Clinical trial NCT01197378
Conditions: Cystinosis
Keywords: cystinosis cysteamine inheritable disease orphan disease CTNS protein, human metabolic disease nephropathic cystinosis
Sponsor: Amgen
Start date: 2010-08-27; Completion date: 2017-06-26
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Cystinosis is an inherited disease that if untreated, results in kidney failure as early as the first decade of life. The current marketed therapy is Cystagon® (cysteamine bitartrate immediate release) which must be taken every six hours for the rest of the patient's life to prevent complications of cystinosis. Cysteamine bitartrate delayed-release capsules (RP103) is a formulation of cysteamine bitartrate that is being studied to see if it can be given less frequently, once every 12 hours, and have similar results to four times a day Cystagon®.

Detailed description:
This is a long-term, open-label, study to determine the safety and tolerability of twice a day treatment with cysteamine bitartrate delayed-release capsules (RP103). It will involve 6-9 monthly clinic visits followed by quarterly clinic visits for the duration of the study and home use of cysteamine bitartrate delayed-release capsules.

Initially, enrollment was open to those patients who had completed the previous Phase 3 Study (RP103-03, NCT01000961). Subsequently enrollment in Study RP103-04 was opened to additional participants, including children aged 1 to 6 years and renal transplant recipients, who had previously been on a stable dose of Cystagon® for at least 21 days.

Study with completed results acquired from Horizon in 2024.

Arms: arm 1: Cysteamine bitartrate delayed-release capsules were administered twice daily for up to 96 months.
Interventions: intervention 1: Cysteamine Bitartrate Delayed-release Capsules
Intervention descriptions: intervention 1: Participants who entered the trial from the RP103-03 study continued treatment with cysteamine bitartrate every 12 hours at the last dose level prescribed during their participation in that study.

Participants not entering the trial from Study RP103-03 were started on twice a day administration of cysteamine bitartrate at a total daily RP103 dose of 70% of their pre-study total daily stable Cystagon® dose.

Protocol documents:
Prot_000.pdf: 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 2 of 91 
Investigator Agreement Page 
Raptor Pharmaceuticals Inc. 
RP103-04 Protocol Amendment 9 
November 18, 2015 
 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will 
discuss this material with them to ensure that they are fully informed about the investigational 
drug and the study protocol. 
 
I agree to conduct this clinical trial according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all federal, state and 
local regulations, as well as with the requirements of the appropriate Institutional Review 
Board or Ethics Committee and any other local and institutional requirements. 
 
 
 
_______________________________________________  
 
_______________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 
_______________________________________________ 
Principal Investigator Full Name (please print) 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 3 of 91 
TABLE OF CONTENTS 
 
CLINICAL PROTOCOL ..................................................................................................1 
INVESTIGATOR AGREEMENT PAGE .......................................................................2 
1. 
LIST OF ABBREVIATIONS ..................................................................................7 
2. 
LIST OF TABLES AND FIGURES .......................................................................9 
3. 
STUDY SYNOPSIS ................................................................................................10 
4. 
INTRODUCTION ..................................................................................................20 
4.1. Investigational Agent ....................................................................................20 
4.2. Background ...................................................................................................20 
4.2.1. Study RP103-01 .............................................................................................21 
4.2.2. Study RP103-03 .............................................................................................25 
4.2.3. Study RP103-02 .............................................................................................33 
4.2.4. Study RP103-05 .............................................................................................34 
4.2.5. Study RP103-06 .............................................................................................36 
4.2.6. Study RP103-HLTA-009 ..............................................................................36 
4.3. Risk/Benefits ..................................................................................................36 
4.4. Dose Rationale ...............................................................................................37 
4.5. Study Rationale .............................................................................................37 
4.6. Study Conduct ...............................................................................................39 
4.7. Study Population ...........................................................................................39 
5. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................40 
5.1. Study Objectives ...........................................................................................40 
5.1.1. Primary Objective ...........................................................................................40 
5.1.2. Secondary Objectives .....................................................................................40 
5.2. Study Endpoints ............................................................................................40 
5.2.1. Safety Endpoints .............................................................................................40 
5.2.2. Pharmacokinetic Endpoints ............................................................................40 
5.2.3. Pharmacodynamic Endpoints .........................................................................40 
 ...................................................................................
 
6. 
OVERALL STUDY DESIGN AND PLAN ..........................................................41 
6.1. Study Design ..................................................................................................41 
6.1.1. Study Visits ....................................................................................................41 
6.1.2. Study Procedures ..........................................................................................42 
6.2. Randomization ..............................................................................................45 
6.3. Duration .........................................................................................................45 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 4 of 91 
7. 
SELECTION OF SUBJECTS ...............................................................................45 
7.1. Inclusion Criteria ..........................................................................................45 
7.2. Exclusion Criteria .........................................................................................46 
7.3. Removal of Subjects from Study Participation..........................................46 
8. 
TREATMENT OF SUBJECTS ............................................................................47 
8.1. Study Treatment ...........................................................................................47 
8.2. Identity of Investigational Products ............................................................48 
8.3. Storage of Investigational Products ............................................................48 
8.4. Concomitant Medications and Excluded Therapies ..................................48 
8.5. Study Treatment Administration and Compliance ...................................49 
9. 
STUDY PROCEDURES ........................................................................................49 
9.1. Schedule of Study Procedures .....................................................................49 
9.1.1. Screening ........................................................................................................49 
9.1.2. Day 1 Study Visit (only for patients who did not complete Study RP103-
03) ...................................................................................................................51 
9.1.3. Day 4 and Day 5 Study Visits (only for patients who did not complete Study 
RP103-03) .......................................................................................................52 
9.1.4. Monthly (± 7 days) Study Visit (only for patients who completed Study 
RP103-03) .......................................................................................................52 
9.1.5. Quarterly (± 7 days) Study Visit .....................................................................53 
9.1.6. End of Study Visit (7 ± 2 days after last study visit or decision to 
terminate) ........................................................................................................54 
 
9.2. Fluid and Dietary Control ............................................................................55 
9.3. Contraception and Hormone Therapy .......................................................57 
9.4. Pharmacokinetic Blood Sample Collecting and Processing......................58 
9.5. Pharmacodynamic Blood Sample Collecting and Processing ..................58 
9.6. Analytical Methodology ...............................................................................58 
9.7. Clinical Laboratory Evaluations .................................................................59 
9.8. Blood Volume ................................................................................................60 
9.9. 12-Lead Electrocardiograms .......................................................................61 
9.10. Physical Examinations..................................................................................61 
9.11. Vital Signs ......................................................................................................61 
9.12. Adverse Event Inquiries ...............................................................................61 
 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 5 of 91 
 
 
 
 
 
 
9.15. Product Accountability ................................................................................63 
10. 
ASSESSMENT OF SAFETY ................................................................................63 
10.1. Definition and Grading Intensity of Adverse Events/Experiences...........63 
10.1.1. 
Stopping Criteria ..............................................................................65 
10.2. Criteria for Determining Relationship to Drug .........................................65 
10.3. Adverse Event Reporting .............................................................................66 
10.4. Follow-up of Adverse Events and Serious Adverse Events ......................68 
11. 
STATISTICAL PLAN ...........................................................................................68 
11.1. Statistical Methods ........................................................................................68 
11.2. Analysis Set....................................................................................................69 
11.3. Sample Size Considerations .........................................................................69 
11.4. Interim Analysis ............................................................................................69 
11.5. Accountability Procedure ............................................................................70 
11.6. Termination Criteria ....................................................................................70 
11.7. Deviation Reporting ......................................................................................70 
12. 
ADMINISTRATIVE ASPECTS ...........................................................................70 
12.1. Change in Protocol .......................................................................................70 
12.2. Disclosure .......................................................................................................70 
12.3. Monitoring .....................................................................................................70 
12.4. Institutional Review Board or Ethics Committee ......................................71 
12.5. Patient Insurance ..........................................................................................71 
12.6. Informed Consent and Assent .....................................................................71 
12.7. Records ..........................................................................................................72 
12.8. Quality Control and Quality Assurance .....................................................72 
12.9. Archiving of Data ..........................................................................................73 
12.10. 
Study Funding ................................................................................73 
13. 
REFERENCES .......................................................................................................74 
14. 
APPENDICES ........................................................................................................76 
14.1. Schedule of Events: Main Study (All Subjects) .........................................76 
 
 
14.3. Declaration of Helsinki .................................................................................79 
14.4. Required Elements of Informed Consent ...................................................84 
14.5. Instructions for Calculating Body Mass Index and Surface Area ...........85 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 6 of 91 
14.6. Pharmacokinetic Sample Collection and Processing .................................86 
14.6.1. 
Collection .........................................................................................86 
14.6.2. 
Processing .........................................................................................86 
14.7. Pharmacodynamic Sample Collection and Processing .............................87 
14.7.1. 
Collection .........................................................................................87 
14.7.2. 
Processing .........................................................................................87 
 
14.9. RP103 DOSING INSTRUCTIONS .............................................................90 
14.9.1. 
RP103 DOSE AND FOOD TIMING ............................................90 
14.9.2. 
RP103 DOSING IN FOOD ............................................................90 
14.9.3. 
RP103 DOSING IN LIQUID .........................................................91 
14.9.4. 
ACCEPTABLE/UNACCEPTABLE FOODS AND LIQUIDS ..91 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 7 of 91 
1. 
List of Abbreviations 
 
Abbreviation or Term Definition/Explanation 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase (Serum Glutamic Pyruvic Transaminase) 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AST (SGOT) 
Aspartate aminotransferase (Serum Glutamic Oxaloacetic 
Transaminase) 
AOC 
Area over the curve 
AUC 
Area under the curve 
AUC0-inf 
Area under the curve from time zero to infinity 
AUC0-t 
Area under the curve from time zero to time of the last quantifiable 
concentration 
BCA 
Bicinchoninic acid 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BSA 
Body surface area 
C 
Celsius 
CFR 
Code of Federal Regulations 
CI 
Confidence intervals 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmin 
Minimum concentration 
Cmax 
Maximum concentration 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
dL 
Deciliter 
EC 
Ethics Committee 
EC-Cystagon 
Enteric-coated Cystagon® Capsules 
ECG 
Electrocardiogram 
 
 
ESI 
Electrospray ionization 
FDA 
Food and Drug Administration 
G 
Gram 
HILC 
Hydrophobic interaction liquid chromatography 
HIPAA 
Health Information Portability and Accountability Act of 1996 
h 
Hour 
HPLC 
High pressure liquid chromatography 
ICF 
Informed consent form 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
Kg 
Kilogram 
L 
Liter 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 8 of 91 
Abbreviation or Term Definition/Explanation 
LLOQ 
Lower limit of quantification 
µg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MS 
Mass spectrometry 
OJ 
Orange juice 
OTC 
Over the counter 
Q6H 
Every 6 hours 
Q12H 
Every 12 hours 
QoL 
Quality of Life 
PD 
Pharmacodynamic 
PE 
Physical examination 
PI 
Principal Investigator 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetic 
PMNC 
Polymorphonuclear and polynuclear granulocytes 
PPD 
Pharmaceutical Product Development, Inc. 
RBC 
Red blood cell 
PVDS 
Pharmacovigilance and Drug Safety 
RP103 
Cysteamine Bitartrate Delayed-release Capsules 
SAE 
Serious adverse event 
SD 
Standard deviation 
SGOT (AST) 
Serum glutamic oxaloacetic transaminase 
SGPT (ALT) 
Serum glutamic pyruvic transaminase 
STV 
Study termination visit 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal elimination phase half-life 
Tmax 
Time to maximum concentration 
UCSD 
University of California San Diego 
ULN 
Upper limit of normal 
 
 
WBC 
White blood cell 
WHO-DRL 
World Health Organization-Drug Reference List 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 9 of 91 
2. 
List of Tables and Figures 
 
Table 1: Pharmacodynamic parameters using an inhibitory effect sigmoid Emax 
model for pooled data of WBC cystine response when cysteamine 
was administered orally as Cystagon® and RP103 to patients ......24 
Table 2: Baseline characteristics for all enrolled patients (ITT) and for patients (PP) 
well controlled (WBC < 2 nmol ½ cystine/ mg protein) during all 
periods under Cystagon®. ..................................................................27 
Table 3: Treatment effect as determined by mixed effects model .....................................28 
Table 4: Principal pharmacokinetic parameters for cysteamine after a single dose at 
steady state ...........................................................................................30 
Table 5: PPI use during crossover .....................................................................................31 
Table 6: Number of unique subjects with at least one Serious Adverse Event (SAE) in all 
patients (ITT population) .....................................................................32 
Table 7: Number of AE and SAE Episodes in all patients (ITT population) .............33 
Table 8: Study Drugs .........................................................................................................47 
Table 9: Clinical Laboratory Tests ....................................................................................59 
 
 
Figure 1: Mean plasma levels of cysteamine in patients receiving 450 mg oral single 
doses of Cystagon® and RP103 .........................................................22 
Figure 2: A regression of AUC_D0-12h for RP103 versus AUC_D0-6h for Cystagon® in 
patients following normalization by dose in mg/kg (diamond 
values represent dose at mg/kg) ........................................................23 
Figure 3: Predicted cystine response to oral cysteamine compared to observed 
response using pooled data from patients receiving Cystagon® and 
RP103 with an inhibitory effect sigmoid Emax model ......................25 
Figure 4: Mean cysteamine concentration and WBC cystine level after a single dose 
of Cystagon® (in red) or a single dose of RP103 (in green) in 38 
patients (Per-Protocol population) ...................................................29 
Figure 5: Quantity of absorbed cysteamine (AUC) vs. Food: Fasted [10 hours before – 4 
hours after], Fed 30 m [fasted 10 hours before, normal meal 1/2h after 
dosing], Fed 2 h [fasted 10 hours before, normal meal 2h after dosing], 
Fed high fat / high caloric [HF HC] 0h [meal at dosing time] .............56 
Figure 6: Time to peak of absorbed cysteamine (Tmax) vs. Food: Fasted [10 hours before – 
4 hours after], Fed 30 m [fasted 10 hours before, normal meal 1/2h 
after dosing], Fed 2 h [fasted 10 hours before, normal meal 2h after 
dosing], Fed high fat / high caloric [HF HC] 0h [meal at dosing 
time] .....................................................................................................57 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 10 of 91 
3. 
Study Synopsis 
 
Protocol Title: 
A Long-Term, Open-Label, Safety and Efficacy Study of  Cysteamine 
Bitartrate Delayed-release Capsules (RP103) in Patients with 
Cystinosis 
Sponsor: 
Raptor Pharmaceuticals Inc. 
7 Hamilton Landing 
Suite 100 
Novato, CA 94949  USA 
Project Phase: 
Phase IIIb 
Indication: 
Cystinosis (children and adults). 
Objectives: 
 
Primary Objective: 
 To assess safety and tolerability of long-term repeat dosing of 
RP103 in patients with cystinosis.  
Secondary Objectives: 
 To 
assess 
the 
steady-state 
pharmacokinetics 
(PK) 
and 
pharmacodynamics (PD) of RP103. 
 
 
 
 
Study Design: 
This is a long-term, open-label study of the safety, tolerability and 
steady-state pharmacokinetics and pharmacodynamics of RP103 in 
pediatric and adult patients with cystinosis. Patients who will have 
completed the last visit of the previous phase III Study (RP103-03) will 
be offered the opportunity to enroll in this extension Study. Additional 
patients, who did not complete the RP103-03 study, may be enrolled 
after completion of the analysis of the RP103-03 Study where the non-
inferior efficacious and safe dose of RP103 versus Cystagon® has been 
determined.  
For patients who completed Study RP103-03, study visits will consist 
of: 
 Screening Visit which occurs simultaneously with the RP103-03 
Period 2 Day 7 (End of Study) visit. 
 Monthly Study Visits which are only for patients who completed 
Study RP103-03 and begin within 1 month (± 7 days) after study 
entry.  Each patient will complete a minimum of 6 consecutive 
Monthly visits. 
 Quarterly Study Visits which will commence for each patient ≥ 
1 month and < 4 months after the patient has completed at least 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 11 of 91 
6 consecutive Monthly visits. Each Quarterly visit will take 
place by the middle of the first month (± 7 days) of each calendar 
quarter (i.e., January 15, April 15, July 15 and October 15).  
For patients who did not complete Study RP103-03, study visits will 
consist of: 
 Screening Visit which may occur up to 28 days prior to Day 1. 
 Dose Confirmation Period (Days 1-5) which includes 3 study 
visits over 5 days. 
 Day 1 includes a morning study visit while the patient is 
fasted, with pre-dose blood samples collected for trough 
cysteamine and peak WBC cystine determination while 
the subject is still taking Cystagon®.  RP103 treatment 
regimen begins at the clinic on the morning of Day 1, 
administered Q12H at a starting total daily RP103 dose 
equal to 70% of the Screening total daily Cystagon® 
dose.  Patients will leave the clinic for Days 2-3 and take 
RP103 as instructed.  
 Days 4 and 5 each include a morning study visit; RP103 
Q12H treatment regimen continues. 
 Quarterly Study Visits which will take place by the middle of 
the first month (± 7 days) of each calendar quarter (i.e., January 
15, April 15, July 15 and October 15).  
All patients, including those who did and those who did not complete 
Study RP103-03, will have an End of Study (EOS) Visit conducted 
within 7 (± 2 days) from the last completed study visit or from the date 
of decision to terminate. 
Planned Sample 
Size: 
Up to 60 patients may be enrolled. Initial sample size depends on the 
number of patients entering the Study from the RP103-03 Safety and 
Efficacy Study. Additional patients may be enrolled after all patients 
from Study RP103-03 have completed participation and results 
demonstrate non-inferiority of RP103 versus Cystagon® in reducing 
WBC cystine levels. 
Total Number Of 
Centers: 
Up to 10 sites in North America and Europe 
Selection Criteria: 
Inclusion Criteria: 
 
1. Male and female subjects must have completed the last visit of 
Study RP103-03 and be willing to continue with RP103 
treatment. 
 
