjects will fast for at least 4 hours post-dose. 
For all Treatments: 
Standardized meals will be provided throughout confinement (e.g., at 4 hours for lunch, 9 hours 
for dinner and 13.5 hours for snacks). The meals will be identical for all periods. 
Water will be restricted from one hour prior to study treatment administration until one hour post-
dose (except the water administered with the study treatment in Treatment C and D). Access to 
water will otherwise be freely available to subjects. 
7. 
Study Restrictions 
Adherence to the restrictions will be confirmed and recorded at each check-in. Subjects who do 
not comply with these restrictions will be assessed by the Investigator/PK Scientists regarding 
their continued participation in the study. 
7.1 
Contraception 
Subjects participating in this study must use an acceptable single- or double-method of 
contraception as defined below: 
 Females: from 21 days prior to first study treatment administration until 28 days after the 
last PK blood sample in the study 
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 Males: from the day of first study treatment administration until 28 days after the last PK 
blood sample in the study 
Table 5. 
Acceptable Effective Methods of Contraception 
Single-Method 
Double-Method (must use at least two) 
Surgically sterile 
Diaphragm with Spermicide 
Non-hormonal IUD  
Postmenopausal 
Cervical cap with Spermicide 
Vasectomy 
Remain abstinent 
Condom with Spermicide 
Hormonal contraception 
Hormonal contraception includes: 
Oral contraceptives, intra-vaginal devices, hormonal IUD, injections, transdermals, and implants 
Male subjects will be instructed not to donate sperm from the day of first study treatment 
administration until at least 28 days after the last PK blood sample in the study. 
7.2 
Concomitant Medications 
Subjects will be required to avoid using medications for the timeframes specified below and 
throughout the study: 
 Depot injection or implant of any drug for 3 months prior to dosing; 
 Prescription medications for 14 days prior to dosing; 
 Any vaccine, including COVID-19 vaccine, for 14 days prior to dosing; 
 Over-the-counter (OTC) medications and natural health products (including herbal 
remedies such as St. John’s wort, homeopathic and traditional medicines, probiotics, food 
supplements such as vitamins, minerals, amino acids, essential fatty acids, and protein 
supplements used in sports) for 7 days prior to dosing (with the exception of the 
occasional use of acetaminophen up to 2 g daily). 
No concomitant medications will be allowed during the study, with the exception of hormonal 
contraceptives, medications required for the medical management of an AE, and medications 
exempted by the Investigator on a case-by-case basis that are judged unlikely to affect the PK 
profile of the study treatment or subject safety (e.g., topical drug products without significant 
systemic absorption). 
Medications taken by subjects before the first dose will be documented as prior medications and 
medications taken by subjects after the first dose through to the last study day will be 
documented as concomitant medications. Any prior or concomitant medication use, other than 
the allowed medications stated above, will be reviewed and evaluated on a case-by-case basis by 
the Investigator and PK Scientists to determine if they affect a subject’s eligibility or continued 
participation in the study, or for potential impact on the study results. In accordance with the 
prescribing information for Kuvan, subjects taking medications known to inhibit folate 
metabolism, or levodopa, after being administered sapropterin, will be monitored. Subjects 
taking medications known to affect nitric oxide-mediated vasorelaxation after being administered 
sapropterin will be monitored for hypotension. 
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7.3 
Drugs, Nicotine and Alcohol 
Subjects will be required to abstain from: 
 Soft or hard drugs from screening and throughout the study; 
 Any nicotine product (including cigarettes) during confinement. No more than 10 
cigarettes per day will be allowed during the washout period. No nicotine products (other 
than cigarettes) will be allowed during the washout period; 
 Alcohol-based products from 48 hours prior to admission until after the last PK blood 
sample collection of each period. 
7.4 
Diet 
Subjects will be required to abstain from: 
 Food or beverages containing grapefruit, Seville orange, starfruit, pomegranate, 
pineapple, or pomelo from 7 days prior to dosing and throughout the study; 
 Food or beverages containing xanthine derivatives or xanthine-related compounds 
(coffee, black/green tea, chocolate) or energy drinks from 48 hours prior to dosing until 
after the last PK blood sample collection of each period; 
 Food containing poppy seeds from 24 hours prior to admission of each period. 
 Chewing gum will be prohibited at all times during the confirment. 
7.5 
Posture and Physical Activity 
Subjects will be required to remain seated and avoid lying down or sleeping for 6 hours after 
study treatment administration. 
Failure of subjects to comply with these requirements does not constitute a deviation from the 
protocol if it is medically necessary, required for procedures, or to go to the bathroom. When 
appropriate, subjects will be accompanied by a staff member while walking. Vigorous activity 
will be prohibited at all times during the confinement. 
8. 
Study Procedures 
Subjects must provide written informed consent (privacy, volunteer, and informed consent) prior 
to initiation of any study procedures. 
Unless otherwise specified, study procedures will be conducted in accordance with clinical site 
SOPs. 
Every effort will be made to schedule and perform the procedures as close to the nominal time as 
possible, giving considerations to appropriate posture conditions, practical restrictions, and other 
procedures to be performed at the same time point. 
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PK blood sample collection will be performed closest to the nominal time. When vital signs 
measurement or ECG recording coincide with a blood collection, they should preferably be 
performed before the blood collection, whenever possible. 
Table 6. 
Scheduled Windows of Allowance for Vital signs and ECG 
Procedure 
Timepoint 
Acceptable Window from Scheduled time
Vitals 
Pre-dose (0-hour) 
Within 180 minutes prior to dosing  
 