OR for patients who did not complete the RP103-03 study:  


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 12 of 91 
 
2. Male and female subject with a documented diagnosis of 
cystinosis. 
3. Subject must be on a stable dose of Cystagon® at least 21 days 
prior to Screening.  
4. [ no longer applicable ] 
5. Within the last 6 months, no clinically significant change from 
normal in liver function tests [i.e., 1.5 times ULN for ALT and 
AST, and/or 1.5 times ULN for total bilirubin] and renal function 
[i.e., estimated GFR (corrected for body surface area)] at 
Screening as determined by the Investigator. 
6. Subject must have an estimated GFR (corrected for body surface 
area) > 30 mL/minute/1.73 m2. 
7. Sexually active female subjects of childbearing potential (i.e., 
not surgically sterile [tubal ligation, hysterectomy, or bilateral 
oophorectomy] or at least 2 years naturally postmenopausal) 
must agree to utilize the same acceptable form of contraception 
from Screening through completion of the Study. The acceptable 
forms of contraception for this Study include hormonal 
contraceptives (oral, implant, transdermal patch, or injection) at 
a stable dose for at least 3 months prior to Screening, barrier 
(spermicidal condom, diaphragm with spermicide), IUD, or a 
partner who has been vasectomized for at least 6 months. For 
pre-pubescent children, a documented attestation of abstinence 
from their parent or guardian will be acceptable. 
8. Subject must be willing and able to comply with the Study 
restrictions and requirements. 
9. Subject or their parent or guardian must provide written 
informed consent and assent (where applicable) prior to 
participation in the Study. 
Exclusion Criteria: 
1. Patients enrolled in the previous Study RP103-03 who did not 
complete their last scheduled study visit or who do not wish to 
continue on treatment with RP103. 
 
AND for patients who did not complete the RP103-03 study: 
 
2. Subjects less than 1 year old. 
3. Subjects with current history of the following conditions or any 
other health issues that make it, in the opinion of the 
Investigator, unsafe for them to participate: 
 Inflammatory bowel disease (if currently active) or prior 
resection of small intestine; 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 13 of 91 
 Heart disease (e.g., myocardial infarction, heart failure, 
unstable arrhythmias, or poorly controlled hypertension) 
90 days prior to Screening; 
 Active bleeding disorder 90 days prior to Screening; 
 History of malignant disease within the last 2 years. 
4. Subject with a hemoglobin level of < 10 g/dL at Screening or, in 
the opinion of the Investigator, a hemoglobin level that would 
make it unsafe for the subject to participate. 
5. [ no longer applicable ] 
6. Subjects with known hypersensitivity to cysteamine and 
penicillamine. 
7. Female subjects who are nursing, planning a pregnancy, known 
or suspected to be pregnant, or with a positive serum pregnancy 
screen. 
8. Subjects who, in the opinion of the Investigator, are not able or 
willing to comply with the protocol. 
Study Drugs: 
RP103: Cysteamine Bitartrate Delayed-release Capsules (75 mg and 
25 mg of cysteamine free-base per capsule). 
Route of 
Administration: 
Oral. 
Study Procedures: 
Initially, only patients who completed Study RP103-03 will be enrolled 
into this long-term study.  Additional patients who did not complete 
Study RP103-03 but qualify for RP103-04 based on current inclusion 
and exclusion criteria may be enrolled after completion of the analysis 
of the RP103-03 Study where the non-inferior efficacious and safe dose 
of RP103 versus Cystagon® has been determined. 
For patients who completed Study RP103-03, study procedures include: 
Screening 
The RP103-04 Screening visit occurs simultaneously with the RP103-
03 Period 2 Day 7 (End of Study) visit.  These patients will continue 
RP103 Q12H treatment at the last dose level prescribed during their 
participation in Study RP103-03. 
Monthly Study Visits 
Study assessments will be made monthly (± 7 days) after study entry 
according to the Schedule of Events. A minimum of six (6) consecutive 
Monthly visits will be completed for each patient. Clinical laboratory 
assessments (hematology, chemistry, urinalysis), physical examination 
(including basic neurological and skin assessments) and vital signs, 
ECG, body weight, body mass index (BMI), body surface area (BSA), 
an Investigator administered 
 
 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 14 of 91 
will be made according to the Schedule of Events. During these visits, 
blood samples for PK (cysteamine) and PD (WBC cystine) will be 
collected 0.5 hour post RP103 dose administered at the clinic.  Patients 
or parents will continue to maintain a daily diary, recording the dose and 
time, of cysteamine medications, proton pump inhibitors (PPI) and other 
gastric acid reducing drugs (prescription and over the counter 
medications). Patients or their parents will return their completed daily 
diary at each scheduled study visit and will receive a new or re-
dispensed daily diary. Concomitant medications and adverse events will 
be collected. 
At or before each Monthly Visit, the Investigator will review available 
safety and PK/PD data and if a patient does not achieve an appropriate 
level of WBC cystine reduction or does not tolerate the dose, the patient 
may have their RP103 dose adjusted or may be terminated from the 
Study. This review will be documented in source and in the CRF as 
appropriate, with the action(s) taken and reasons for such action(s).  
Quarterly Study Visits 
Quarterly visits will commence for each patient ≥ 1 month and < 4 
months after the patient has completed 6 consecutive Monthly visits. 
Each Quarterly visit will take place by the middle of the first month (± 
7 days) of each calendar quarter (i.e., January 15, April 15, July 15 and 
October 15).  Clinical laboratory assessments (hematology, chemistry, 
urinalysis), physical examination (including basic neurological and skin 
assessments), vital signs, ECG, body weight, body mass index (BMI), 
body surface area (BSA), an Investigator administered 
 
 
will be made according to the Schedule of 
Events. During these visits, blood samples for PK (cysteamine) and PD 
(WBC cystine) will be collected 0.5 hour post RP103 dose administered 
at the clinic.  Patients or parents will continue to maintain a daily diary, 
recording the dose and time, of cysteamine medications, proton pump 
inhibitors (PPI) and other gastric acid reducing drugs (prescription and 
over the counter medications). Patients or their parents will return their 
completed daily diary at each scheduled study visit and will receive a 
new or re-dispensed daily diary. Concomitant medications and adverse 
events will be collected. 
At or before each Quarterly Visit, the Investigator will review available 
safety and PK/PD data and if a patient does not achieve an appropriate 
level of WBC cystine reduction or does not tolerate the dose, as 
determined by the Investigator, the patient may have their RP103 dose 
adjusted or may be terminated from the Study. This review will be 
documented in source and in the CRF as appropriate, with the action(s) 
taken and reasons for such action(s). 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 15 of 91 
For patients who did not complete Study RP103-03, study procedures 
include: 
Screening 
The Screening visit may occur up to 28 days prior to Day 1. 
Medical and medication histories and clinical laboratory assessment 
(hematology, chemistry, urinalysis), physical examination (including 
basic neurological and skin assessments)  and vital signs, ECG, body 
weight, body mass index (BMI), body surface area (BSA), adverse 
events determination, concomitant medications, an Investigator 
administered 
 
 
 
 will be 
made according to the Schedule of Events. 
All adult patients or parent or guardian of pediatric patients will begin 
completing a daily diary medication log, recording the dose and time of 
cysteamine medications, proton pump inhibitors (PPI) and other gastric 
acid reducing drugs (prescription and over the counter medications).  
Dose Confirmation Period (Days 1-5) 
This period includes 3 study visits over 5 days: 
Day 1: If this visit is more than 7 days after the Screening date, 
some assessments must be repeated as specified in the Schedule 
of Events.  This is a morning study visit while the patient is 
fasted, with pre-dose (within 15 minutes prior to the first RP103 
dose) blood samples collected for trough cysteamine and peak 
WBC cystine determination while the subject is still taking 
Cystagon®.  RP103 treatment regimen begins at the clinic on the 
morning of Day 1, administered Q12H at a starting RP103 total 
daily dose equal to 70% of the Screening total daily dose of 
Cystagon®.  Subjects will leave the clinic for Days 2-3 and take 
RP103 fasted, as instructed in Sections 9.2 and 14.8. 
Days 4 and 5:  Each day includes a morning visit. 0.5 hour (30 
minute) post-dose blood samples for plasma cysteamine (PK) 
and WBC cystine (PD) determination will be collected.  RP103 
Q12H treatment regimen continues at the starting total daily 
dose.  Once the Investigator receives WBC cystine results for 
the Dose Confirmation Period, an RP103 dose adjustment may 
be prescribed so that it can be implemented before the subject 
returns for their next study visit (Quarterly Visit 1). 
Quarterly Study Visits 
Quarterly visits will take place by the middle of the first month (± 7 
days) of each calendar quarter (i.e., January 15, April 15, July 15 and 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 16 of 91 
October 15).  Clinical laboratory assessments (hematology, chemistry, 
urinalysis), physical examination (including basic neurological and skin 
assessments), vital signs, ECG, body weight, body mass index (BMI), 
body surface area (BSA), an Investigator administered 
 
 
will be made according to the Schedule of 
Events. During these visits, blood samples for PK (cysteamine) and PD 
(WBC cystine) will be collected 0.5 hour post RP103 dose administered 
at the clinic at each scheduled study visit.  Patients or parents will 
continue to maintain a daily diary, recording the dose and time, of 
cysteamine medications, proton pump inhibitors (PPI) and other gastric 
acid reducing drugs (prescription and over the counter medications). 
Patients or their parents will return their completed daily diary at each 
scheduled study visit and will receive a new or re-dispensed daily diary. 
Concomitant medications and adverse events will be collected 
throughout the Study. 
At or before each Quarterly Visit, the Investigator will review available 
safety and PK/PD data and if a patient does not achieve an appropriate 
level of WBC cystine reduction or does not tolerate the dose, as 
determined by the Investigator, the patient may have their RP103 dose 
adjusted or may be terminated from the Study. This review will be 
documented in source and in the CRF as appropriate, with the action(s) 
taken and reasons for such action(s). 
The following study procedures apply to all RP103-04 subjects, whether 
or not they participated in the previous Study RP103-03: 
Study Termination: 
Patients who either complete the Study or terminate the Study early will 
have an End of Study (EOS) visit within 7 days (± 2 days) of their last 
completed study visit.  Clinical laboratory assessments, physical 
examination, vital signs, ECG, 
 
will be performed according to the Schedule 
of Events.   Blood samples for PK (cysteamine) and PD (WBC cystine) 
will be collected 0.5 hour post RP103 dose administered at the clinic. 
For patients who have transitioned back to Cystagon®, PK and PD 
samples will be collected immediately prior to their next Cystagon® 
dose. Adverse events and concomitant medications will be collected.  
 
 
 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 17 of 91 
 
 
Other Study Procedures: 
Females of child-bearing potential will provide a menstrual cycle 
history and be administered a serum pregnancy test at Screening (new 
patients only), and at each scheduled study visit. Height, weight, BMI 
and BSA determination will be performed at each visit according to the 
Schedule of Events. 
Safety Assessments: The following safety parameters will be evaluated: 
 
Clinical laboratory tests; 
 
Vital sign measurements; 
 
Physical examination, basic neurological and skin assessment 
findings; 
 
ECG findings; 
 
Incidence of AEs, SAEs. 
In addition to clinical and laboratory assessments, patient safety will be 
monitored by recording adverse events (AEs) and serious adverse events 
(SAEs) through the Study. Any patient that becomes pregnant during 
the Study will be terminated from the Study and the pregnancy will be 
promptly reported to the Sponsor but will not be considered a SAE.  
If a patient has any clinically significant, Study drug-related 
abnormalities at the conclusion of the End of Study visit, the 
Investigator will determine if the patient has to be followed further. If 
the Investigator determines that a patient has abnormalities that require 
additional monitoring, the patient may be asked to return to the clinic 
until the abnormalities resolve or will be allowed to return home and 
will be followed up by telephone until resolution. 
AEs, whether serious or non-serious, will be followed to resolution to 
the extent possible regardless of whether the patient(s) is (are) still 
participating in the Study. Where appropriate, medical tests and 
examinations will be performed to document resolution of event(s). 
Outcome may be classified as resolved, resolved with sequelae, 
continuing, fatal, or unknown (lost to follow-up). 
 
 
 
 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 18 of 91 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Assessments: 
The following efficacy parameters will be evaluated: 
 0.5 hour post dose cysteamine concentration and WBC cystine 
level. 
Study Endpoints: 
Safety Endpoints: 
 The safety profile of RP103 will be investigated by safety 
reviews conducted by the Investigator at or prior to each 
Monthly or Quarterly visit and through adverse event report 
monitoring (including attribution of treatment-emergent adverse 
events and serious adverse events [SAEs]), physical 
examination (including basic neurological and skin assessment 
findings), vital signs, ECG and clinical laboratory testing as 
outlined in the Schedule of Events. 
Pharmacokinetic Endpoint: 
 The trough plasma cysteamine concentration will be measured 
from samples collected 0.5 hour post dose at each study visit. 
Pharmacodynamic Endpoint: 
 The WBC cystine content will be measured from samples 
collected 0.5 hour post dose at each study visit. 
: 
 
 
  
 
 
Duration of the 
Study: 
Patients will be followed until Study termination; which can occur by 
patient, physician or Sponsor request, or until the RP103 drug is 
available through the appropriate marketing approval, or until the 
Sponsor terminates development of RP103 for this indication for any 
reason.  Approximate treatment time in the Study is up to 96 months. 
However, a subject may withdraw consent or be withdrawn from the 
study prior to completion. 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 19 of 91 
Statistical 
Analyses: 
This Study is designed to assess the long-term safety and tolerability and 
long-term efficacy of RP103 delayed-release cysteamine bitartrate 
capsules in patients with cystinosis.  
Assessment Instruments: 
 
 
  
Other Determinations: 
Demographic and disposition data, Study drug administration, medical 
history, prior and concomitant medications, AEs, clinical laboratory 
measurements, vital signs, ECG measurements and physical 
examination findings will be summarized. Descriptive statistics for 
continuous data will include mean, standard deviation, median, min, 
max. For discrete data counts and percentages in each category will be 
tabulated. Descriptive summaries of mean and mean changes from 
screening will be presented for the safety laboratory parameters 
(hematology, serum chemistry and urinalysis, as applicable), vital signs 
and ECGs. The overall incidence of subjects with adverse events will be 
summarized by System Organ Class (SOC) and Preferred Term (PT) 
using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Summaries by maximum 
severity, drug –relationship (as determined by the investigator) and drug 
discontinuation will also be presented. In addition, summaries of 
annualized exposure adjusted AE rates as well as summaries of the 
incidence of subjects with AEs by study year of onset (Year 1, Year 2 
and Year 3 or later) will be generated. The overall incidence of subjects 
with serious adverse events (SAEs) will be summarized by SOC and PT. 
The annualized exposure adjusted SAE rates as well as the incidence by 
study year will also be tabulated. Safety laboratory values outside 
reference ranges will be flagged in laboratory listings. 
Non-parametric tests will be used to compare mean 
 
 
domains and summary component scores over time between Screening 
and last acquired assessment. Trends in gastric acid reducing 
medications (prescription and OTC) and 
 
 
 
 
 
 
 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 20 of 91 
4. 
Introduction 
 
4.1. 
Investigational Agent 
 
Cysteamine Bitartrate Delayed-release Capsules (RP103) are a beaded, enteric-coated, 
delayed-release form of the bitartrate salt of cysteamine (an aminothiol, β-
mercaptoethylamine), the microspheronized beads  are further hard gelatin 
encapsulated and intended for oral administration. Cysteamine Bitartrate Delayed-
release Capsules (RP103) will be available for use in this Study in 25 mg and 75 mg 
capsules (expressed as cysteamine free-base).   
 
4.2. 
Background 
 
Cystinosis is an autosomal recessive inborn error of metabolism in which the transport 
of cystine out of lysosomes is reduced or absent.  Cystinosis is a rare disease 
characterized by the accumulation of cystine and formation of crystals damaging 
various organs, especially the kidney, leading to renal tubular Fanconi Syndrome and 
progressive glomerular failure, with end stage renal failure by the end of the first decade 
of life. In four studies of cystinosis patients before cysteamine was available, renal 
death (need for transplant or dialysis) occurred at median age of less than 10 years 
(Cystagon® Package Insert, 2007). Patients with cystinosis also experience growth 
failure, rickets, and photophobia due to cystine deposits in the cornea. With time, most 
organs are damaged, including the retina, muscles and central nervous system 
(Cystagon® Package Insert, 2007). Cysteamine is an aminothiol that reacts within 
lysosomes resulting in a thiol-disulfide interchange reaction that converts cystine into 
cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome 
in patients with cystinosis (Cystagon® Package Insert, 2007). 
 
Cystinosis currently affects approximately 500 people in the United States and 800 in 
Europe.  Children with the disorder, if untreated, suffer progressive kidney failure, 
damage to multiple organs and a failure to grow to normal height.  Most children who 
suffer this condition undergo kidney transplantation, typically in the first decade of life 
(Gahl, Balog et al. 2007). Cystagon® capsules contain cysteamine bitartrate, a cystine-
depleting agent, which needs to be administered every 6 hours (Q6H) around the clock. 
This regimen has been associated with poor adherence. There is evidence that such 
failure to adhere to the strict Q6H dosing regimen results in more rapid deterioration of 
kidney function (Kleta, Bernardini et al. 2004) and the need for earlier hemodialysis 
and kidney transplantation in poorer adherent patients. 
 
Cysteamine is moderately bound to human plasma proteins, predominantly to albumin, 
with mean protein binding of about 52%.  Plasma protein binding is independent of 
concentration over the concentration range achieved clinically with the recommended 
doses (Cystagon® Package Insert, 2007). 
 
The pharmacokinetics and pharmacodynamics of Cystagon® were studied in eleven 
pediatric patients with nephropathic cystinosis who received 225 to 550 mg of 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 21 of 91 
cysteamine bitartrate every 6 hours daily for more than one year.  Following repeated 
oral administration of 225 to 550 mg cysteamine bitartrate, the mean time to maximum 
plasma concentration (Tmax) occurred at about 1.4 hours post dose with mean steady-
state peak plasma concentration (Cmax) and area under the concentration-time curve 
(AUC) of 2.6 μg/mL and 6.3 μg·hr/mL, respectively. The apparent volume of 
distribution (V/F) and apparent plasma clearance (Cl/F) of cysteamine were 156 L and 
1.2 L/min, respectively (Belldina, Huang et al. 2003). 
 