>0 hours 
±20 minutes 
ECG 
Pre-dose (0-hour) 
From check-in to dosing 
>0 hours 
±30 minutes 
 
8.1 
Screening Procedures (-30 to -1) 
Recruitment into this study will initially involve Pharma Medica Research Inc. recruitment 
procedures and general screening, during which volunteers will voluntarily consent to and sign 
an ERB/IRB approved Volunteer Consent Form (VCF) and Privacy Consent Form (PCF). 
An ICF specific to this study will be signed by all subjects prior to any study specific procedures 
occurring. 
Screening will include the following procedures either at the screening visit or at Period 1  
check-in: 
 Screening evaluations (Screening consent: Inclusion/Exclusion Criteria); 
 Medical and medication history; 
 Demographic data collection and height and weight measurements, as well as BMI 
calculation; 
 Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be measured 
after the subjects have been resting for at least 3 minutes in a sitting position; 
 12-lead ECG will be recorded after the subjects have been resting in a semi-recumbent or 
supine position;  
 Blood and urine sample collection. 
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Table 7. 
Blood and Urine Tests Performed at Screening 
Biochemistry 
Hematology 
Urinalysis 
Random glucose 
Total bilirubin 
BUN 
Creatinine 
Alkaline phosphatase 
Calcium 
LD 
AST (SGOT) 
ALT (SGPT) 
Serum electrolytes (sodium, 
potassium, and chloride) 
GGT 
FSH  
LH 
Note: FSH and LH will be tested 
only in female subjects with a 
menstrual history consistent with 
being postmenopausal. 
CBC with differential: 
 
WBC count with 
differential 
 
Hemoglobin 
 
Hematocrit 
 
RBC count and indices 
Platelet count 
Specific gravity 
pH 
Leukocytes 
Nitrites 
Protein 
Glucose 
Ketones 
Blood 
Microscopic examination 
Note: microscopic examination will 
only be performed when any of the 
following urinalysis tests are 
reported abnormal (i.e., outside of 
normal ranges): leukocyte, nitrite, 
protein, and/or blood. The 
microscopic examination will be 
conducted on the same urine sample 
as the abnormal urinalysis test. 
Serology 
Drugs of Abuse 
Immunohematology 
HIV-1 and HIV-2 antibodies 
HCV antibody 
HBsAg  
 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Methadone 
Opiates 
Phencyclidine 
Tricyclic antidepressants 
-HCG (females only) 
Abbreviations: ALT (SGPT) = alanine aminotransferase; AST (SGOT) = aspartate aminotransferase; -HCG = 
beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CBC = complete blood count; FSH = 
follicle-stimulating hormone; GGT = gamma glutamyl transpeptidase; HBsAg = hepatitis B surface antigen; HCV = 
hepatitis C virus; HIV = human immunodeficiency virus; LD = Lactate dehydrogenase; LH = luteinizing hormone; 
RBC = red blood cell; WBC = white blood cell. 
8.2 
Test/ Procedures at check-in 
Check-in of Period 1 
 ICF signature for the study (if not done before); 
 Medical and medication history; 
 Any outstanding screening procedure that is not completed, or needs to be repeated; 
 Complete physical examination including assessments of the following: head, eyes, ears, 
nose, throat (HEENT), neck, chest, lungs, abdomen, musculoskeletal, dermatological, 
cardiovascular/peripheral vascular, and general neurological examination; 
 Temperature measurement;  
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 Weight; 
 Urine drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiates, phencyclidine, and tricyclic antidepressants); 
 Urine -HCG and serum -HCG (females only);  
 Breath alcohol; 
 Confirm inclusion/exclusion criteria. 
Check-in of Period 2, 3, 4  
 Temperature measurement;  
 Urine drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiates, phencyclidine, and tricyclic antidepressants); 
 
-HCG 
-HCG (females only);  
 Breath alcohol; 
 Medical and medication history. 
Clinical study personnel reserve the right to conduct additional testing (e.g., breath alcohol test, 
diagnostic imaging) at any time throughout the study. 
8.3 
On-study procedures:  
 Temperature measurement daily; 
 Vital signs (blood pressure and pulse rate) will be measured after the subjects have been 
resting for at least 3 minutes in a sitting position: before dosing (0-hour), and at 4 and 
6 hours post-dose;  
 12-lead ECG will be recorded after the subjects have been resting in a semi-recumbent or 
supine position: before dosing (0-hour), at 4 and 6 hours post-dose; 
 Study treatment administration; and 
 Pharmacokinetic Blood Sample Collection: -1, -0.5, pre-dose (0), and 0.333, 0.667, 1, 
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose. 
Table 8. 
Time Windows for PK Blood Samples 
Day 
Time point 
Time window 
1 
-1 hour, and -0.5 hour  
±5 minutes 
Pre-dose (0-hour) 
Within 5 minutes 
0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 
5, 5.5, and 6 hours 
±1 minute 
8, 12, and 16 hours 
±3 minutes 
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2 
24 hours 
±3 minutes 
 
Samples collected outside the acceptable window will not be considered as protocol deviations, 
but rather the actual clock time of each sample collection will be recorded. 
8.4 
End of study procedures 
End-of-study for each subject is defined as the last study specific procedure in the last period of 
the study or the last study specific procedure prior to the discontinuation of a subject from the 
study. 
End-of-study will include the following procedures: 
 A brief physical examination including assessments of the following: HEENT, chest, 
lungs, abdomen, dermatological, cardiovascular/peripheral vascular, and areas of note 
elicited from the subject; 
 Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be measured 
after the subjects have been resting for at least 3 minutes in a sitting position;  
 12-lead ECG will be recorded after the subjects have been resting in a semi-recumbent or 
supine position; and 
 Blood and urine sample collection. 
Table 9. 
Blood and Urine Tests Performed at End of Study 
Biochemistry 
Hematology 
Urinalysis 
Random glucose 
Total bilirubin 
BUN 
Creatinine 
Alkaline phosphatase 
Calcium 
LD 
AST (SGOT) 
ALT (SGPT) 
GGT 
Serum electrolytes (sodium, 
potassium, and chloride) 
CBC with differential: 
 