 
4.2.1. Study RP103-01 
 
A first pilot study (i.e., Study RP103-01) was completed in order to assess the 
pharmacokinetics (i.e., Cmax and Tmax), pharmacodynamics (i.e., WBC cystine levels), 
safety and tolerability of Cysteamine Bitartrate Delayed-release Capsules (RP103) 
compared to Cystagon® in 9 patients with cystinosis.  All 9 subjects (7 males, 2 
females) that enrolled into the RP103-01 Study completed treatment.  The average age 
and weight of the subjects was 12.8 (4.76) years and 36.83 (9.174) kg, respectively. 
 
There were a total of 27 AEs reported, of which 9/27 (33.3%) were considered possibly 
or probably related to study drug. Twenty-five (25) of 27 (92.6 %) of AEs were mild 
in intensity.  There was 1/27 (3.7%) moderate (abdominal pain) and 1/27 (3.7%) severe 
(hypokalemia) judged not related and unlikely related (respectively) to study drug. 
Eight (8) of 9 (88.9%) subjects experienced at least one treatment-emergent adverse 
event (AE). The most common AEs were thirstiness (8/27, 29.6%), vomiting (6/27, 
22.2%), nausea (3/27, 11.1%) and constipation (2/27, 7.4%), and are consistent with 
cystinosis patients receiving cysteamine treatment.  There were no study 
discontinuations due to an adverse event and no SAEs reported during the study. 
 
The individual results of the non-compartmental analysis show that the 
pharmacokinetics of RP103 is consistent with a delayed-release formulation 
demonstrating a later Tmax (i.e., 2.78 ± 1.56 and 1.22 ± 0.51 hours for RP103 and 
Cystagon®, respectively) and a longer half-life (5.85 ± 2.89 and 1.90 ± 0.58 hours for 
RP103 and Cystagon®, respectively, although the difference in half-lives might have 
been amplified due to truncated pharmacokinetic (PK) measurements, i.e. 0 to 6 hours 
for Cystagon® and 0 to 12 hours for RP103.   The Cmax for RP103 (33.06 ± 18.22 
µmol/L) was also lower than the corresponding value for Cystagon® (42.02 ± 21.49 
µmol/L).  The plasma levels of cysteamine, determined at the end of a 12 hour dosing 
interval for RP103, were also considerably higher (2.89 ± 1.47 µmol/L) than those 
predicted for an equivalent dose of Cystagon® (~0.5 µmol/L) at 12 hours after dosing, 
based on its observed half-life.  The AUC0-12h for RP103 was substantially lower than 
that for Cystagon® (118.2 ± 54.6 and 211.9 ± 124.6 µmol*h/L, respectively); recall that 
twice the Cystagon® dose is required to provide 12 hour coverage. However, the AUC∞ 
for equivalent doses of both products were similar (~120-150 µmol*h/L) suggesting 
that there was still exposure to cysteamine after 12 hours for RP103. 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 22 of 91 
Following normalization to a 450 mg dose, the maximum plasma levels, AUC0-6h and 
AUC0-12h (calculated directly from the plasma level data for RP103 and from doubling 
the AUC0-6h value for Cystagon® to represent two doses) were lower for RP103 (27.70 
± 14.99 µmol/L, 75.93 ± 39.22 µmol*h/L and 99.26 ± 44.21 µmol*h/L respectively) 
than for Cystagon® (37.72 ± 12.10 µmol/L, 96.00 ± 37.81 µmol*h/L and 192.00 ± 
75.62 µmol*h/L respectively). The dose normalized AUC∞, however, was slightly 
higher for RP103 compared to Cystagon® (120.29 ± 50.06 and 107.35 ± 38.21 
µmol*h/L for RP103 and Cystagon®, respectively) and this appeared to be largely due 
to the apparent longer half-life of RP103 (5.85 ± 2.89 h) compared to Cystagon® (1.90 
± 0.58 h).  It was also noteworthy that the Tmax for RP103 (2.78 ± 1.56 h) occurred later 
than for Cystagon® (1.22 ± 0.51 h) and as shown in Figure 1 for averaged data. 
 
 
Figure 1: Mean plasma levels of cysteamine in patients receiving 450 mg oral 
single doses of Cystagon® and RP103 
 
A regression of the AUC0-12h normalized by dose in mg/kg (AUC_D0-12h) for RP103 
versus AUC0-6h normalized by dose in mg/kg (AUC_D0-6h) for Cystagon® (Figure 2) 
suggests a linear relationship with a slope of 1.4136. Thus, to achieve an equivalent 
exposure of cysteamine over a 12 hour dosing interval as measured by AUC0-12h, a 
single dose of RP103 will have to be equal to 2/1.4136 = 1.4148 times a single dose of 
Cystagon®, which corresponds to a daily dose of RP103 equal to 70% of a daily dose 
of Cystagon®. As it can also be seen on this Figure 2 when using the administered dose 
of Cystagon® for relating to individual AUCs, there is a poor correlation between dose 


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Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
Page 26 of 91 
Pharmacokinetic (cysteamine) and pharmacodynamic (WBC cystine) profiles after 
RP103 over 12 hours were comparable to PK and PD profiles after Cystagon® over 6 
hours. There were no unexpected side effects compared to using Cystagon® and all 
patients who regularly used PPIs or antacid medication while under Cystagon® but one, 
were able to discontinue regular concomitant PPI or antacid medications while under 
RP103, which might account for the higher proportion of reported gastro-intestinal (GI) 
adverse events under RP103 vs. Cystagon®.  
Patient Characteristics 
Forty-three patients were randomized. Thirty-eight patients were included in the 
primary efficacy analysis, as defined beforehand in the statistical analysis plan. 
 
The Intent-To-Treat (ITT) population has 5 more patients than the Per-Protocol (PP) 
population: 1) two siblings withdrew from the study because one of them had pre-study 
planned orthopedic surgery, unrelated to disease or treatment, and the family decided 
to withdraw both children related to travel difficulties;  2) three subjects had a 3-day 
average WBC cystine level > 2 nmol ½ cystine/mg protein during one of the periods 
under Cystagon® and could not therefore be considered as well controlled under 
Cystagon®, as pre-specified the Statistical Analysis Plan.  Patients were mostly 
children, male or female, with an average age of almost 12 years old. 
 
The first initiated US center enrolled slightly more patients than the other sites that 
were initiated afterwards. Seven patients were screened twice because the first time 
their WBC cystine level > 1 nmol ½ cystine/mg protein and had therefore to be 
terminated early. They came back after an amendment to the protocol modified this 
limit and allowed six of these patients with < 2 nmol ½ cystine/mg protein to be 
enrolled.  Baseline characteristics are summarized in Table 2. 
 


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IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
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ITT: Intent-To-Treat 
PP: Per Protocol 
N 
43 
38 
Age (year) 
11.7 ± 4.2 
11.9 ± 4.4 
Children (2 < age <= 12) 
27 
25 
Adolescents (12 < age <= 
21) 
15 
15 
Adults (>21) 
1 
1 
Male (n / %) 
24 / 56 % 
22 / 58 % 
Height (cm) 
139.5 ± 18.9 
139.1 ± 19.1 
Weight (kg) 
36.0 ± 14.2 
34.5 ± 12.1 
Body Mass Index (kg/m2) 
17.8 ± 2.8 
17.2 ± 2.1 
Body Surface Area (m2) 
1.17 ± 0.30 
1.14 ± 0.28 
Daily Cystagon® Dose (mg) 
1,849 ± 536 
1,801 ± 511 
Daily Cystagon® Dose 
(mg/kg) 
55.8 ± 15.2 
56.5 ± 14.6 
WBC Cystine 
(nmol ½ cystine/ mg 
protein) 
  
0.63 ± 0.31 
WBC Cystine 
< 1 nmol ½ cystine/ mg 
protein 
  
33 (87%) 
 
Table 2: Baseline characteristics for all enrolled patients (ITT) and for patients 
(PP) well controlled (WBC < 2 nmol ½ cystine/ mg protein) during all periods 
under Cystagon®. 
 
Primary Outcome, WBC cystine levels 
The average peak WBC cystine level (LS mean ± SE) measured in the Per-Protocol 
population of patients treated with Cystagon® was 0.54 ± 0.05 nmol ½ cystine/mg 
protein, compared to an average peak value of 0.62 ± 0.05 nmol ½ cystine/mg protein 
for patients treated with RP103. The mean difference was 0.08 nmol ½ cystine/mg 
protein, with a 95.8% confidence interval of 0.00-0.16 (α=0.02104). This 0.16 upper 
end of the confidence interval was far lower than the 0.3 non-inferiority limit agreed a 
priori with FDA, determining that the study with RP103 achieved the non-inferiority 
endpoint. Table 3 summarizes the results of the mixed effects model regarding 
treatment effect on peak WBC cystine level. Based on the pre-hoc non-inferiority 
margin of 0.3, the new delayed-release, gastroresistant Q12H formulation of 
cysteamine bitartrate, RP103, was not inferior to the marketed immediate release Q6H 


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IND 103,694: Study RP103-04 
 
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formulation of cysteamine bitartrate, Cystagon®, in maintaining low WBC cystine 
levels in patients with cystinosis. 
 
Note: The same analysis in the ITT population with the inclusion of the 3 not-well-
controlled patients under Cystagon® (i.e. who had a WBC cystine > 2 nmol 
½ cystine/mg protein during the Cystagon® periods of the crossover) would have led to 
the conclusion that RP103 was not only non-inferior but also superior to Cystagon® 
with a difference of -0.27 ± 0.36, this mean difference RP103-Cystagon® being far in 
favor of RP103 and an upper limit of the 95.8% CI even lower (0.09 instead of 0.16) 
than in the PP population. 
 
Per-Protocol (PP) Population  (N=38) 
WBC Cystine (LS Mean) 
in mg ½ cystine/mg protein 
0.54 ± 0.05 
0.62 ± 0.05 
Treatment Effect 
(LS Mean ± SE;  95% CI) 
0.08 ± 0.04;  0 to 0.16 
Intent-to-Treat (ITT) Population  (N=41) 
WBC Cystine (LS Mean) 
in mg ½ cystine/mg protein 
0.97 ± 0.19 
0.70 ± 0.19 
Treatment Effect 
(LS Mean ± SE; 95% CI) 
-0.27 ± 0.36;  -0.63 ± 0.09 
 
Table 3: Treatment effect as determined by mixed effects model 
 
Additionally, the endpoint was achieved at a lower average daily dose of RP103, 
compared to Cystagon®. Patients enrolled in the study were required to be “well 
controlled” under the existing Cystagon® therapy. The starting dose of RP103 for 
patients was initially set at 70% of their established dose of Cystagon®. The protocol 
allowed for a single RP103 dose increase of 20-25%, based on intermediate WBC 
cystine results, to reflect the current standard of care in establishing appropriate dosing 
of Cystagon® in cystinosis patients. Approximately one-third of patients who started at 
70% remained at 70% of their starting Cystagon® dose throughout the study. The 
remaining two-thirds of these patients had their RP103 dose increased. On average, the 
total daily, steady-state dose of RP103 in patients in the Phase 3 clinical trial was 82% 
of their established, incoming dose of Cystagon®. Of 9 patients who started the study, 
following a protocol amendment, at 80% of their starting Cystagon® dose, one needed 
to have his daily dose of RP103 increased from 80% to 100% of the regular daily dose 
of Cystagon®. 
 
This treatment effect on peak WBC cystine levels is further confirmed by 
pharmacokinetic and pharmacodynamic profiles over 6 hours after a morning dose of 
Cystagon® and over 12 hours after a morning dose of RP103, dosed at a lower to 
equivalent daily dose (70% to 100%) (see Figure 4). Patients at 90% were however 
treated at this level of dose not for longer than 5-8 days before final PK/PD evaluation 


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IND 103,694: Study RP103-04 
 
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instead of 3 weeks, (and the recommended dose increase was not executed at all for 2 
of the patients prior to endpoint analysis, even though their reported dose reflects the 
adjustment to 90%).  A slower absorption of cysteamine due to the delayed release 
formulation RP103 drives the pharmacokinetics and leads to a similar peak of 
cysteamine as after Cystagon® but with a prolonged plateau. 
 
Figure 4: Mean cysteamine concentration and WBC cystine level after a single 
dose of Cystagon® (in red) or a single dose of RP103 (in green) in 38 patients (Per-
Protocol population) 
 
Pharmacokinetic Analysis 
Mean values for principal cysteamine PK parameters after one dose under steady-
state treatment with Cystagon® or RP103, peak plasma concentration Cmax, area under 
the concentration-time curve over 6 hours AUC0-6h for Cystagon® and 12 hours AUC0-
12h for RP103, Tmax, terminal elimination half-life t½, apparent plasma clearance Cl/F 
and apparent volume of distribution Vd/F are listed in Table 4. Since every patient 
was regularly treated with a different dose of Cystagon® as determined before 
enrollment by their level of WBC cystine, dose-adjusted AUCinf D was also 
calculated. 
 
PK parameters for Cystagon® are consistent with what is described in the Cystagon® 
Package Insert: Cmax = 2.6 mg/L, total exposure AUC0-6h = 378 min*mg/L, Tmax = 96 
min, Cl/F = 1.2 L/min and apparent volume of distribution Vd/F = 156 L. 
 
PK parameters for RP103 are consistent with what was observed in the first pilot 
RP103-01 study. As expected, since RP103 is a delayed-released formulation of the 
same compound, cysteamine bitartrate, as Cystagon®, Tmax = 187 ± 89 min for RP103 


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is significantly longer than Tmax = 72 ± 31 min for Cystagon®, but the apparent plasma 
clearances are similar, Cl/F = 1.33 ± 0.50 L/min for Cystagon® vs. Cl/F = 1.11 ± 0.58 
L/min for RP103. 
 
 
Cystagon® 
RP103 
CMAX (mg) 
2.73 ± 1.36 
3.70 ± 1.72 
TMAX (min) 
72 ± 31 
187 ± 89 
AUC0-12H (min*mg/L) 
357 ± 150 
739 ± 334 
T½ (min) 
90 ± 23 
254 ± 408 
Cl/F (L/min) 
1.33 ± 0.50 
1.11 ± 0.58 
Vd/F (L) 
180 ± 112 
356 ± 376 
AUCINF_D (min*mg/L) 
0.85 ± 0.30 
1.05  ± 0.45 
 
Table 4: Principal pharmacokinetic parameters for cysteamine after a single 
dose at steady state 
 
However, in order to provide further PK comparison between Cystagon® and RP103, 
it is important to remember that all the patients except one under RP103 received a 
lower daily dose than their corresponding dose of Cystagon® (most of the patients 
switched from 100% Cystagon® daily dose to 70% RP103 daily dose, with some who 
had their RP103 dose increased by 25%, and a few patients switched from 100% 
Cystagon® daily dose to 80% RP103 daily dose, with only one who had the RP103 dose 
increased to 100%, this in order to maintain a comparable WBC cystine level). This 
total daily dose is divided in 4 equal doses given 4 times a day for Cystagon® but 
divided in only 2 equal doses given 2 times a day for RP103. 
 
 


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IND 103,694: Study RP103-04 
 
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As for standard of care with Cystagon®, the long-term treatment dose of RP103 to use 
for every patient will ultimately be determined by the peak WBC cystine level, as a 
resultant combination of PK and PD effect. Based on the present results, the authors 
would recommend that patients already well controlled under a stable daily dose of 
Cystagon®, be switched to an initial RP103 total daily dose equal to 70% of the (Q6H) 
total daily dose of Cystagon®.  If deemed necessary based on subsequent WBC cystine 
measurements, the RP103 dose could be titrated up in 10% increments to reach an 
optimal, steady-state dose. 
 
Anti-acid Medications 
Eighteen (47%) of the thirty eight per-protocol patients in the study took proton pump 
inhibitors (PPIs) due to side effects from Cystagon®. Fifteen (39%) of these thirty eight 
patients were even on prophylactic PPI use coming into the study and/or during the 
Cystagon® treatment arm, meaning taking at least 1 PPI once per day. 5 patients, or 
13% of total, took PPIs at some point during the RP103 treatment arm.  Of these, 4 
patients (11% of total) took PPIs not more than 3 times in the 3-week RP103 treatment 
arm. One patient (3% of total) took PPIs frequently during the RP103 treatment 
arm.  This same patient took PPIs frequently during the Cystagon® treatment arm. One 
patient (3% of total) took PPIs on the RP103 treatment arm but not on the Cystagon 
treatment arm.  This patient took PPIs not more than 3 times during the 3-week RP103 
treatment arm. 
 
Overall, PPIs were taken 453 times during the Cystagon® treatment period vs. 58 times 
during the RP103 treatment period.  That is an 87% reduction in PPI use during 
identical time periods.  If the one patient who took PPIs frequently on both RP103 and 
Cystagon® is excluded, then the reduction in PPI use was 98% (Table 5) 
 
 
Number of pills / 
Number of patients Cystagon RP103 
Period 1 
233 / 11  
51 / 2 * 
Period 2 
220 / 7 * 
7 / 3  
Total 
453 / 18  
58 / 5 
* Only one patient used PPIs regularly during RP103 treatment (50 pills): 
(182/6) and (1/1) = > 98% reduction 
Table 5: PPI use during crossover 
 
Safety Results 
There was no unexpected serious adverse event (SAE) either under RP103 or under 
Cystagon®. More patients experienced at least one SAE under RP103 than under 
Cystagon® (respectively 6 vs. 1) but only one SAE under RP103 was considered by the 
Principal Investigator (PI) as possibly related to cysteamine treatment (Table 6). This 




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IND 103,694: Study RP103-04 
 
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MedDRA System Organ 
Class 
2-week 
Run-In 
(Cystagon®) 
3-week 
Crossover 
(Cystagon®) 
3-week 
Crossover 
(RP103) 
Both 
Crossover 
Periods 
Number of ITT patients at risk 
43 
41 
43 
41 
Number of AE Episodes 
17 
26 
75 
18 
 
Related 
Not 
Related 
Not 
Related 
Not 
Related 
Not 
Gastrointestinal disorders 
1 
4 
8 
3 
24 
10 
5 
4 
Metabolism and nutrition 
disorders 
0 
0 
1 
4 
0 
3 
1 
1 
Nervous system disorders 
0 
2 
0 
1 
2 
4 
0 
2 
Cardiac disorders 
0 
0 
0 
3 
0 
1 
1 
0 
General disorders and 
administration site conditions 
0 
0 
0 
0 
1 
2 
0 
1 
Infections and infestations 
0 
3 
0 
1 
0 
3 
0 
0 
Renal and urinary disorders 
0 
0 
0 
1 
1 
1 
1 
0 
Skin and subcutaneous tissue 
disorders 
0 
0 
0 
1 
1 
1 
0 
1 
Vascular disorders 
0 
1 
0 
1 
1 
2 
0 
1 
Musculoskeletal and 
connective tissue disorders 
0 
0 
0 
0 
0 
2 
0 
1 
Respiratory, thoracic and 
mediastinal disorders 
0 
5 
0 
2 
0 
5 
0 
0 
Injury, poisoning and 
procedural complications 
0 
1 
0 
0 
0 
3 
0 
0 
Investigations 
0 
0 
0 
0 
0 
1 
0 
1 
Ear and labyrinth disorders 
0 
0 
0 
0 
0 
0 
0 
1 
Eye disorders 
0 
0 
0 
0 
0 
0 
0 
1 
Psychiatric disorders 
0 
0 
0 
0 
0 
1 
0 
0 
Note: Any AE starting and resolving in one of the 3 periods Run-In, Cross-Over Period 1 and Cross-
Over Period 2 would be counted once for that period. Any AE starting in the Run-In and resolving in the 
Cross-Over period 1 would be counted once in both periods. Any AE starting either in the Run-In or in 
the Cross-Over treatment period 1 and resolving in the Cross-Over treatment period 2,would be counted 
once in the 'Both Cross-Over periods' column. 
 
Table 7: Number of AE and SAE Episodes in all patients (ITT population) 
 
There was no difference in terms of changes under treatment for clinical laboratory 
parameters between Cystagon® and RP103 during the trial. 
 
4.2.3. Study RP103-02 
 
This was a single center, bioequivalence, open-label, randomized, 2-period, 2-
sequence, crossover study. The objective of this study was to compare the rate and 
extent of absorption of two different modes of administration of Cysteamine Bitartrate 
Delayed-release Capsules (RP103) following a single dose of 600 mg administered 
under fed conditions. The two modes of administration were: 1) intact delayed-release 
capsules and 2) content of opened delayed-release capsules mixed with applesauce. 
Due to well-known very variable bioavailability of cysteamine (Dohil, Fidler et al. 


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IND 103,694: Study RP103-04 
 
Amendment 9:  18 November 2015 
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2006), a sequential design that incorporated an interim analysis after completion of 
Stage 1 was planned. If bioequivalence was concluded at that time, then the study 
would have been stopped. The study would also have been stopped if the ratio A/B for 
AUC0-inf, AUC0-t, or Cmax was outside the 80.00% to 125.00% boundaries. Otherwise, 
the study would proceed to Stage 2 with 20 additional subjects.  
 
The pharmacokinetic (PK) parameters could not be accurately estimated following 
Stage 1 due to low blood concentrations of cysteamine. There appeared to be a lag time 
for absorption of intact capsules, as the majority of subjects did not have detectable 
levels of cysteamine until 6 hours after dosing, whereas more than half the subjects had 
detectable concentrations of cysteamine within 1 hour of dosing in the opened capsules 
treatment. Overall, approximately 40% of the plasma cysteamine concentrations 
between 0.5 and 12 hours were below the limit of quantitation for the opened capsules 
treatment and 72% were below the limit of quantitation for the intact capsules 
treatment. Therefore, the study was stopped after Stage 1 and the protocol was amended 
to include Stage 3. For Stage 3, four subjects already enrolled in Stage 1 were retested 
following the same procedures for intact capsules, but under fasted conditions. Stage 3 
was conducted at the same clinical site as Stage 1, and the same protocol requirements 
and procedures were followed. A comparison of PK parameters obtained in the subset 
(n=4) of subjects who received the intact capsules treatment in fed and fasted states 
showed more rapid drug absorption under fasted conditions (median Tmax of 3.25 hours 
versus 6.0 hours for fasted versus fed treatment). Mean Cmax was approximately 1.8-
fold higher and mean AUC was 1.6-fold higher for fasted as compared to fed subjects. 
Half-life was approximately 2.30 hours for both treatments. The study was stopped 
following Stage 3. 
 
There were no deaths or severe adverse events reported in subjects who received single 
doses of RP103. No subjects were withdrawn from the study due to adverse events. 
 
4.2.4. Study RP103-05 
 
The objective of this study was to compare the rate and extent of absorption of two 
different modes of administration of cysteamine bitartrate delayed-release capsules 
(RP103) following a single dose of 600 mg administered under fasted conditions.  The 
two modes of administration were: 1) intact delayed-release capsules and 2) content of 
opened delayed-release capsules. 
 
 
 
 
 
Concentration data for 19 of 20 subjects who received active drug was included in the 
BE analysis in Periods 1 and 2.  One subject was excluded from the study following 
Period 1 and 1 subject was excluded just prior to Period 3 due to an AE. 
 
The rate and extent of absorption, as measured by AUC, Cmax, and Tmax, was similar 


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for both the opened and intact capsule treatments when administered under fasted 
conditions. All estimates of the ratios for the parameters AUC(0-t), AUC(0-inf), and 
Cmax were near 1.00, and the 94.12% confidence intervals for all comparisons were 
within the acceptance range for bioequivalence of 0.80 - 1.25, and there were no 
significant sequence or period effects observed. 
 
Parallel-Group Meal Delay Period 3 
The number of subjects in each of the 4 meal delay treatment groups ranged from 3 to 
5 subjects each. A decreased rate and extent of absorption was observed for both the 
opened and intact capsule treatments when a meal was administered 30 minutes 
following drug administration compared to fasted conditions. There appeared to be no 
difference in AUC or Cmax between the 2 hour meal, compared with fasted conditions 
for the opened capsules treatment and for the intact capsules treatment. 
 
No statistically significant treatment differences were found among the 4 meal delay 
treatment groups, however, this finding may be attributed to the small sample sizes of 
the meal delay groups. 
 
Safety Results 
There were a total of 19 AEs reported during the crossover BE portion of the study 
(Periods 1 and 2). One subject in each treatment group was withdrawn from the study 
due to an AE prior to Period 3. 
 
The most frequently reported AEs in the crossover BE portion of the study were in the 
gastrointestinal (GI) disorders SOC. Gastrointestinal disorders were reported in 5 of 20 
subjects (25.0%) in the opened capsule group and 3 of 19 subjects (15.8%) in the intact 
capsule group. The GI events were primarily single episodes of nausea and abdominal 
pain. One subject reported a short episode of diarrhea at approximately 64 hours 
following dosing in Period 1, and no subjects vomited. Seventeen out of 19 AEs in the 
crossover BE portion of the study were considered possibly or probably related to the 
study drug by the Investigator. 
 
The most frequently reported AEs in the meal delay portion of the study were in the 
gastrointestinal (GI) disorders SOC. Gastrointestinal disorders were reported in 9 of 17 
(52.9%) of the subjects in the meal delay portion of the study and were observed more 
frequently in subjects who consumed their meal 2 hours after dosing than in subjects 
in the 30 minute meal groups. Three of 4 subjects (75.0%) in the opened capsule/2 hour 
meal delay group (AM2) experienced GI AEs and 4 of 5 subjects (80.0%) in the intact 
capsule/2 hour meal delay group (BM2) experienced GI AEs. One subject each in the 
30 minute meal delay groups experienced GI AEs. Four subjects (23.5%) vomited 
during the meal delay portion of the study, and 3 of the 4 subjects experienced vomiting 
following the 2-hour meal delay. One subject experienced severe stomach ache, 
headache and shakiness, and another experienced severe nausea.  Treatment with 
ondansetron, loperamide and IV fluids were given for multiple events of vomiting or 
diarrhea in 2 subjects. The majority of the events began between 2 and 4 hours after 
dosing. Thirty-five out of 36 AEs in the crossover BE portion of the study were 


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considered possibly or probably related to the study drug by the Investigator. 
 
There were no significant changes in clinical safety laboratory results, vital signs or 
ECGs. 
 
4.2.5. Study RP103-06 
 
Study RP103-06 was designed to demonstrate bioequivalence (BE) between oral 
administration of intact RP103 capsules with orange juice, and contents of opened 
capsules mixed with applesauce, taken orally.  This was a single-center, open-label, 
randomized, 2 period, 2 sequence, crossover BE study.  The design is identical to the 
previous BE study (RP103-05) with one exception:  Treatment A (intact capsules) was 
administered with acidic juice, while Treatment B (capsule contents) was again 
sprinkled in a small amount of applesauce. 
 
The outcome of Study RP103-06 was the same as for the previous BE Study RP103-
05:  The rate and extent of absorption, as measured by AUC, Cmax and Tmax, were 
similar for the intact and opened capsule treatments when administered under fasted 
conditions. 
 
4.2.6. Study RP103-HLTA-009 
 
 
4.3. 
Risk/Benefits 
 
Cystagon® (cysteamine bitartrate) is a cystine-depleting agent that is the only cystinosis 
treatment approved by FDA. Cystagon® is indicated for the management of 
nephropathic cystinosis in children and adults. Cystagon® is contraindicated in patients 
who have developed hypersensitivity to it or to cysteamine or penicillamine 
(Cystagon® Package Insert, 2007). 
 
The most common adverse events (> 5%) associated with cysteamine were vomiting 
35%, anorexia 31%, fever 22%, diarrhea 16%, lethargy 11%, and rash 7% (Cystagon® 
Package Insert, 2007). Less common adverse events associated with cysteamine 
include: CNS symptoms such as seizures, dizziness, lethargy, somnolence, depression, 
and encephalopathy; gastrointestinal tract symptoms including nausea, vomiting, 
anorexia and abdominal pain, sometimes severe. In addition, gastrointestinal ulceration 
and bleeding have been reported in patients on cysteamine therapy. Cysteamine has 
occasionally been associated with reversible leucopenia, abnormal liver function 
studies, skin lesions, headache, tinnitus, diplopia, blurry vision, loss of vision, pain 
behind the eye or pain with eye movement (Cystagon® Package Insert, 2007). 
 
Patient adherence with Cystagon® is challenging due to significant adverse effects, 
dosing frequency, and the need for life-long treatment from the age of diagnosis. Since 
Cystagon® must be taken Q6H around the clock; patients must be awakened in the 
middle of the night to take their medication in order to maintain adequate white blood 


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cell cystine levels. One recent study demonstrated that only about 25% (5 of 22) of 
patients were actually adhering to with the Q6H regimen (Levtchenko, van Dael et al. 
2006). A Q6H dosing schedule must be maintained for the rest of the patient’s life, 
therefore preventing patients and / or their caregivers from obtaining a full night’s 
sleep. Many of these patients are in their formative years where sleep plays a major 
role in patient well-being and overall health. A change from Q6H to Q12H is not merely 
for patient convenience, as the Q6H dosing must be adhered to for an entire lifetime, 
there is evidence that failure to adhere to this strict Q6H dosing regimen results in rapid 
deterioration of kidney function (Kleta, Bernardini et al. 2004). Thus, improved patient 
adherence will ultimately delay the time to kidney failure or the morbidity and mortality 
associated with renal replacement therapy such as dialysis or transplant, and hence 
greatly improves both the patient’s quality and quantity of life. 
 
Patients successfully completing the RP103-03 Study will be offered the opportunity 
to participate in this Study (i.e., Study RP103-04). 
 
4.4. 
Dose Rationale 
 
According to results obtained from Study RP103-01, it was predicted that RP103 
should be administered twice a day, where the total daily RP103 dose is 70% of the 
patient’s total daily Cystagon® dose (see Section 4.2). Furthermore, in the RP103-01 
study, a dose of RP103 up to 167% of the entry level total daily Cystagon® dose has 
been studied and RP103 has been found to be safe and well-tolerated. 
 
Patients completing RP103-03 and entering this Study will have received a stable dose 
of either RP103 or Cystagon® prior to Screening. Patients will continue to receive their 
Q12H RP103 dose as determined in the phase III Study (RP103-03). Patients that did 
not complete the RP103-03 study but qualify for the study based on the inclusion and 
exclusion criteria, may be enrolled after completion of the analysis of the RP103-03 
Study where the non-inferior efficacious and safe dose of RP103 versus Cystagon® has 
been determined. Patients that did not complete the RP103-03 study must be receiving 
a stable dose of Cystagon® prior to study entry and will have a starting Q12H RP103 
dose at a total daily dose which is 70% of their total daily stable Cystagon® dose, 
administered twice a day. 
 
If a subject does not achieve a meaningful reduction of WBC cystine level i.e., < 1 
nmol ½ cystine/mg protein (see below for a discussion of this limit) or does not tolerate 
the dose, as determined by the Investigator, the subject may have their RP103 dose 
adjusted or may be terminated from the Study.  
 
4.5. 
Study Rationale 
 
Accurate measurements of intracellular cystine content are mandatory for the diagnosis 
and for the monitoring of the effects of cysteamine treatment. There are two 
components to the measurement, that for cystine content, and that for indexing the 
cystine content to the protein level of the cells in which it is measured.  


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Several methods have been developed to measure cystine content in leucocytes. They 
differ according to the type of cells used. Historically, cystine has been measured in 
mixed leucocyte preparations, despite the fact that it accumulates preferentially in 
polymorphonuclear granulocytes (PMNC). 
 
Normal subjects have PMNC cystine levels lower than 0.25 nmol ½ cystine/mg 
protein.  The diagnosis of cystinosis is confirmed when the PMNC cystine levels are > 
2 nmol ½ cystine/mg protein.  
 
Cystinosis is treated specifically using cysteamine to reduce intracellular cystine levels. 
Following early publications (Thoene, Oshima et al. 1976), it was thought that the 
PMNC cystine level should be maintained lower than 2 nmol ½ cystine/mg protein for 
the treatment of cystinosis with cysteamine to be effective. For patients treated with 
Cystagon®, leukocyte cystine measurements are useful to determine appropriate dosage 
and drug adherence. “When measured 5 to 6 hours after Cystagon® administration, the 
goal should be a level < 1 nmol ½ cystine/mg protein. In some patients with poorer 
tolerability for Cystagon®, patients may still receive benefit with a white blood cell 
cystine level of less than 2 nmol ½ cystine/mg protein” (Cystagon® Package Insert, 
2007).  
 
Variability exists in the measured cystine content in cells.  Some of the variability arises 
from the types of cells harvested for the measurement.  An even greater source of 
variation of the cystine level stems from the method used to determine the amount of 
protein used to normalize the result of the cystine assay with respect to total amount of 
protein in the cells. Although there is no explicit reference in the Cystagon® Package 
Insert as to which protein assay should be used to determine that the cystine level is 
less than 1 nmol ½ cystine/mg protein, the first laboratories known for measuring WBC 
cystine, have used the Lowry assay, which makes the Lowry assay as the method of 
reference, by default. The methods for the analysis of cystine and cellular total protein 
in white blood cells (WBC) for the current study were validated at 
 West 
Lafayette, IN under GLP principles (good laboratory practice or GLP specifically 
refers to a quality system of management controls for research laboratories and 
organizations to try to ensure the uniformity, consistency, reliability, reproducibility, 
quality, and integrity of chemical safety and efficacy tests). For that reason, 
uses 
what is presently considered as the gold-standard assay to determine the amount of 
protein, the bicinchoninic acid assay (BCA) total protein method instead of the Lowry 
method. BCA is also used by some of the cystine determination laboratories that 
analyze patient samples in the US and Europe because, in addition to its being 
considered a more accurate assay for protein measurement, BCA is also better suited 
to implementing with rapid turnaround times and method robustness in a GLP 
compliant way than Lowry. However, during the conduct of this study, it was observed 
that the reported concentrations for cystine in WBC lysate from patient samples 
analyzed at 
 appeared to be consistently higher than the historical data that had 
been obtained previously from these patients at the cystine determination laboratories 
at academic medical centres that perform these assays, while on Cystagon. To address 


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this concern, a series of analytic experiments was initiated to determine if the GLP 
methods validated at 
 were generating results equivalent to those previously 
reported under the Lowry method (Powell KL, Langman CB, Pediatr Nephrol 2012). 
 
Based on these experiments, it was determined that the Lowry vs. BCA protein results 
had to be adjusted as follows: 
protein amount[Lowry] = protein amount[BCA] * 1.6999 - 0.0648 
 
The correction factor ensures the patients participating in the study to receive a safe 
and appropriate dose of RP103 in an effort to get their WBC cystine levels similar to 
levels reported historically (prior to their enrollment in Raptor’s clinical studies). This 
also allows WBC cystine results reported from the clinical studies to be consistent with 
all previous clinical trials and surveys, as well as with previous Cystagon® guidelines. 
 
Regular Q6H daily treatment with Cystagon® has been shown to diminish the rate of 
renal dysfunction as well as promoting improved growth in children with cystinosis 
(Kleta, Bernardini et al. 2004). Current guidelines for following WBC cystine levels 
are based on obtaining blood 5 to 6 hours after the last dose of Cystagon® (Schneider 
2004). White blood cell (WBC) cystine content rapidly decreases after Cystagon® 
ingestion, but can return to predose levels within 6 hours (Smolin, Clark et al. 1988). 
 
RP103 dose will then be increased by approximately 10% on regular time intervals 
until the WBC cystine level is < 1 nmol ½ cystine/mg protein or until the patient 
experiences some tolerability issue.  
 
4.6. 
Study Conduct 
 
This Study will be conducted in compliance with the protocol and any amendments 
approved by the local Institutional Review Boards (IRBs) or Ethics Committees (ECs), 
and according to FDA and ICH E6 Guideline for Good Clinical Practice.  The 
Investigator must adhere to the protocol as detailed in this document and agree that the 
Sponsor must approve any change(s) to the protocol prior to seeking approval from the 
IRB or EC.  
 