WBC count with 
differential 
 
Hemoglobin 
 
Hematocrit 
 
RBC count and indices 
Platelet count 
 
Specific gravity 
pH 
Leukocytes 
Nitrites 
Protein 
Glucose 
Ketones 
Blood 
Microscopic examination 
Note: microscopic examination will 
only be performed when any of the 
following urinalysis tests are 
reported abnormal (i.e., outside of 
normal ranges): leukocyte, nitrite, 
protein, and/or blood. The 
microscopic examination will be 
conducted on the same urine sample 
as the abnormal urinalysis test. 
Immunohematology 
-HCG (females only) 
-HCG = 
beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CBC = complete blood count; GGT = gamma 
glutamyl transpeptidase; LD = Lactate dehydrogenase; RBC = red blood cell; WBC = white blood cell. 
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For subjects who are removed or withdrawn from the study, end-of-study procedures will still be 
conducted. Subjects who do not return for end-of-study procedures will be considered lost-to-
follow-up. 
If a subject is not able to repeat any end-of-study tests at the clinic, they may repeat the test with 
their local healthcare provider/laboratory. All external results will be reviewed by the 
Investigator. 
8.5 
Pharmacokinetic Assessments 
8.5.1 
Pharmacokinetic Blood Sample Collection and Processing 
In each period, blood samples for PK analysis will be collected via an intravenous catheter or by 
direct venipuncture. 
The PK Scientists will be contacted to evaluate the subject’s continued participation in the study 
if any of the following incidents occur in any period: 
 The 24-hour scheduled blood draw is missed; or 
 At least two consecutively scheduled blood draws are missed. 
The impact of these incidents on the estimation of PK parameters will be made as close to the 
time of occurrence as possible. 
The planned volume of blood to be collected for this study, including that collected for eligibility 
and safety purposes, should not exceed 500 mL. Additional tests or blood draws could be 
performed, if deemed required by the Investigator or study staff. 
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
laboratory manual. 
Plasma concentrations of the study treatment will be determined using a validated analytical 
method. Details of the analytical method will be provided in a separate document. 
8.6 
Safety and Tolerability Assessments 
Subjects will be monitored throughout the study by the clinical staff for AEs. Adequate medical 
surveillance will be assured during the confinement period. The Investigator will be on-site until 
4 hours after the last subject is dosed and on call throughout the study. If necessary, the 
Investigator or designee at the clinical site or a healthcare professional in a nearby hospital will 
administer treatment for any AE(s). A crash cart or emergency bag containing the necessary 
rescue material and appropriate medications will be available in the clinic to allow rapid 
intervention in case of emergency. 
Safety parameters will be assessed by the Investigator or designee, using the clinical site 
acceptance ranges as suggested guidelines in making the medical assessment. 
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For eligibility purposes, abnormal vital signs measurements or clinical laboratory test results 
may be repeated up to two times if an abnormal result is observed at the initial reading. 
Moreover, abnormalities found in the ECG may need to be confirmed by repeated 
measurements. In the event that the participation of a subject in the study is delayed and some 
screening procedures had been performed outside of the prescribed screening window, outdated 
screening procedures can be repeated. 
Safety assessments scheduled during the study will be repeated according to the clinical site 
SOPs or upon request from the Investigator or designee. Any abnormal repeated measurement 
will be evaluated and repeated, if judged necessary. Further action may be taken upon the 
Investigator or designee’s request. 
8.7 
Adverse Events 
8.7.1 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with the treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
8.7.2 
Recording of Adverse Events 
AEs will be recorded and evaluated for their seriousness, severity, and relationship to the study 
treatment. AEs will be collected and documented from the time of signing the ICF and throughout 
the study. AEs will be followed-up until complete resolution, or until the Investigator or designee 
judges safe to discontinue follow-up. The severity of AEs and relationship to the study treatment 
will be classified according to the sections below. 
AEs will be classified according to the Medical Dictionary for Regulatory Activities (MedDRA) 
and reported with respect to severity, duration, relationship to study treatment(s) and action taken. 
8.7.3 
Assessment of Severity 
The severity of AEs will be described and documented using the following definitions: 
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Table 10. 
Severity of Adverse Events 
Severity 
Description 
Mild 
Awareness of signs and symptoms, but are easily tolerated; are of minor irritant type; 
causing no limitations of usual activities. Signs or symptoms may require minor 
action. 
Moderate 
Discomfort severe enough to cause some limitations of usual activities and may 
require action. 
Severe 
Incapacitating with inability to carry out usual activities or significantly affects 
clinical status, and requires specific action and/or medical attention. 
 
8.7.4 
Assessment of Relationship to Study Treatment 
Each AE must be classified based on medical judgment and according to the following 
relationship categories: probable, possible, remote/unlikely, and unrelated. The definitions for 
the relationship categories are as follows: 
Table 11. 
Adverse Event Relationship Categories 
Category 
Description 
[Related] 
Probable 
(must have first three 
points) 
This category applies to AEs that are considered, with a high degree of certainty, to 
be related to the investigational product. An AE may be considered probable, if: 
1. It follows a reasonable temporal sequence from the administration of the study 
treatment. 
2. It cannot be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors or other modes of 
therapy administered to the participant. 
3. It disappears or decreases on cessation or reduction in dose (there are important 
exceptions when an AE does not disappear upon discontinuation of the study 
treatment, yet relatedness clearly exists; e.g. (1) bone marrow depression, (2) 
tardive dyskinesias). 
4. It follows a known pattern of response to the suspected study treatment.  
5. It reappears upon re-challenge. 
[Related] 
Possible 
(must have first two 
points) 
This category applies to AEs in which the connection with the investigational product 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possible if, or when: 
1. It follows a reasonable temporal sequence from the administration of the study 
treatment. 
2. It may have been produced by the participant’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the participant. 
3. It follows a known pattern of response to the suspected study treatment. 
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Remote/Unlikely 
(must have first two 
points) 
In general, this category is applicable to an AE that meets the following criteria: 
1. It does not follow a reasonable temporal sequence from the administration of the 
study treatment. 
2. It may readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant. 
3. It does not follow a known pattern of response to the suspected study treatment. 
4. It does not reappear or worsen when the study treatment is re-administered. 
Unrelated 
This category is applicable to AEs that are judged to be clearly and incontrovertibly 
due only to extraneous causes (disease, environment, etc.), and do not meet the 
criteria for medication relationship listed under remote/unlikely, possible, or 
probable. 
 