4.7. 
Study Population 
 
Patients (male or female) with nephropathic cystinosis that successfully completed 
Study RP103-03 will be eligible for enrollment. Additional patients with cystinosis that 
did not complete the RP103-03 study but qualify for the study based on the inclusion 
and exclusion criteria, may be enrolled after completion of the analysis of the RP103-
03 Study where the non-inferior efficacious and safe dose of RP103 versus Cystagon® 
has been determined.  
 
 


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5. 
Study Objectives and Endpoints 
 
5.1. 
Study Objectives 
 
The objective of this Study is to assess the long-term safety, tolerability, 
pharmacokinetics and pharmacodynamics of RP103 in pediatric and adult patients with 
cystinosis. 
 
5.1.1. Primary Objective 
 To assess safety and tolerability of long-term repeat dosing of RP103 in patients 
with cystinosis. 
 
5.1.2. Secondary Objectives 
 To assess the steady-state pharmacokinetics (PK) and pharmacodynamics (PD) 
of RP103. 
 
 
 
 
 
5.2. 
Study Endpoints 
 
5.2.1. Safety Endpoints 
 
The safety profile of RP103 will be investigated by safety reviews conducted by the 
Investigator at or prior to each Monthly or Quarterly visit and through adverse event 
report monitoring (including attribution of treatment-emergent adverse events and 
serious adverse events [SAEs]), physical examination (including basic neurological 
and skin assessment findings), vital signs, ECG and clinical laboratory testing as 
outlined in the Schedule of Events (Appendix 14.1). 
 
5.2.2. Pharmacokinetic Endpoints 
 
The trough plasma cysteamine concentration will be measured from samples collected 
0.5 hour post dose at each study visit. 
 
5.2.3. Pharmacodynamic Endpoints 
 
The WBC cystine content will be measured from samples collected 0.5 hour post dose 
at each study visit. 
 
 
 
 
 
 
 
 
 
 


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6. 
Overall Study Design and Plan 
 
6.1. 
Study Design 
 
This is a long-term, open-label Study of the safety, tolerability and steady-state 
pharmacokinetics and pharmacodynamics of RP103 in pediatric and adult patients with 
cystinosis.  Initially only patients who completed the previous phase III Study RP103-
03 will be offered the opportunity to enroll in this extension Study. 
Additional patients who did not complete Study RP103-03 but qualify for RP103-04 
based on current inclusion and exclusion criteria may be enrolled after completion of 
the analysis of the RP103-03 Study where the non-inferior efficacious and safe dose of 
RP103 versus Cystagon® has been determined. 
 
6.1.1. Study Visits 
For patients who completed Study RP103-03, study visits consist of: 
 Screening Visit:  The RP103-04 Screening visit occurs simultaneously with the 
RP103-03 Period 2 Day 7 (End of Study) visit.  These patients will continue 
RP103 Q12H treatment at the last dose level prescribed during their 
participation in Study RP103-03. 
 Monthly Study Visits are only for patients who completed Study RP103-03 and 
will begin within 1 month (± 7 days) after study entry.  Each patient will 
complete a minimum of 6 consecutive Monthly visits. 
 Quarterly Study Visits will commence for each patient ≥ 1 month and < 4 
months after the patient has completed at least 6 consecutive Monthly visits. 
Each Quarterly visit will take place by the middle of the first month (± 7 days) 
of each calendar quarter (i.e., January 15, April 15, July 15 and October 15).  
 End of Study (EOS) Visit will be conducted within 7 (± 2 days) from the last 
completed study visit or from the date of decision to terminate. 
For patients who did not complete Study RP103-03, study visits consist of: 
 Screening Visit which may occur up to 28 days prior to Day 1. 
 Dose Confirmation Period (Days 1-5) which includes 3 study visits over 5 days. 
o Day 1 includes a morning study visit while the patient is fasted, with 
pre-dose blood samples collected for trough cysteamine and peak WBC 
cystine determination while the subject is still taking Cystagon®.  RP103 
treatment regimen begins at the clinic on the morning of Day 1, 
administered Q12H at a starting total daily RP103 dose equal to 70% of 
the Screening total daily Cystagon® dose.  Patients will leave the clinic 
for Days 2-3 and take RP103 as instructed. 


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o Days 4 and 5 each include a morning study visit; RP103 Q12H treatment 
regimen continues. 
 Quarterly Study Visits will commence for each patient by the middle of the first 
month (± 7 days) of each calendar quarter (i.e., January 15, April 15, July 15 
and October 15).  
 End of Study (EOS) Visit will be conducted within 7 (± 2 days) from the last 
completed study visit or from the date of decision to terminate. 
 
6.1.2. Study Procedures 
For patients who completed Study RP103-03, study procedures include: 
Screening 
The RP103-04 Screening visit occurs simultaneously with the RP103-03 Period 2 Day 
7 (End of Study) visit.  These patients will continue RP103 Q12H treatment at the last 
dose level prescribed during their participation in RP103-03. 
Monthly Study Visits 
Only patients who completed Study RP103-03 will attend Monthly Visits.  These visits 
will be made monthly (± 7 days) after study entry according to the Schedule of Events, 
Appendix 14.1.  A minimum of six (6) consecutive Monthly visits will be completed 
for each patient.  Clinical laboratory assessments (hematology, chemistry, urinalysis), 
physical examination (including basic neurological and skin assessments) and vital 
signs, ECG, body weight, body mass index (BMI), body surface area (BSA), an 
Investigator administered 
 
 
 
 will be made according to the Schedule of Events. 
During these visits, blood samples for PK (cysteamine) and PD (WBC cystine) will be 
collected 0.5 hour post RP103 dose administered at the clinic.  Patients or parents will 
continue to maintain a daily diary, recording the dose and time, of cysteamine 
medications, proton pump inhibitors (PPI) and other gastric acid reducing drugs 
(prescription and over the counter medications). Patients or their parents will return 
their completed daily diary at each scheduled study visit and will receive a new or re-
dispensed daily diary. Concomitant medications and adverse events will be collected. 
At or before each Monthly Visit, the Investigator will review available safety and 
PK/PD data and if a patient does not achieve an appropriate level of WBC cystine 
reduction or does not tolerate the dose, the patient may have their RP103 dose adjusted 
or may be terminated from the study. This review will be documented in source and in 
the CRF as appropriate, with the action(s) taken and reasons for such action(s). 
Quarterly Study Visits 
Quarterly visits will commence for each patient ≥ 1 month and < 4 months after the 
patient has completed 6 consecutive Monthly visits. Each Quarterly visit will take place 


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by the middle of the first month (± 7 days) of each calendar quarter (i.e., January 15, 
April 15, July 15 and October 15).  Clinical laboratory assessments, clinical laboratory 
assessment (hematology, chemistry, urinalysis), physical examination (including basic 
neurological and skin assessments)  and vital signs, ECG, body weight, body mass 
index (BMI), body surface area (BSA), 
 
 
 
 will be 
made according to the Schedule of Events.  
During these visits, blood samples for PK (cysteamine) and PD (WBC cystine) will be 
collected 0.5 hour post RP103 dose administered at the clinic.  Patients or parents will 
continue to maintain a daily diary, recording the dose and time, of cysteamine 
medications, proton pump inhibitors (PPI) and other gastric acid reducing drugs 
(prescription and over the counter medications). Patients or their parents will return 
their completed daily diary at each scheduled study visit and will receive a new or re-
dispensed daily diary. Concomitant medications and adverse events will be collected. 
At or before each Quarterly Visit, the Investigator will review available safety and 
PK/PD data and if a patient does not achieve an appropriate level of WBC cystine 
reduction or does not tolerate the dose, as determined by the Investigator, the patient 
may have their RP103 dose adjusted or may be terminated from the Study. This review 
will be documented with the action(s) taken and reasons for such action(s). 
For patients who did not complete Study RP103-03, study procedures include: 
Screening 
The Screening visit may occur up to 28 days prior to Day 1. 
Medical and medication histories and clinical laboratory assessment (hematology, 
chemistry, urinalysis), physical examination (including basic neurological and skin 
assessments) and vital signs, ECG, body weight, body mass index (BMI), body surface 
area (BSA), adverse events determination, concomitant medications, an Investigator 
administered 
 
 
 
 will be made according to the Schedule of Events, 
Appendix 14.1. 
All adult patients or parent or guardian of pediatric patients will begin completing a 
daily diary medication log, recording the dose and time, of cysteamine medications, 
proton pump inhibitors (PPI) and other gastric acid reducing drugs (prescription and 
over the counter medications).  
Dose Confirmation Period (Days 1-5) 
This period entails 3 study visits over 5 days, required only for patients that did not 
complete Study RP103-03. 
 Day 1:  If this visit is more than 7 days after the Screening date, some 
assessments must be repeated as specified in the Schedule of Events.  This is a 
morning study visit while the patient is fasted, with pre-dose (within 15 minutes 


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prior to the first RP103 dose) blood samples collected for trough cysteamine 
and peak WBC cystine determination while the subject is still taking 
Cystagon®.  RP103 treatment regimen begins at the clinic on the morning of 
Day 1, administered Q12H at a starting RP103 total daily dose equal to 70% of 
the Screening total daily dose of Cystagon®. 
 Days 4 and 5:  Each day includes a morning visit.  0.5 hour (30 minute) post-
dose blood samples for plasma cysteamine (PK) and WBC cystine (PD) 
determination will be collected.  RP103 Q12H treatment regimen continues at 
the starting total daily dose.  Once the Investigator receives WBC cystine results 
for the Dose Confirmation Period, and RP103 dose adjustment may be 
prescribed so that it can be implemented before the subject returns for their next 
study visit (Quarterly Visit 1). 
Quarterly Study Visits 
Quarterly visits will take place by the middle of the first month (± 7 days) of each 
calendar quarter (i.e., January 15, April 15, July 15 and October 15).  Clinical 
laboratory assessments, clinical laboratory assessment (hematology, chemistry, 
urinalysis), physical examination (including basic neurological and skin assessments)  
and vital signs, ECG, body weight, body mass index (BMI), body surface area (BSA), 
an Investigator administered 
 
 
 
 will be made according to the 
Schedule of Events.  
During these visits, blood samples for PK (cysteamine) and PD (WBC cystine) will be 
collected 0.5 hour post RP103 dose administered at the clinic.  Patients or parents will 
continue to maintain a daily diary, recording the dose and time, of cysteamine 
medications, proton pump inhibitors (PPI) and other gastric acid reducing drugs 
(prescription and over the counter medications). Patients or their parents will return 
their completed daily diary at each scheduled study visit and will receive a new or re-
dispensed daily diary. Concomitant medications and adverse events will be collected. 
At or before each Quarterly Visit, the Investigator will review available safety and 
PK/PD data and if a patient does not achieve an appropriate level of WBC cystine 
reduction or does not tolerate the dose, as determined by the Investigator, the patient 
may have their RP103 dose adjusted or may be terminated from the Study. This review 
will be documented in source and in the CRF as appropriate, with the action(s) taken 
and reasons for such action(s). 
 
Study Termination: 
Patients who either complete the Study or terminate the Study early will have an End 
of Study (EOS) visit within 7 days (± 2 days) of their last completed study visit.  
Clinical laboratory assessments, physical examination, vital signs, ECG, 
 
 will be performed according to 
the Schedule of Events, Appendix 14.1.  Blood samples for PK (cysteamine) and PD 


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(WBC cystine) will be collected 0.5 hour post RP103 dose administered at the clinic. 
For patients who have transitioned back to Cystagon®, PK and PD samples will be 
collected immediately prior to their next Cystagon® dose. Adverse events and 
concomitant medications will be collected.  
Other Study Procedures: 
Females of child-bearing potential will provide a menstrual cycle history and be 
administered a serum pregnancy test at Screening (new patients only), and at each 
scheduled study visit. Height, weight, BMI and BSA determination will be performed 
at each visit according to the Schedule of Events. 
 
6.2. 
Randomization 
 
Patients will not be randomized. 
 
6.3. 
Duration 
 
Patients will be followed until Study termination; which can occur by patient, physician 
or Sponsor request, or until the RP103 drug is available through the appropriate 
marketing approval, or until the Sponsor terminates development of RP103 for this 
indication for any reason.  Approximate treatment time in the Study is 96 months. 
However, a subject may withdraw consent or be withdrawn from the study prior to 
completion. 
 
7. 
Selection of Subjects 
 
7.1. 
Inclusion Criteria 
 
The following criteria must be met by all subjects considered for Study participation. 
 
7.1.1 Male and female subjects must have completed the last visit of Study RP103-
03 and be willing to continue on RP103 treatment. 
 
OR for patients who did not complete the RP103-03 study:  
 
7.1.2 Male and female subjects with a documented diagnosis of cystinosis. 
7.1.3 Subjects must be on a stable dose of Cystagon® at least 21 days prior to 
Screening. 
7.1.4 [ no longer applicable ] 
7.1.5 Within the last 6 months, no clinically significant change from normal in liver 
function tests [i.e., 1.5 times ULN for ALT and AST, and/or 1.5 times ULN for 
total bilirubin] and renal function [i.e., estimated GFR (corrected for body 
surface area)] at Screening as determined by the Investigator. 
7.1.6 Subjects must have an estimated GFR (corrected for body surface area) > 30 
mL/minute/1.73 m2. 


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7.1.7 Sexually active female subjects of childbearing potential (i.e., not surgically 
sterile [tubal ligation, hysterectomy, or bilateral oophorectomy] or at least 2 
years naturally postmenopausal) must agree to utilize the same acceptable form 
of contraception from Screening through completion of the Study. The 
acceptable forms of contraception for this Study include hormonal 
contraceptives (oral, implant, transdermal patch, or injection) at a stable dose 
for at least 3 months prior to Screening, barrier (spermicidal condom, 
diaphragm with spermicide), IUD, or a partner who has been vasectomized for 
at least 6 months. For pre-pubescent children, a documented attestation of 
abstinence from their parent or guardian will be acceptable. 
7.1.8 Subject must be willing and able to comply with the Study restrictions and 
requirements. 
7.1.9 Subject or their parent or guardian must provide written informed consent and 
assent (where applicable) prior to participation in the Study. 
 
7.2. 
Exclusion Criteria 
 
7.2.1. Patients enrolled in the previous Study RP103-03 who did not complete their 
last scheduled study visit or who do not wish to continue on treatment with 
RP103. 
 
AND for patients who did not complete the RP103-03 study: 
 
7.2.2. Subjects less than 1 year old. 
7.2.3. Subjects with current history of the following conditions or any other health 
issues that make it, in the opinion of the Investigator, unsafe for them to 
participate:  
 Inflammatory bowel disease (if currently active) or prior resection of small 
intestine; 
 Heart disease (e.g., myocardial infarction, heart failure, unstable 
arrhythmias, or poorly controlled hypertension) 90 days prior to Screening; 
 Active bleeding disorder 90 days prior to Screening; 
 History of malignant disease within the last 2 years. 
7.2.4. Subject with a hemoglobin level of < 10 g/dL at Screening or, in the opinion 
of the Investigator, a hemoglobin level that would make it unsafe for the 
subject to participate. 
7.2.5. [ no longer applicable ] 
7.2.6. Subjects with known hypersensitivity to cysteamine and penicillamine. 
7.2.7. Female subjects who are nursing, planning a pregnancy, known or suspected 
to be pregnant, or with a positive serum pregnancy screen. 
7.2.8. Subjects who, in the opinion of the Investigator, are not able or willing to 
comply with the protocol. 
 
7.3. 
Removal of Subjects from Study Participation 
 




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a Specific ingredients/purity will be identified on the Certificate of Analysis (or equivalent) that is 
supplied for RP103. 
b Provided strength is as cysteamine free base. 
 
8.2. 
Identity of Investigational Products 
 
The 25 mg strength Cysteamine Bitartrate Delayed-release Capsules (RP103, test 
product) are a size 
 
 in white 
ink.  They are provided in 60-count bottles. 
The 75 mg strength Cysteamine Bitartrate Delayed-release Capsules 
 
 
in white ink.  They are provided in 150-count bottles. 
 
8.3. 
Storage of Investigational Products 
 
Cysteamine Bitartrate Delayed-release Capsules (RP103) should be stored at the 
conditions specified in the current study pharmacy manual. 
 
8.4. 
Concomitant Medications and Excluded Therapies 
 
All patients will be asked about concomitant medications at study entry and at each 
study visit. For patients entering the Study on a chronic concomitant medication, 
adequate clarification of the reason for taking that medication must be documented in 
source documentation (e.g., medical history). Information about medications used 
during after study entry must also be recorded.  Patients must observe the restrictions 
listed here for the specified time periods and throughout the study. 
 
Patients entering the Study on Cystagon® will be asked to stop gastric acid reducing 
medications at least 12 hours before receiving their first dose of RP103 until Study 
termination. In cases of intolerable gastric upset, gastric acid reducing medications will 
be allowed, at the discretion of the Investigator.  All gastric upset adverse events will 
be captured and recorded. All concomitant medications used to treat adverse events 
should be captured and recorded appropriately. 
 
At Screening, the patient or parent will be provided with a daily diary to record protocol 
specified cysteamine medications, proton pump inhibitors (PPI) and other gastric acid 
reducing drugs, including over the counter gastric acid reducing medications, and 
instructed on its completion. At each clinic visit, the staff will review the diary for 
completion, collect completed diaries and re-dispense or issue a new one. Continued 
non-compliance with the diaries may be considered a reason for early Study 
termination. All diaries will be collected at Study completion. 
 


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Illegal or recreational alcohol or drug use is not allowed during the study. If the 
Investigator suspects illegal or recreational alcohol or drug use, alcohol or drug tests 
may be administered at the discretion of the Investigator. 
 
8.5. 
Study Treatment Administration and Compliance 
 
All study treatments administered in the clinic will be under the supervision of clinic 
personnel. Patients not entering the trial from Study RP103-03 will be started on twice 
a day administration of RP103, where the total daily RP103 dose is 70% of their total 
daily stable Cystagon® dose.  
 
If during the study any patient does not achieve a meaningful reduction of WBC cystine 
level (i.e., < 1 nmol ½ cystine/mg protein) or does not tolerate the dose, as determined 
by the Investigator, the patient may have their RP103 dose adjusted or may be 
terminated from the study.  
 
A daily diary of cysteamine and gastric acid reducing medications will be maintained 
throughout the study. 
 
9. 
Study Procedures 
 
Before any Study-specific procedures are performed, the patient and legal guardian (if 
appropriate) must receive an explanation of all Study procedures and must sign and 
date an Institutional Review Board (IRB) or Ethics Committee (EC)-approved written 
informed consent and assent (if applicable) form. 
 
9.1. 
Schedule of Study Procedures 
 
9.1.1. Screening 
 
For patients who completed Study RP103-03: 
 The following data can be obtained from the RP103-03 Screening visit: 
o Demographics. 
o Medical history. 
o Medication history. 
o Menstrual history for females of childbearing potential. 
 The following data can be obtained from the RP103-03 Termination visit: 
o Clinical laboratory 
o Physical examination 
o 12-lead ECG 
o Vital signs 
 Dispense RP103 study medication. 
 Schedule return clinic visit for Monthly Visit 1. 


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For patients who did not complete Study RP103-03: 
 Review inclusion/exclusion criteria. 
 Record demographics. 
 Record medical history. 
 Record medication history. 
 Record menstrual history for females of childbearing potential. 
 Perform a physical examination (see Section 9.10). 
 Obtain clinical laboratory samples (serum chemistry, hematology, and urinalysis, 
see Section 9.7). 
 Collect a cysteamine PK sample pre-dose RP103 administration. Actual collection 
time will be recorded. 
 Collect a WBC cystine PD sample pre-dose RP103 administration (which should 
be 5-6 hours post last Cystagon® administration). Actual collection time will be 
recorded. 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature, see Section 9.11). 
 Obtain a 12-lead ECG (see Section 9.9). 
 Provide training for Daily Diary log of cysteamine and gastric acid reduction 
medications. Provide copy of daily medication diary. 
 Schedule return clinic visits for Days 1, 4 and 5. 
 
For all patients: 
 Obtain serum pregnancy test from females of childbearing potential. 
 Measure height and weight. 
 Calculate BMI and BSA (see Appendix 14.5). 
 
 
 
 
 
 
 Prepare subjects for study participation by informing them of study restrictions and 
procedures. 
 Provide copy of daily medications diary. 
 Record concomitant medications. 
 Monitor AEs. 
 


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For patients whose Screening visit was > 7 days prior to Day 1, complete the following 
prior to RP103 dosing: 
 
 Re-assess inclusion/exclusion criteria. 
 Record any changes since Screening to medical history, medication history, 
menstrual history for females of childbearing potential. 
 Obtain serum pregnancy test from females of childbearing potential. 
 Measure height and weight. 
 Calculate BMI and BSA (see Appendix 14.5). 
 Perform a physical examination (see Section 9.10). 
 Collect a cysteamine PK sample pre-dose RP103 administration. Actual collection 
time will be recorded. 
 Collect a WBC cystine PD sample pre-dose RP103 administration. Actual 
collection time will be recorded. 
 Obtain clinical laboratory tests (serum chemistry, hematology, and urinalysis, see 
Section 9.7). 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature, see Section 9.11). 
 Obtain a 12-lead ECG approximately 3 hours (± 15 minutes) post RP103 
administration (see Section 9.9). 
 
 
 
 
 
 
 Record concomitant medications. 
 Monitor AEs. 
 
9.1.2. Day 1 Study Visit (only for patients who did not complete Study RP103-03) 
 
 Collect and review completed diary. 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature). 
 Subjects should be fasting for at least 2 hours prior to the following blood sample 
collections and subsequent RP103 dosing. 
o Collect a cysteamine PK sample pre-dose RP103 administration. Actual 
collection time will be recorded. 
o Collect a WBC cystine PD sample pre-dose RP103 administration. Actual 
collection time will be recorded. 


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 Administer a Q12H dose of RP103 with a starting total daily RP103 dose equal to 
70% of their total daily Cystagon® dose. Study drug should be administered with 
an acceptable food or liquid as described in Appendix 14.9. 
 A meal or snack will be ingested between 30 and 60 minutes after RP103 dosing. 
 Obtain a 12-lead ECG approximately 3 hours (± 15 minutes) post RP103 
administration (see Section 9.9). 
 Record concomitant medications. 
 Monitor AEs. 
 Dispense RP103 and instructions for home administration. 
 Confirm return clinic visits for Days 4 and 5. 
 
9.1.3. Day 4 and Day 5 Study Visits (only for patients who did not complete Study 
RP103-03) 
 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature). 
 Subjects should be fasting for at least 2 hours prior to RP103 dosing. 
 Collect a cysteamine PK sample 0.5 hour (30 minutes) post-dose RP103 
administration. Actual collection time will be recorded. 
 Collect a WBC cystine PD sample 0.5 hour (30 minutes) post-dose RP103 
administration. Actual collection time will be recorded. 
 Administer a Q12H dose of RP103 with a starting total daily RP103 dose equal to 
70% of their total daily Cystagon® dose. Study drug should be administered with 
an acceptable food or liquid as described in Appendix 14.9. 
 A meal or snack will be ingested between 30 and 60 minutes after RP103 dosing. 
 Record concomitant medications. 
 Monitor AEs. 
 Dispense RP103 and instructions for home administration. 
 Schedule return clinic visit for Quarterly Visit 1. 
 
9.1.4. Monthly (± 7 days) Study Visit (only for patients who completed Study RP103-
03) 
 
 Collect and review the completed diary. 
 Obtain serum pregnancy test (females of childbearing potential). 
 Perform physical examination (see Section 9.10). 


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 Measure height and weight. 
 Calculate BMI and BSA (see Appendix 14.5). 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature, see Section 9.11) within 30 minutes prior to RP103 administration. 
 Obtain clinical laboratory tests (serum chemistry, hematology, and urinalysis, see 
Section 9.7) prior to RP103 administration. 
 Obtain a 12-lead ECG (see Section 9.9). 
 Subjects should be fasting for at least 2 hours prior to RP103 dosing. 
 A meal or snack will be ingested between 30 and 60 minutes after RP103 dosing.  
 Administer Q12H RP103 dose with an acceptable food or liquid as described in 
Appendix 14.9. 
 Collect a cysteamine PK sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
 Collect a WBC cystine PD sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
 
 
 
 
 
 
 Dispense RP103 for home administration. 
 Dispense new diary. 
 Record concomitant medications. 
 Monitor AEs. 
 Schedule return clinic visit. 
 
Perform a safety and PK/PD review prior to or at the study visit. If a patient does not 
achieve a meaningful reduction of WBC cystine level (i.e., < 1 nmol ½ cystine/mg 
protein) or does not tolerate the dose, as determined by the Investigator, the patient may 
have their RP103 dose adjusted or may be terminated from the Study.  
 
9.1.5. Quarterly (± 7 days) Study Visit 
 
 Collect and review completed diaries. 
 Obtain serum pregnancy test (females of childbearing potential). 
 Perform physical examination (see Section 9.10). 
 Measure height and weight. 
 Calculate BMI and BSA (see Appendix 14.5). 


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 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature, see Section 9.11) within 30 minutes prior to RP103 administration. 
 Obtain clinical laboratory tests (serum chemistry, hematology, and urinalysis, see 
Section 9.7) prior to RP103 administration. 
 Obtain a 12-lead ECG (see Section 9.9). 
 Subjects should be fasting for at least 2 hours prior to RP103 dosing. 
 A meal or snack will be ingested between 30 and 60 minutes after RP103 dosing. 
 Administer Q12H RP103 dose with an acceptable food or liquid as described in 
Appendix 14.9. 
 Collect a cysteamine PK sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
 Collect a WBC cystine PD sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
 
 
 
 
 
 
 Dispense RP103 for home administration. 
 Dispense new diary. 
 Record concomitant medications. 
 Monitor AEs. 
 Schedule return clinic visit. 
Perform a safety and PK/PD review prior to or at the study visit. If a patient does not 
achieve a meaningful reduction of WBC cystine level (i.e., < 1 nmol ½ cystine/mg 
protein) or does not tolerate the dose, as determined by the Investigator, the patient may 
have their RP103 dose adjusted or may be terminated from the Study. 
9.1.6. End of Study Visit (7 ± 2 days after last study visit or decision to terminate)  
For all patients: 
 Collect and review completed diary. 
 Perform physical examination (see Section 9.10). 
 Measure height and weight. 
 Calculate BMI and BSA (see Appendix 14.5). 
 Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature, see Section 9.11). 
 Obtain clinical laboratory tests (serum chemistry, hematology, and urinalysis, see 
Section 9.7). 
 Obtain a 12-lead ECG (see Section 9.9). 
 
 
 
 


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 Administer the VAS measurement of swallowing difficulty (see Section 9.13). 
 Record concomitant medications. 
 Monitor AEs. 
For patients still receiving RP103 treatment: 
 Subjects should be fasting for at least 2 hours prior to RP103 dosing. 
 A meal or snack will be ingested between 30 and 60 minutes after RP103 dosing. 
 Administer Q12H RP103 dose with an acceptable food or liquid as described in 
Appendix 14.9. 
 Collect a cysteamine PK sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
 Collect a WBC cystine PD sample 0.5 hour (30 minutes) post RP103 dose 
administration. Actual collection time will be recorded. 
For patients that terminated from the Study and transitioned onto Cystagon® treatment: 
 Collect a cysteamine PK sample immediately prior to their next Cystagon® dose 
administration. Actual collection time will be recorded. 
 Collect a WBC cystine PD sample immediately prior to their next Cystagon® dose 
administration. Actual collection time will be recorded. 
If a subject has any clinically significant, Study drug-related abnormalities at the 
conclusion of the study termination, the Investigator will determine if the subject has 
to be followed further. If the Investigator determines that a subject has abnormalities 
that require additional monitoring, the subject may be asked to return to the clinic until 
the abnormalities resolve or will be allowed to return home and will be followed up by 
telephone until resolution. If the subject is to be followed up, the Medical Monitor (or 
designated representative) should be notified. Every effort should be made to arrange 
follow-up evaluations at appropriate intervals to document the course of the 
abnormalities. 
 
 
 
  
 
 
  
9.2. 
Fluid and Dietary Control 
Data from studies RP103-02 (see Section 4.2.3) and RP103-05 (see Section 4.2.4) in 
healthy volunteers suggests a significant food effect on cysteamine absorption: the 
more food that is taken around cysteamine dosing, the less the fractional absorption of 
cysteamine is observed (Figure 5) and the more variable is this absorption (Figure 6). 
This food effect had been anecdotally noticed in one patient taking Cystagon® (Smolin, 


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IND 103,694: Study RP103-04 
 
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Clark et al. 1988) but no other publication about the subject could be found, despite the 
recommendation by the Agencies of taking Cystagon® with food to decrease GI effects. 
 
Figure 5: Quantity of absorbed cysteamine (AUC) vs. Food: Fasted [10 hours before – 4 hours 
after], Fed 30 m [fasted 10 hours before, normal meal 1/2h after dosing], Fed 2 h [fasted 10 
hours before, normal meal 2h after dosing], Fed high fat / high caloric [HF HC] 0h [meal at 
dosing time]  
 


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Figure 6: Time to peak of absorbed cysteamine (Tmax) vs. Food: Fasted [10 hours before – 4 
hours after], Fed 30 m [fasted 10 hours before, normal meal 1/2h after dosing], Fed 2 h [fasted 
10 hours before, normal meal 2h after dosing], Fed high fat / high caloric [HF HC] 0h [meal at 
dosing time]  
 
In patients, as predicted by the inhibitory Emax pharmacodynamic model (see Figure 3), 
the more variable the absorption of cysteamine, the more variable is the peak of WBC 
cystine level (some measurements being then > 1 nmol ½ cystine/mg protein).  
This food effect may explain the intermittency of GI side effects observed in patients 
with cystinosis treated with Cystagon® (Elenberg, Norling et al. 1998): for those 
patients who are regularly taking cysteamine with a significant amount of food, their 
dose of cysteamine, adjusted based on their peak of WBC cystine level, is significantly 
higher than if they were taking cysteamine fasted, and with an increased risk of side 
effects on the days where they would eat significantly less than usual. 
 
In these studies in healthy volunteers, very few and only minor GI side-effects were 
seen when subjects ingested RP103 while fasted. Therefore Raptor recommends as best 
practice for patients to try to avoid food for 2 hours before and at least 30 minutes after 
RP103 administration. In case patients cannot comply with this recommendation, 
patients should ingest only a small amount of food around the time of RP103 dosing 
(from 1 hour before to 1 hour afterwards) and importantly, withhold dairy products 
during this time window. 
 
RP103 should be administered with an acceptable food or liquid as described in 
Appendix14.9 RP103 Dosing Instructions, and not with water. During study visits, 
food will be available for the patient to eat at between 30 and 60 minutes after taking 
study medication while at the clinic in a (2h) fasted state.  
 
9.3. 
Contraception and Hormone Therapy 
 
9.3.1. Women 
 
For women subjects who did not already provide this information during RP103-03, 
they will be asked about their menstrual cycle history (including date of last period; 
menses regularity; typical duration and normalcy; any abnormal discharges; and 
excessive bleeding).  
 
Women of childbearing potential who are sexually active must be non-lactating and 
have a negative serum pregnancy test at Screening and use any one of the following 
acceptable methods of contraception until Study termination: 
 Hormonal contraceptives (oral, implant, transdermal patch, or injection) at a stable 
dose for at least 3 months prior to Screening. 
 Placement of copper-containing intrauterine device (IUD). 
 Spermicidal condoms. 


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 Diaphragm with spermicide. 
 Male partner who has had a vasectomy for at least 6 months. 
 
Women of non-childbearing potential who have a negative serum pregnancy test at 
Screening must also meet at least 1 of the following criteria: 
 Be postmenopausal, defined as having been amenorrheic for least 2 years and a 
serum follicle-stimulating hormone (FSH) >30 IU/L. 
 Have had a hysterectomy, a bilateral oophorectomy or tubal ligation. 
 If child is pre-pubescent, documented attestation of abstinence from their parent or 
guardian or documentation by the investigator that abstinence has been discussed 
with the subject, parent or guardian.  
 
9.3.2. Men 
 
All men who have not had a vasectomy and their partners will be asked to practice 
appropriate contraception, as described above, during the Study.  
 
9.4. 
Pharmacokinetic Blood Sample Collecting and Processing 
 
Plasma PK samples will be collected at the timepoints specified in the Schedule of 
Events (see Appendix 14.1). Blood can be drawn by separate venipunctures, indwelling 
catheters, peripherally inserted central catheter (PICC) line or by combinations of these 
or other suitable methods. The indwelling or PICC line should be managed as 
prescribed by the clinic procedures. Collection and processing instructions can be 
found in Appendix 14.6. 
 
9.5. 
Pharmacodynamic Blood Sample Collecting and Processing 
 
Blood samples for WBC cystine determination will be collected at the timepoints 
specified in the Schedule of Events (see Appendix 14.1). Blood can be drawn by 
separate venipunctures, indwelling catheters, peripherally inserted central catheter 
(PICC) line or by combinations of these or other suitable methods. The indwelling or 
PICC line should be managed as prescribed by the clinic procedures. Collection and 
processing instructions can be found in Appendix 14.7. Priority for blood sampling 
should be given to blood collected for WBC cystine determination. 
 
9.6. 
Analytical Methodology 
 
Plasma cysteamine concentration will be determined using methods employing 
Hydrophilic Interaction Liquid Chromatography (HILC) high pressure liquid 
chromatography (HPLC) tandem mass spectrometry (HPLC-MS/MS) (Dalton and 
Turner 2005; Dohil, Fidler et al. 2006). White blood cell (WBC) cystine concentration 
will be determined using high performance liquid chromatography-electrospray 


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ionization tandem mass spectrometry (LC-ESI-MS/MS) (Dalton and Turner 2005; 
Dohil, Fidler et al. 2006). 
 
 
9.7. 
Clinical Laboratory Evaluations 
Clinical laboratory (hematology and chemistry) and urinalysis will be performed 
according to the Schedule of Events (see Appendix 14.1). 
 
  Females of 
childbearing potential will provide a serum sample for a pregnancy testing during 
Screening at each study visit. 
Clinical safety laboratory tests will be performed by a central laboratory. For patient 
safety, clinical laboratory samples to manage patient adverse events may be analyzed 
using the clinic’s local laboratory.  Table 9 summarizes tests that will be performed. 
The Investigator will monitor the laboratory test findings. If any laboratory test on or 
after the first study drug treatment is abnormal, it will be followed at the discretion of 
the Investigator. Abnormal laboratory tests, including ECGs, may, in the opinion of the 
Investigator, be considered clinically significant and, thus, constitute or be associated 
with an AE. In such cases, they must be reported on the AE page of the CRF. Any 
abnormal clinical lab that is determined not to be clinically significant will have a 
description of the reason for this determination documented on the lab CRF. 
Table 9: Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit 
Alanine aminotransferase 
Bilirubin 
Hemoglobin 
Albumin 
Blood (qualitative) 
Mean corpuscular hemoglobin  
Aspartate aminotransferase 
Color 
Mean corpuscular hemoglobin 
concentration 
Alkaline phosphatase 
Glucose 
Mean corpuscular volume 
Amylase 
Ketones 
Erythrocytes 
Conjugated bilirubin 
Leukocyte esterase 
Red cell distribution width 
Total bilirubin 
Nitrite 
Platelet count 
Blood urea nitrogen 
pH 
Leukocytes  
Calcium 
Protein 
Differential (absolute, %) 
Bicarbonate 
Specific gravity 
Basophils 
Chloride 
Turbidity 
Eosinophils 
Total cholesterol 
Urobilinogen 
Lymphocytes  
Creatinine 
Microscopic examination 
Monocytes 
Gamma glutamyl transpeptidase 
 
Neutrophils 
Glucose 
 
Reticulocyte count 
Lactate dehydrogenase 
 
 
Phosphorus 
 
 
Potassium 
 
 
Total protein 
 
 
Sodium 
 
 
Triglycerides 
 


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Uric acid 
 
Other Laboratory Tests 
Serum pregnancy test 
Human chorionic gonadotropin as applicable 
 
9.8. 
Blood Volume 
Assuming the approximate participation of 96 months, the estimated volume of blood 
drawn (in mL) per subject is provided below, for subjects who did participate in the 
previous pivotal Study RP103-03 and for those who did not (i.e. enrolled under RP103-
04 Protocol Amendment 5). The total blood volume for quarterly visits is proportionate 
to the number of visits completed. The maximum number of visits is listed in the tables 
below. 
RP103-03 Study Completers 
Study 
Visit 
Maximum 
# Visits 
Chemistry 
& 
Hematology 
PK 
PD 
Pregnancy 
TOTAL 
without 
pregnancy 
tests 
TOTAL 
with 
pregnancy 
tests 
Screening 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
Monthly 
Visits 
9 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
85.5 mL 
90 mL 
Quarterly 
Visits 
30 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
285 mL 
300 mL 
Study Exit 
Visit 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
 
 
 
 
 
 
389.5 mL 
410 mL 
RP103 Naïve (subjects enrolled under RP103-04 Protocol Amendment 5) 
Study 
Visit 
Maximum 
# Visits 
Chemistry 
& 
Hematology 
PK 
PD 
Pregnancy 
TOTAL 
without 
pregnancy 
tests 
TOTAL 
with 
pregnancy 
tests 
Screening 
Visit 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
Day 1 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
Day 4 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
Day 5 
1 
4.5 mL 
1.0 
mL 
4.0 
mL 
0.5 mL 
9.5 mL 
10 mL 
Quarterly 
Visits 
32 
4.5 
1.0 
4.0 
0.5 
304 mL 
320 mL 
Study Exit 
Visit 
1 
4.5 
1.0 
4.0 
0.5 
9.5 mL 
10 mL 
 
 
 
 
 
 
351.5 mL 
370 mL 
For any subject who participates in the optional PK substudy an additional 18 mL will 
be collected (over a 12 hour period). 