8.7.5 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: 
 Results in death; 
 Is life-threatening (i.e., its occurrence places the subject at immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity; 
 Is a congenital anomaly/birth defect; 
 Is otherwise considered to be an important medical event that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. Medical and 
scientific judgement should be exercised in deciding whether an event should be considered 
as an Important Medical Event. Examples of such medical events include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at home; 
o Blood dyscrasias or convulsions that do not result in hospitalization; 
o Development of drug dependency or drug abuse. 
8.7.6 
Reporting of Adverse Events 
8.7.6.1 
Serious Adverse Event Reporting to the Sponsor 
Any SAE will be reported to the Sponsor (or representative) within 24 hours of learning of the 
event. The notification must be directed to: 
SAE contact information: 
Patrizia Mesiti  
Regulatory Affairs Pharma Manager  
and Head of Pharmacovigilance  
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APR Applied Pharma Research s.a. 
Via Corti 5 
CH - 6828 Balerna 
Switzerland 
Email: apr.vigilance@apr.ch 
8.7.6.2 
Serious Adverse Event Reporting to the IEC and Regulatory Agency(ies) 
It is the responsibility of the clinical site to report suspected, unexpected, serious adverse reactions 
(SUSARs) to the IEC responsible for the study per their policies. Report of fatal or life-threatening 
SUSARs must be made as soon as possible, but no later than 7 calendar days after first knowledge 
of the event. Report of SUSARs that are neither fatal nor life-threatening must be made as soon as 
possible, but no later than 15 calendar days after first knowledge of the event. 
The Sponsor (or representative) is responsible for notifying the regulatory agency(ies) of SUSARs 
observed during the study conduct per their regulations, as soon as possible but no later than 
7 calendar days after becoming aware of the information when fatal or life-threatening, or 
15 calendar days when neither fatal nor life-threatening. The Sponsor (or representative) is 
responsible to comply with any other applicable regulatory requirement(s) related to the reporting 
of SAE to other regulatory authority(ies). 
8.7.7 
Pregnancy 
In the event a dosed female participant or the female partner of a dosed male participant (i.e., has 
received at least one dose of the investigational product) becomes pregnant during or shortly 
after participation in the study, this pregnancy will be reported to the Sponsor (or representative) 
within 24 hours of first knowledge of the event. Any subject who becomes pregnant during the 
study will be immediately withdrawn. Follow-up information regarding the course and outcome 
of the pregnancy will be documented (after obtaining the consent of the female partner) as per 
site’s SOP. If the outcome of the pregnancy meets the criteria of reportable event, reporting of 
the event to the IEC responsible for the study and/or to applicable regulatory agency(ies) will be 
performed as per site’s SOP. 
8.8 
Premature Termination of the Study 
The study may be prematurely terminated by the Investigator following consultation with the 
Sponsor, by the Sponsor or by the regulatory authorities. Following a decision to discontinue the 
trial, the Investigator will promptly inform the active study subjects and the IEC responsible for 
this trial, stating the reasons for discontinuation of the study. It is the responsibility of the 
Sponsor (or representative) to report the premature termination of the study to the regulatory 
authority(ies), when required by the applicable regulatory requirement(s). 
9. 
Statistical Analyses 
For all PK analysis, all concentrations below the limit of quantification will be set to 0. 
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Samples with invalid concentration (due to bioanalytical or clinical issue) will be replaced by 
“0.00” when it occurs prior to dosing for PK parameters calculation. Otherwise, they will be set 
to missing for tabulation, graphical representation, and calculation purposes if it occurs after 
dosing. 
The primary objective of this study is to evaluate the relative bioavailability of a new oral 
suspension formulation. Since this study is exploratory, no formal hypothesis testing is defined. 
9.1 
Analysis Populations 
9.1.1 
Safety Population 
The safety population is defined as all subjects who receive at least one dose of the study 
treatment. 
9.1.2 
Pharmacokinetic Population 
The PK population will include all subjects data from the safety population who complete at 
least two periods, including Treatment B, and for whom the PK profile can be adequately 
characterized. 
9.1.3 
Pharmacokinetic Statistical Population 
The PK statistical population will include all subject’s data from the PK population who 
complete at least two periods, where a statistical comparison can be made for at least one PK 
parameter and who have not experienced any protocol deviations or other circumstances to 
exclude the subject from the PK statistical analysis. 
Individual period data will be excluded if a baseline-corrected pre-dose concentration (at time 
0-hour) greater than 5% of the corresponding Cmax is observed for a subject. 
9.1.4 
Samples to be Assayed 
Samples from subjects included in the PK dataset and who experience vomiting within the 
criteria for removal, as defined in the section 5.4 will be assayed. 
9.2 
Pharmacokinetic Parameters 
The actual post-dose sample collection times will be used in the PK analysis. 
The following PK parameters and observations will be calculated based on data from the PK 
population by a standard non-compartmental method in Phoenix™ WinNonlin® (version 8.3 or 
later) for baseline-corrected and uncorrected sapropterin: 
 AUC0-t: Area under the concentration-time curve from time zero until the last observed 
concentration, as calculated by the linear up/log down variant of the trapezoidal method. 
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 AUC0-inf: Area under the concentration-time curve from time zero to infinity 
(extrapolated) 
 Residual area: Percentage of AUC0-inf due to extrapolation from the time of the last 
observed concentration to infinity, calculated as [1 – (AUC0-t/AUC0-inf)] x 100 
 Cmax: Maximal observed concentration 
 Tmax: Time when the maximal concentration is observed 
 Tlag: Time of observation prior to the first observation with a measurable (non-zero) 
concentration. 
 T½ el: Terminal elimination half-life 
 Kel: Terminal elimination rate constant 
 Cl/F: Apparent clearance 
 Vz/F: Apparent volume of distribution 
 R2: Coefficient of determination obtained from regression analysis 
Additional PK parameters may be calculated. Kel, T½ el, and AUC0-inf parameters will not be 
estimated for concentration-time profiles where the terminal linear phase is not clearly defined. 
Sapropterin is an endogenous compound and therefore, should be analyzed both with and 
without baseline correction. Pharmacokinetic parameters will be calculated based on uncorrected 
plasma concentrations and baseline-corrected plasma concentrations, as appropriate. Baseline 
corrected for sapropterin will be performed by calculating the mean plasma pre-dose levels for 
each subject within each period of the study using the measured concentrations at the -1, -0.5, 
and the 0-hour time points. The mean of these pre-dose values will be the baseline for that period 
for that subject. The baseline value will be subtracted from all subsequent measured 
concentrations (including 0-hour) for the same subject within the same period. Negative baseline 
adjusted levels will be set to zero before the PK analysis. No adjustment of the pre-dose or 
post-dose concentrations will be performed for the baseline uncorrected data. 
9.3 
Pharmacokinetic Statistical Analysis 
Statistical analysis described in this section will be based on the PK statistical population. 
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales.  
Descriptive statistics for the PK parameters of baseline-corrected and uncorrected sapropterin 
will be calculated. Descriptive statistics will include number of observations, arithmetic mean, 
standard deviation, geometric mean (where applicable), coefficient of variation (CV), median, 
minimum, and maximum. 
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Statistical analysis will be performed on quality assured data, with unbalanced sequences if 
necessary, from subjects in the statistical dataset. The PROC MIXED procedure from SAS® 
(version 9.4 or later) will be used. 
ANOVA will be performed on log-transformed AUC0-t, AUC0-inf, and Cmax parameters at the 
alpha level of 0.05 on uncorrelated data, the statistical model will include sequence, treatment, 
period, and subject(sequence) as a random effect.  
ANCOVA (Analysis of Co-Variance) on log-transformed AUC0-t, AUC0-inf, and Cmax parameters 
at the alpha level of 0.05 will be applied for baseline corrected analysis, using the actual total 
dose included in the ANOVA statistical model as a covariate, the statistical model will include 
sequence, treatment, period, and actual total dose as fixed effects and subject(sequence) as a 
random effect.  
In case the study is dosed in groups, considering the study conduct will occur at the same clinical 
site, assignment to groups is random, and the dosing of the groups will occur within a relatively 
short timeframe, it is not anticipated that dosing in groups will impact the study results. As such, 
the group effect will not be considered in the statistical model.  
Using the same statistical model, the least-squares-means, the differences between the treatments 