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If the Investigator suspects alcohol or drug abuse, additional urine or blood samples 
may be collected. 
9.9. 
12-Lead Electrocardiograms 
Standard 12-lead ECGs will be used for the ECG evaluation. All scheduled ECGs 
should be performed after the subject has rested quietly in the supine position for at 
least 5 minutes. A single, 10-second, 12-lead ECG will be obtained on all subjects as 
shown in the Schedule of Events (see Appendix 14.1). All ECGs will be retained as a 
paper copy in the subject’s source records. The ECGs will be recorded at the specified 
timepoints at a speed of 25 mm/sec and amplitude of 10 mm/mV. 
To ensure safety, a qualified individual at the clinic will review the ECGs. If an 
abnormality is noted, it may be appropriate to repeat an abnormal ECG to rule out 
improper lead placement. It is important that leads be placed in approximately the same 
positions each time to achieve precise ECG recordings. If a machine-read ECG is found 
to be abnormal, repeat measurements may not be necessary if a qualified physician’s 
interpretation determines that the abnormality noted on the machine reading is not 
clinically significant. Any such determination will be recorded with the reason for the 
assessment on the eCRF. 
ECGs will be recorded on appropriate and standardized ECG recorders. Built-in 
computer algorithms may be used to facilitate ECG interpretation and measurement of 
intervals. 
9.10. Physical Examinations 
Physical examinations will be performed according to the Schedule of Events (see 
Appendix 14.1). The physical examination will include assessments of the following: 
general appearance, eyes, ears, nose and throat, chest (heart, lungs), abdomen 
(palpation, GI sounds), extremities and skin. The Investigator will also conduct a basic 
neurological examination. 
 
9.11. Vital Signs 
 
Blood pressure may be measured in the seated position. Screening blood pressure may 
be retested 3 times at intervals of no less than 5 minutes between each measurement. 
Vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate, and oral body 
temperature) will be measured according to the Schedule of Events (see Appendix 
14.1). Blood pressure will be measured with the arm supported at the level of the heart, 
and recorded to the nearest 1 mm Hg. The subject should be at rest for at least 5 minutes 
before the blood pressure is measured. The use of automated devices for measuring 
blood pressure and heart rate are acceptable. When done manually, heart rate will be 
measured in the brachial or radial artery for at least 30 seconds. 
 
9.12. Adverse Event Inquiries 
 




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9.15. Product Accountability 
 
Cysteamine Bitartrate Delayed-release Capsules (RP103) will be supplied by the 
Sponsor or its representative.  The Investigational Pharmacy will record the lot 
numbers. Accountability will be performed on the clinical trial supply. The Investigator 
or a designee will verify and acknowledge receipt of the RP103 by signing and 
returning all required forms. All medication must be stored in a secured area under the 
proper storage requirements with access restricted to the Investigator or designees. 
Medication designated for this clinical Study must not be administered to any subjects 
other than those enrolled in this specific investigation and may not be used for any 
laboratory or animal research. All medication dispensed to subjects must be properly 
labeled and accurately recorded on the drug accountability records maintained at the 
pharmacy. A copy of this record must be returned to the Sponsor or its designee on 
completion of the Study for accountability purposes. A clinical research associate will 
periodically review the drug accountability during the Study. At the end of the Study, 
all unused and expired medication will be retained until disposition of study medication 
has been made by the Sponsor or its designee. 
 
10. 
Assessment of Safety 
 
10.1. Definition and Grading Intensity of Adverse Events/Experiences 
 
An adverse event/experience (AE) is any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporarily associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product. A treatment emergent adverse event is an event that first appears during 
treatment, which was absent before or which worsens relative to the pre-treatment state. 
 


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Adverse events/experiences comprise all disturbances of general health status, 
subjective and objective disease symptoms (including laboratory abnormalities), and 
accidents observed in the context of a clinical trial, irrespective of a possible causal 
relationship with the administration of the trial substance. Events occurring in the 
framework of a clinical trial during drug-free, and post-treatment periods, or in a 
reference group receiving drug therapy, are also to be designated as AEs.  
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death; 
 Is life threatening (life threatening refers to an event in which the subject was at 
immediate risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability or incapacity; 
 Is a congenital anomaly or birth defect; or 
 Is medically significant, and though not included in the above list, is an important 
medical event that may jeopardize the subject or require medical intervention to 
prevent one of the outcomes listed above. Discontinuation of Study drug or conduct 
of additional diagnostic evaluations, will not, by themselves, satisfy the criterion 
for a medically significant event. 
 
All AEs, whether volunteered, elicited, or noted on physical examination, will be 
recorded throughout the study. 
 
Where possible, the severity of AEs will be categorized Common Terminology Criteria 
for Adverse Events (CTCAE), Version 3.0 [Cancer Therapy Evaluation Program, 
2003] or otherwise as follows: 
 
 MILD (Grade 1): experience is minor and does not cause significant discomfort 
to subject or change in activities of daily living (ADL); subject is aware of 
symptoms but symptoms are easily tolerated; 
 
 MODERATE (Grade 2): experience is an inconvenience or concern to the subject 
and causes interference with ADL, but the subject is able to continue with ADL. 
 
 SEVERE (Grade 3): experience significantly interferes with ADL and the subject 
is incapacitated and/or unable to continue with ADL. 
 
 LIFE THREATENING (Grade 4): experience that, in the view of the 
Investigator, places the subject at immediate risk of death from the event as it 


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occurred (i.e., it does not include an event that had it occurred in a more severe 
form, might have caused death)5. 
 
By the CTCAE criteria defined above, the Grade 5 category is death. 
 
10.1.1. Stopping Criteria 
 
Close monitoring of the patients during the study will be performed.  Any decision to 
stop the clinical trial will be immediately communicated to all Investigators and to the 
FDA and competent authorities of any other participating countries as applicable. 
Individual patient dosing will be stopped if: 
 A patient exhibits a treatment-emergent adverse event of Common Terminology 
Criteria for Adverse Events (CTCAE) grade 3 or higher and not likely related to 
the underlying disease. 
A patient will be discontinued if they exhibit an: 
 Unexplained fever (> 38.5°C) for > 24 hours. 
The study will be halted and FDA will be consulted if: 
 One or more unexpected drug-related deaths. 
 Onset of one or more drug-related cases of: 
- 
Heart failure (NYHA Class II or greater); 
- 
Respiratory failure (Type 1 or Type 2); 
- 
Acute liver failure (associated with an international normalized ratio (INR) of 
greater than 1.5, and any degree of mental alteration (encephalopathy) in a 
patient without preexisting cirrhosis); 
- 
Malignant hypertension (i.e., Diastolic blood pressure > 140 mmHg); 
- 
Nephrotic syndrome which includes protein in the urine (more than 3.5 grams 
per day) and one or more of the following clinically significant symptoms: low 
blood protein levels and/or high cholesterol levels and/or high triglyceride 
levels and/or edema. 
 
10.2. Criteria for Determining Relationship to Drug 
 
Assessment of causality of suspected AEs is based on associative connections (time or 
place), pharmacological explanations, previous knowledge of the drug, presence of 
                                                 
 
 
 
 
5 per CTCAE Version 4.0 [published 2009 May 28th] 


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characteristic clinical or pathological phenomena, exclusion of other causes, and 
absence of alternative explanations. The Investigator will be asked to assess the causal 
relationship to the Study drug according to the following classifications: 
 
 Not related:  Time relationship with Study drug administration is nonexistent or 
other factors, certain or probable, to have been causative. 
 
 Unlikely:  Time relationship with Study drug administration is doubtful or other 
factors, certain or probable, to have been causative. 
 
 Possible:  Time relationship with Study drug administration may exist. Other 
possible causative factors may exist (e.g., concurrent disease or concomitant 
medication). Improvements on rechallenge or dose reduction (if performed) may or 
may not have been seen. 
 
 Probable:  Time relationship with Study drug administration likely exists. No other 
possible causative factors may exist (not reasonably explained by the subject’s 
known clinical state or concomitant medication). Improvements on rechallenge or 
dose reduction (if performed) have occurred. Recurrence of symptoms on 
rechallenge (if performed) has occurred. A specific laboratory investigation (if 
performed) has confirmed the relationship. 
 
 Definite:  Those events for which there is no shadow of doubt that they are a 
consequence of administration of the test product. It is likely that such events will 
be widely documented and generally accepted as having association with the test 
product or that they reoccurred after rechallenge (if performed). 
 
10.3. Adverse Event Reporting 
 
All AEs and SAEs must be reported, whether or not considered attributable to the test 
product. 
 
Refer to the most current Investigator’s Brochure for reference to safety information 
which lists the adverse reactions expected for the study product and their frequency of 
occurrence. 
 
Any death is an SAE by definition and must be reported to Pharsafer Associates Ltd.     
Whether or not the AE or SAE is expected or unexpected will be assessed by Raptor 
Pharmacovigilance and Drug Safety (PVDS) according to a pre-specified Safety 
Monitoring Plan (i.e., the current Investigator Brochure will be used as reference).  It 
is PVDS’s responsibility to make this assessment and to generate and distribute/submit 
any expedited regulatory reports as appropriate, e.g. IND Safety Reports and Suspected 
Unexpected Serious Adverse Reaction (SUSARs). 
Medical judgement will be used for events that may not be immediately life threatening 
or result in death or hospitalization, but that may jeopardize the subject or may require 


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intervention to prevent one of the other outcomes listed in the definition above; to 
determine if the event ought to be reported as a Serious Adverse Event. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
All SAEs must be reported, whether or not considered attributable to the test product, 
on a separate SAE Report Form. As much information as possible should be supplied 
at the time of the initial report with at least the following information:  
 
 Subject, treatment, and Study identifiers; 
 Investigator’s name and address; 
 Description of the event, action taken, and outcome; 
 Date and time of onset of the event and current status; 
 Any suspect (Study or concomitant) drug, with its start date, dose, and form of 
administration; 
 Reason the AE is regarded as serious; 
Current assessment of causality; and 
 Any other available diagnostic information that will contribute to the 
understanding of the event.  
 
The Investigator must report to 
 within 24 hours of when the 
Investigator is aware of the occurrence of the SAE, whether or not the SAE is related 
to the Study drug. An initial written report should be submitted within 24 hours of the 
Investigator’s awareness of the event, consisting of the SAE report form accompanied 
by the demographics, medical history, AE, and the concomitant medications pages 
from the CRF. All pertinent information must be followed by a full written follow-up 
report to 
 within 3 calendar days. As complete a report as 
possible, (e.g., results of any additional tests) should be forwarded within 8 additional 
calendar days to 
 Any significant new information on the 
SAE and final outcome must be supplied promptly to 
 
 will notify the Lead Investigator of any significant safety 
findings arising from all SAE reports. 
 
The SAEs must be reported to the Medical Monitor/Sponsor medical representative: 
 
 
 
 
 
  
 


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Investigators will be notified of any SUSAR reports or unanticipated safety concern 
occurring in other sites conducting studies on RP103.  Investigators will notify their 
local IRB or EC of such reports or safety concerns in accordance with regulatory 
requirements.  
If an Investigator has safety concerns he/she wishes to discuss with the Raptor Medical 
Monitor he/she should contact the Raptor Medical Monitor. 
10.4. Follow-up of Adverse Events and Serious Adverse Events 
The reference time point for adverse events is the period from signing the informed 
consent through the final study visit. Adverse events/experiences will be followed until 
the event resolves or stabilizes and must be recorded on the AE eCRF.  If clinically 
significant findings are present at the Study termination, a determination will be made 
about each persistent clinically significant finding. If not clinically important (i.e., does 
not pose a health risk to the subject) then follow-up will cease. If clinically important, 
additional follow-up will continue on a case-by-case basis until satisfactory resolution 
or resolution with sequelae is determined. Any SAE assessed as not related to Study 
drug will be followed as clinically indicated until its resolution or, if not resolving, until 
considered stable or until the completion study visit, whichever comes first. Any SAE 
assessed as related to Study drug will be followed as clinically indicated until its 
resolution or resolution with sequelae is determined. 
Outcome may be classified as resolved, resolved with sequelae, continuing, fatal, or 
unknown (lost to follow-up). 
Pregnancy 
If a female subject becomes pregnant during the Study, the Sponsor’s Medical Monitor 
must be notified immediately. Although pregnancy is not considered an SAE, an 
abnormal outcome of pregnancy may lead to a SAE. Therefore, the SAE Report Form 
will be used to report the pregnancy of a female Study participant to the Sponsor. 
Pregnancies must be followed until birth, termination of the pregnancy, or loss of 
subject follow-up. 
11. 
Statistical Plan 
11.1. Statistical Methods 
This Study is designed to assess the safety and tolerability of Cysteamine Bitartrate 
Delayed-release Capsules (RP103) in patients with cystinosis.  
A statistical analysis plan will be developed that describes in detail, the statistical 
methods to be used and will be finalized prior to database lock. This document may 
modify the plans outlined in the protocol; however, any major modifications of the 
Study endpoint definitions will be reflected in a protocol amendment. 
Demographic and disposition data, drug administration, medical history, prior and 
concomitant medications, AEs, clinical laboratory measurements, vital signs, ECG 
measurements and physical examination findings will be summarized. Descriptive 
summaries of mean and mean changes from screening will be presented for the safety 
laboratory parameters (hematology, serum chemistry and urinalysis, as applicable), 


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vital signs and ECGs.  The overall incidence of subjects with adverse events will be 
summarized by System Organ Class (SOC) and Preferred Term (PT) using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Summaries by maximum severity, drug –relationship (as determined by the 
investigator) and drug discontinuation will also be presented. In addition, summaries 
of annualized exposure adjusted AE rates as well as summaries of the incidence of 
subjects with AEs by study year of onset (Year 1, Year 2 and Year 3 or later) will be 
generated. The overall incidence of subjects with serious adverse events (SAEs) will 
be summarized by SOC and PT. The annualized exposure adjusted SAE rates as well 
as the incidence by study year will also be tabulated.  Safety laboratory values outside 
reference ranges will be flagged in laboratory listings. 
AEs will be categorized using MedDRA, and listed by verbatim, primary term and 
SOC. SAEs will include MedDRA coding of primary and secondary (non serious) 
event terms. 
 
 
 
 
 
 
 
 
Cysteamine concentrations and WBC cystine levels will be summarized per patient.  
Pharmacokinetics: 
The steady-state plasma concentration profiles of cysteamine will be determined for 
each patient and the AUC0-t, Cmin, Cmax, Tmax and t½ PK parameters will be estimated 
using non-compartmental methods. 
11.2. Analysis Set 
All subjects who receive at least 1 dose of Study drug (RP103) will be included in the 
safety analysis set. All subjects who complete all protocol-specified dosing days 
(RP103) with evaluable PK, PD data will be included in the PK, PD analysis sets. 
11.3. Sample Size Considerations 
Sample size is determined by the number of patients who participated in the previous 
phase III Study (RP103-03) and any additional patients, who did not complete the 
RP103-03 study, who enroll after all patients that participated in RP103-03 have 
completed and data have been analyzed. 
11.4. Interim Analysis 
An interim safety analysis will be performed in time to provide a safety update during 
the NDA process. 


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11.5. Accountability Procedure 
Missing values will not be imputed. 
11.6. Termination Criteria 
All ongoing enrolled patients will continue to be dosed until patient withdrawal, or the 
Investigator withdraws the patient from the Study. 
11.7. Deviation Reporting 
The following protocol deviations will be recorded and summarized in the final report: 
1) eligibility (inclusion/exclusion) violations, 2) study drug dosing violations, 3) 
excluded medication violations, 4) procedures performed outside the protocol-
specified window, 5) procedures not done, 6) subject non-compliance and 7) other, to 
be specified by the Investigator. 
All protocol deviations will be presented in a data listing. 
12. 
Administrative aspects 
 
12.1. Change in Protocol 
 
There will be no alterations in the protocol without prior agreement between the 
Sponsor’s representative, the IRB/EC, and the Investigator. Protocol amendments will 
be submitted to Regulatory Authorities and to the Investigators for submission and 
reviewed by IRB/ECs. 
 
12.2. Disclosure 
 
All information provided regarding the Study, as well as all information 
collected/documented during the course of the Study will be regarded as confidential. 
The Investigator agrees not to disclose such information in any way without prior 
written permission from the Sponsor.  
 