least-squares-means, and the corresponding standard errors of these differences will be estimated 
for log-transformed AUC0-t, AUC0-inf, and Cmax parameters. Based on these statistics, the ratios of 
the geometric means for treatments and the corresponding 90% confidence interval will be 
calculated for the following comparisons: 
 Treatment A versus Treatment D 
 Treatment B versus Treatment D 
 Treatment C versus Treatment D  
 Treatment B versus Treatment C 
 Treatment A versus Treatment C 
 Treatment B versus Treatment A 
These contrasts will be estimated separately using only the data from the treatments involved in 
the comparison.  
Treatment differences in Tmax will be evaluated by a nonparametric approach (Wilcoxon signed 
rank test) on the untransformed values. 
These statistics will be used to evaluate the effect of food on the test formulation and the 
performance of the test formulation with and without water.  
Additional PK statistical analysis may be performed. For example, an analysis with potency 
corrected data (to adjust the ratio and 90% CI for the comparison between Test and Reference 
B/D), in the event that the measured study treatment content of the lots of the Test and Reference 
products would differ by more than 5%. 
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9.4 
Safety and Tolerability Analysis 
Demographic parameters will be summarized descriptively. 
Safety and tolerability analysis will be performed for all subjects in the safety population. No 
inferential statistical analysis of safety data is planned. 
Safety and tolerability of sapropterin dihydrochloride will be evaluated through the assessment 
of AEs (i.e., seriousness, severity, relationship to the study treatment, outcome, duration, and 
management), vital signs, 12-lead ECGs, clinical laboratory tests, and physical examinations. 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA). 
TEAEs will be tabulated by treatment. Safety and tolerability data will be reported using 
descriptive statistics. 
10. Data Collection 
The source data will be collected on paper as per site SOPs. Source data will reflect the 
ALCOA+ principles, then they should be attributable, legible, contemporaneous, original, 
accurate, and complete. Source documents will be maintained in order to maintain data integrity. 
The Investigator and/or the clinical staff have the responsibility of ensuring the accuracy, 
completeness, legibility, and timeliness of the source data. 
Details on the data management process will be described in a data management plan (DMP). 
11. Regulatory Considerations and Quality Assurance 
11.1 IEC Approval of Protocol and Other Study Documents 
The Investigator(s) agree to provide the IEC with all appropriate documents, including a copy of 
the protocol/amendments, ICFs, advertising text (if any), and any other written information 
provided to study subjects. The trial will not begin until the Investigators have obtained the IEC 
favourable written approvals for the above-mentioned study documents. A properly executed 
written ICF shall be read, signed, and dated by each subject prior to entering the trial or prior to 
performing any study procedure. Adequate information will be provided to subjects in order for 
the subject to make an informed decision regarding his/her participation. Prior to signing any 
consent form, subjects will be allowed adequate time to consider the potential risks associated 
with their participation in the study. The original signed and dated ICF will be kept at the clinical 
site and a copy will be given to the subject. 
In the event that the protocol is amended, the revised protocol must be approved by the IEC prior 
to its implementation, unless the changes involve only logistical or administrative aspects of the 
trial. If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
obtaining each subject’s consent. 
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The Investigator and the Sponsor’s representative must sign the protocol and its amendments (if 
any) before initiating the study. 
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
11.2 Compliance 
This study will be conducted in compliance with the protocol, GCP, all applicable regulations, 
including the Federal Food, Drug and Cosmetic Act, U.S. applicable Code of Federal 
Regulations (title 21), and any IEC requirements relative to clinical studies. The study will also 
be conducted in compliance with the recommendations laid down in the most recent version of 
the Declaration of Helsinki, with the exception that registration of such Phase 1 trials in a 
publicly accessible database is not mandatory. As required by the Canadian regulatory agency, a 
Clinical Trial Application (CTA) will be submitted before the beginning of the study and a No 
Objection Letter (NOL) must be received prior to enrollment. 
11.3 Quality Assurance and Monitoring 
The Sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of the 
study data presented to the Sponsor lies with the Investigator generating the data. When 
applicable, quality assurance procedures will be performed according to the site SOPs. 
The study will be monitored internally according to the site monitoring plan and SOP to ensure 
that it is conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements. The Sponsor is entitled to access information about the status of the 
study and to review the original documents of the study. In addition, the Sponsor may decide to 
engage an external consultant for monitoring activities. 
The Sponsor may arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, SOPs, GCP, and all applicable 
regulatory requirements. In such case, audits will be independent of and separate from the 
routine monitoring and quality control functions. 
11.4 Financial Disclosure and Obligations 
The Investigator is required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under local 
legislation and regulations. In addition, the Investigator must provide to the Sponsor any relevant 
changes that occur during the course of the study. 
Neither the Sponsor nor Pharma Medica Research Inc. is financially responsible for further 
testing or treatment of a subject for any medical condition that may be detected during the 
screening process. 
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11.5 Insurance 
For the purpose of study related injury of subjects, the Sponsor will have valid insurance for the 
duration of the study and for at least 30 days after the end of the study. Pharma Medica 
Research Inc. will have valid liability insurance at all times subjects are at the clinical facility. 
11.6 Confidentiality and Retention of Study Records 
This document contains trade secrets and commercial information that is confidential and may 
not be disclosed to third parties. Persons to whom this study protocol is disclosed must be 
informed that all the information herein is confidential and may not be further divulged. These 
restrictions will apply as well to all future communications if deemed privileged or confidential. 
Publication of the study results may only be allowed with written permission from the Sponsor. 
All information on a subject obtained during the conduct of the study will be kept confidential. 
Subjects will be identified by an anonymized identifier on all samples and study records 
provided to the Sponsor or designee. In compliance with ICH GCP, the Sponsor’s authorized 
representatives, monitor(s), auditor(s), IEC, and regulatory authority(ies) will be granted direct 
access to the subject’s original trial-related records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations. Consent from the subject for disclosure of such information will 
be obtained in writing in the ICF. In addition, should a subject require medical care or 
hospitalization during the course of the study, the clinical site may contact the treating physician 
with the subject’s consent, except that consent may not be requested if there is an emergency 
situation. If the results of the study are published, the subject’s identity will remain confidential. 
The clinical site will maintain adequate study records according to local and agency applicable 
regulatory requirements and data integrity principles. The Sponsor will be notified prior to the 
destruction of study records or their moving from the site. 
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12. References 
1 
Kuvan, Prescribing Information. Version revised on 03/2020. Drug Databases, FDA. 
Available online at: www.accessdata.fda.gov/scripts/cder/daf/ 
2 
Kuvan, Product Monograph. Version revised on JUL 05, 2022. Drug Product Database, 
Health Canada. Available online at: health-products.canada.ca/dpd-bdpp/index-eng.jsp  
3 
Musson D.G., et al. Relative Bioavailability of Sapropterin From Intact and Dissolved 
Sapropterin Dihydrochloride Tablets and the Effects of Food: A Randomized, Open-Label, 
Crossover Study in Healthy Adults. Clinical Therapeutics. Volume 32, Number 2, 2010. 
4 
Kuvan, Clinical Pharmacology and Biopharmaceutics Review(s). Version submitted on 
FEB 09, 2013. Drug Databases, Available online at: 
www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205065Orig1s000ClinPharmR.pdf 
5 
Center for Drug Evaluation and Research (CDER), FDA. Guidance for Industry: 
Bioavailability Studies Submitted in NDAs or INDs – General Considerations. April 2022. 
6 
FDA Draft Guidance on Sapropterin Dihydrochloride Tablets. Recommended Sep 2008; 
Revised Sep 2012. 
7 
Center for Drug Evaluation and Research (CDER), FDA. Guidance for Industry: Assessing 
the Effects of Food on Drugs in INDs and NDAs — Clinical Pharmacology 
Considerations. 
 
IRB Reviewed - June 12, 2024