Any publication of the results, either in part or in total (articles in journals or 
newspapers, oral presentations, abstracts, etc.) by the Investigator(s) or their 
representative(s), shall require prior notification and review, within a reasonable time 
frame, by the Sponsor, and cannot be made in violation of the Sponsor’s confidentiality 
restrictions or to the detriment of the Sponsor’s intellectual property rights. 
 
12.3. Monitoring 
 
The Sponsor will designate a Sponsor’s Study Monitor (i.e., clinical research associate) 
who will be responsible for monitoring this clinical trial. The Sponsor’s Study Monitor 
will monitor the Study conduct; insure the proper completion and retention of original 
source documentation completion and retention, accurate Study drug accountability 


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records and prompt data entry to eCRF. To this end, the Sponsor’s Study Monitor will 
visit the Study site at suitable intervals and be in frequent contact through verbal and 
written communication. It is essential that the Sponsor’s Study Monitor have access to 
all documents (related to the Study and the individual participants) at any time these 
are requested. In turn, the Sponsor’s Study Monitor will adhere to all requirements for 
subject confidentiality as outlined in the Informed consent form (ICF). The 
Investigator(s) or their representative(s) will be expected to cooperate with the 
Sponsor’s Study Monitor, to be available during a portion of the monitoring visit to 
answer questions, and to provide any missing information. Investigator(s) or their 
representative(s) are required to respond in writing to any deficiencies or protocol 
deviations noted by the monitor in the site visit report.   
 
12.4. Institutional Review Board or Ethics Committee 
 
In accordance with 21 CFR 56, the protocol, advertisement, and Informed Consent 
Form (ICF) and assents will be reviewed and approved by the IRB or EC. The Sponsor 
will supply relevant material for the Investigator to submit to the IRB/EC for the 
protocol’s review and approval. Verification of the IRB/EC unconditional approval of 
the protocol and the written ICF/assent statement will be transmitted to the Investigator.  
 
The IRB/EC will be informed by the Investigator(s) or their representative(s) of 
subsequent protocol amendments and of serious and unexpected AEs. Approval for 
protocol amendments will be transmitted in writing to the Investigator. If requested, 
the Investigator(s) or their representative(s) will permit audits by the IRB/EC, Sponsor 
Representatives and Regulatory inspections by providing direct access to source 
data/documents.  
 
The Investigator(s) or their representative(s) will provide the IRB/EC with progress 
reports at appropriate intervals (not to exceed one year) and a Study Progress Report 
following the completion, termination, or discontinuation of the Investigator(s)’ 
participation in the Study. 
 
12.5. Patient Insurance 
 
If applicable, patient insurance will be secured according to national or local 
requirements. Where applicable, the name and address of the relevant insurance 
company, the certificate of insurance, the policy number and the sum insured will be 
provided in the Investigator’s File. 
 
12.6. Informed Consent and Assent 
 
Written informed assent for the Study will be obtained from all pediatric patients and 
informed consent will be obtained from their parents or legal guardian before protocol-
specific procedures are carried out. For adults above the age of 18 years written 
informed consent for the Study will be obtained before protocol-specific procedures 
are carried out. The ICF/assents generated by the Investigator(s) or their 


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representative(s) will be approved (along with the protocol) by the IRB or EC and will 
be acceptable to the Sponsor. 
 
The Investigator(s) or their representative(s) will explain the nature of the Study and 
the action of the test product, and will provide time for subject’s questions and answers. 
 
The patient (or parent) will be informed that participation is voluntary and that they can 
withdraw from the Study at any time. In accordance with 21 CFR 50, the informed 
consent process shall be documented by the use of a written ICF approved by the IRB 
or EC and will be signed by the subject prior to protocol-specific procedures being 
performed. The consent process will be completely documented in each subject’s 
source record. 
 
The patient (or parent) will be given a copy of the signed consent/assent, and the 
originals will be maintained with the patient’s records. 
 
12.7. Records 
 
The results from Screening and data collected during the Study will be recorded in the 
patient’s CRF (either paper or electronic CRF). To maintain confidentiality, the patients 
will be identified only by numbers and/or initials. 
 
If applicable, the completed CRFs will be transferred to the Sponsor or designee and 
copies of each CRF will be retained by the Investigator. All source documents, records, 
and reports will be retained by the Study site in accordance with 21 CFR 312.62(c). All 
primary data, or copies thereof (e.g., laboratory records, CRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the Study and are necessary for the reconstruction and 
evaluation of any Study report, will be retained in the Study site archives. 
 
12.8. Quality Control and Quality Assurance 
 
Accurate, consistent and reliable data will be ensured through the use of standard 
practices and procedures. Site initiation visits will be conducted at the clinical site. 
Experienced clinical research associate(s) (CRAs) will monitor the Study and verify 
that the data is accurate. Sponsor, or designee, representatives of the FDA or other 
Regulatory Agencies, including the IRB/EC representatives, may also conduct an audit 
of the study. Sponsor will contract with a qualified contract research organization(s) 
(CRO) to perform the data management of this trial. The Medical Monitor, CRAs and 
site personnel will be trained by the CRO and/or Sponsor. Analysis of samples for 
plasma cysteamine and WBC cystine will be performed by a central bioanalytical 
laboratory contracted by Raptor. Drug Safety Reporting will be the responsibility of 
Sponsor or its representative. System backups for data stored at the CRO, and records 
retention for the Study data will be consistent with the standard procedures for the 
CRO. 
 


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12.9. Archiving of Data 
 
The Investigator shall arrange for the retention of the patient identification codes for at 
least 15 years after completion or discontinuation of the Study. Patient files and all 
original source documents shall be kept for the maximum period of time permitted by 
the hospital or institution. The Investigator shall retain the trial related essential 
documents until the Sponsor informs the Investigator these documents are no longer 
needed.  
 
All data and documents shall be made available at the request of relevant authorities. 
The Investigator shall inform the Sponsor before any records are destroyed. 
 
12.10. Study Funding 
 
The Sponsor will support the work of the Investigator. All details are fixed in the 
individual contracts or financial agreements. 
 
 
 


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13. 
References 
 
Belldina, E. B., M. Y. Huang, et al. (2003). "Steady-state pharmacokinetics and 
pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis 
patients." Br J Clin Pharmacol 56(5): 520-525. 
Bieri, D., R. A. Reeve, et al. (1990). "The Faces Pain Scale for the self-assessment of the 
severity of pain experienced by children: development, initial validation, and 
preliminary investigation for ratio scale properties." Pain 41(2): 139-150. 
Dalton, N. and C. Turner (2005). "Leukocyte cystine: The key measurement." J Inherit 
Metab Dis 28: 1206-1207. 
Dohil, R., M. Fidler, et al. (2006). "Understanding intestinal cysteamine bitartrate 
absorption." J Pediatr 148(6): 764-769. 
Elenberg, E., L. L. Norling, et al. (1998). "Feeding problems in cystinosis." Pediatr Nephrol 
12(5): 365-370. 
Gahl, W. A., J. Z. Balog, et al. (2007). "Nephropathic cystinosis in adults: natural history and 
effects of oral cysteamine therapy." Ann Intern Med 147(4): 242-250. 
Hicks, C. L., C. L. von Baeyer, et al. (2001). "The Faces Pain Scale-Revised: toward a 
common metric in pediatric pain measurement." Pain 93(2): 173-183. 
Powell KL, Langman CB. An unexpected problem in the clinical assessment of cystinosis. 
Pediatr Nephrol 2012. 
Kleta, R., I. Bernardini, et al. (2004). "Long-term follow-up of well-treated nephropathic 
cystinosis patients." J Pediatr 145(4): 555-560. 
Levtchenko, E. N., C. M. van Dael, et al. (2006). "Strict cysteamine dose regimen is required 
to prevent nocturnal cystine accumulation in cystinosis." Pediatr Nephrol 21(1): 110-
113. 
Schneider, J. A. (2004). "Treatment of cystinosis: simple in principle, difficult in practice." J 
Pediatr 145(4): 436-438. 
Smolin, L. A., K. F. Clark, et al. (1988). "A comparison of the effectiveness of cysteamine 
and phosphocysteamine in elevating plasma cysteamine concentration and decreasing 
leukocyte free cystine in nephropathic cystinosis." Pediatr Res 23(6): 616-620. 
Thoene, J. G., R. G. Oshima, et al. (1976). "Cystinosis. Intracellular cystine depletion by 
aminothiols in vitro and in vivo." J Clin Invest 58(1): 180-189. 
Varni, J. W., C. A. Limbers, et al. (2007). "Impaired health-related quality of life in children 
and adolescents with chronic conditions: a comparative analysis of 10 disease clusters 
and 33 disease categories/severities utilizing the PedsQL 4.0 Generic Core Scales." 
Health Qual Life Outcomes 5: 43. 
Varni, J. W., C. A. Limbers, et al. (2007). "Parent proxy-report of their children's health-
related quality of life: an analysis of 13,878 parents' reliability and validity across age 
subgroups using the PedsQL 4.0 Generic Core Scales." Health Qual Life Outcomes 5: 
2. 
von Baeyer, C. L. (2001). "The Faces Pain Scale - Revised (English & French)." Pediatric 
Pain Sourcebook, from www.painsourcebook.ca. 
Ware, J. E., Jr., R. H. Brook, et al. (1986). "Comparison of health outcomes at a health 
maintenance organisation with those of fee-for-service care." Lancet 1(8488): 1017-
1022. 


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Ware, J. E., Jr. and C. D. Sherbourne (1992). "The MOS 36-item short-form health survey 
(SF-36). I. Conceptual framework and item selection." Med Care 30(6): 473-483. 
 








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14.3. Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended by the: 
 
29th WMA General Assembly, Tokyo, Japan, October 1975. 
35th WMA General Assembly, Venice, Italy, October 1983. 
41st WMA General Assembly, Hong Kong, September 1989. 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 
1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002. 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 
2004. 
 
A. 
INTRODUCTION 
1. 
The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other 
participants in medical research involving human subjects.  Medical research 
involving human subjects includes research on identifiable human material or 
identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people.  
The physician's knowledge and conscience are dedicated to the fulfillment of 
this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the 
physician with the words, "The health of my patient will be my first 
consideration," and the International Code of Medical Ethics declares that, "A 
physician shall act only in the patient's interest when providing medical care 
which might have the effect of weakening the physical and mental condition of 
the patient." 
4. 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-being 
of the human subject should take precedence over the interests of science and 
society. 
6. 
The primary purpose of medical research involving human subjects is to 
improve prophylactic, diagnostic and therapeutic procedures and the 
understanding of the etiology and pathogenesis of disease.  Even the best proven 
prophylactic, diagnostic, and therapeutic methods must continuously be 
challenged through research for their effectiveness, efficiency, accessibility and 
quality. 


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7. 
In current medical practice and in medical research, most prophylactic, 
diagnostic and therapeutic procedures involve risks and burdens. 
8. 
Medical research is subject to ethical standards that promote respect for all 
human beings and protect their health and rights.  Some research populations 
are vulnerable and need special protection.  The particular needs of the 
economically and medically disadvantaged must be recognized.  Special 
attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom 
the research is combined with care. 
9. 
Research Investigators should be aware of the ethical, legal and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements.  No national ethical, legal or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for 
human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. 
It is the duty of the physician in medical research to protect the life, health, 
privacy, and dignity of the human subject. 
11. 
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific 
literature, other relevant sources of information, and on adequate laboratory 
and, where appropriate, animal experimentation. 
12. 
Appropriate caution must be exercised in the conduct of research which may 
affect the environment, and the welfare of animals used for research must be 
respected. 
13. 
The design and performance of each experimental procedure involving human 
subjects should be clearly formulated in an experimental protocol.  This 
protocol should be submitted for consideration, comment, guidance, and where 
appropriate, approval to a specially appointed ethical review committee, which 
must be independent of the investigator, the Sponsor or any other kind of undue 
influence.  This independent committee should be in conformity with the laws 
and regulations of the country in which the research experiment is performed.  
The committee has the right to monitor ongoing trials.  The researcher has the 
obligation to provide monitoring information to the committee, especially any 
serious adverse events.  The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects. 
14. 
The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with the 
principles enunciated in this Declaration. 


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15. 
Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically 
competent medical person.  The responsibility for the human subject must 
always rest with a medically qualified person and never rest on the subject of 
the research, even though the subject has given consent. 
16. 
Every medical research project involving human subjects should be preceded 
by careful assessment of predictable risks and burdens in comparison with 
foreseeable benefits to the subject or to others.  This does not preclude the 
participation of healthy volunteers in medical research.  The design of all 
studies should be publicly available. 
17. 
Physicians should abstain from engaging in research projects involving human 
subjects unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed.  Physicians should cease any 
investigation if the risks are found to outweigh the potential benefits or if there 
is conclusive proof of positive and beneficial results. 
18. 
Medical research involving human subjects should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
subject.  This is especially important when the human subjects are healthy 
volunteers. 
19. 
Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the results 
of the research. 
20. 
The subjects must be volunteers and informed participants in the research 
project. 
21. 
The right of research subjects to safeguard their integrity must always be 
respected.  Every precaution should be taken to respect the privacy of the 
subject, the confidentiality of the patient's information and to minimize the 
impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
22. 
In any research on human beings, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail.  The subject should 
be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal.  After ensuring that the 
subject has understood the information, the physician should then obtain the 
subject's freely-given informed consent, preferably in writing.  If the consent 
cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
23. 
When obtaining informed consent for the research project the physician should 
be particularly cautious if the subject is in a dependent relationship with the 
physician or may consent under duress.  In that case the informed consent 
should be obtained by a well-informed physician who is not engaged in the 
investigation and who is completely independent of this relationship. 


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24. 
For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the investigator 
must obtain informed consent from the legally authorized representative in 
accordance with applicable law.  These groups should not be included in 
research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent 
persons. 
25. 
When a subject deemed legally incompetent, such as a minor child, is able to 
give assent to decisions about participation in research, the investigator must 
obtain that assent in addition to the consent of the legally authorized 
representative. 
26. 
Research on individuals from whom it is not possible to obtain consent, 
including proxy or advance consent, should be done only if the physical/mental 
condition that prevents obtaining informed consent is a necessary characteristic 
of the research population.  The specific reasons for involving research subjects 
with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review 
committee.  The protocol should state that consent to remain in the research 
should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
27. 
Both authors and publishers have ethical obligations.  In publication of the 
results of research, the investigators are obliged to preserve the accuracy of the 
results.  Negative as well as positive results should be published or otherwise 
publicly available.  Sources of funding, institutional affiliations and any 
possible conflicts of interest should be declared in the publication.  Reports of 
experimentation not in accordance with the principles laid down in this 
Declaration should not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH 
COMBINED WITH MEDICAL CARE 
 
The physician may combine medical research with medical care, only to the 
extent that the research is justified by its potential prophylactic, diagnostic or 
therapeutic value.  When medical research is combined with medical care, 
additional standards apply to protect the patients who are research subjects. 
 
The benefits, risks, burdens and effectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic 
methods.  This does not exclude the use of placebo, or no treatment, in studies 
where no proven prophylactic, diagnostic or therapeutic method exists.1 
 
At the conclusion of the study, every patient entered into the study should be 
assured of access to the best proven prophylactic, diagnostic and therapeutic 
methods identified by the study.2 
 
The physician should fully inform the patient which aspects of the care are 
related to the research.  The refusal of a patient to participate in a study must 
never interfere with the patient-physician relationship. 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 83 of 91 
 
In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, with 
informed consent from the patient, must be free to use unproven or new 
prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating 
suffering.  Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy.  In all cases, new 
information should be recorded and, where appropriate, published.  The other 
relevant guidelines of this Declaration should be followed. 
1) 
Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-
controlled trial and that in general this methodology should only be used in the absence of existing 
proven therapy.  However, a placebo-controlled trial may be ethically acceptable, even if proven therapy 
is available, under the following circumstances: 
- 
Where for compelling and scientifically sound methodological reasons its use is necessary to 
determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or 
- 
Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor 
condition and the patients who receive placebo will not be subject to any additional risk of 
serious or irreversible harm.  All other provisions of the Declaration of Helsinki must be 
adhered to, especially the need for appropriate ethical and scientific review. 
2) 
Note of clarification on paragraph 30 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that it is necessary during the study planning process to identify 
post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified 
as beneficial in the study or access to other appropriate care.  Post-trial access arrangements or other care 
must be described in the study protocol so the ethical review committee may consider such arrangements 
during its review. 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 84 of 91 
14.4. Required Elements of Informed Consent 
 
The informed consent discussion, the written informed consent form, and any other 
written information provided to subjects should include explanations of the following: 
A. 
That the trial involves research. 
B. 
The purpose of the trial. 
C. 
The trial treatments, and the probability for random assignment to each 
treatment. 
D. 
The trial procedures to be followed, including all invasive procedures. 
E. 
The subject's responsibilities. 
F. 
The experimental aspects of the trial. 
G. 
The reasonably foreseeable risks or inconveniences to the subject. 
H. 
The reasonably expected benefits. When there is no intended clinical benefit to 
the subject, the subject should be made aware of this. 
I. 
The alternative procedures or courses of treatment that may be available, and 
their important potential benefits and risks. 
J. 
The compensation or treatment available to the subject in the event of trial-
related injury. 
K. 
The anticipated prorated payment, if any, to the subject for participating in the 
trial. 
L. 
The anticipated expenses, if any, to the subject for participating in the trial. 
M. 
That the subject's participation in the trial is voluntary and that the subject may 
refuse to participate or withdraw from the trial, at any time, without penalty or 
loss of benefits to which the subject is otherwise entitled. 
N. 
That the monitors, auditors, IRB, and regulatory authorities will be granted 
direct access to the subject's original medical records for verification of clinical 
trial procedures or data, without violating the confidentiality of the subject, to 
the extent permitted by the applicable laws and regulations and that, by signing 
a written informed consent form, the subject or the subject's legally acceptable 
representative is authorizing such access. 
O. 
That the records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws or regulations, will not be made publicly 
available. If the results of the trial are published, the subject’s identity will 
remain confidential. 
P. 
That the subject or the subject's legally acceptable representative will be 
informed in a timely manner if information becomes available that may be 
relevant to the subject's willingness to continue participation in the trial. 
Q. 
The person to contact for further information regarding the trial and the rights 
of trial subjects, and whom to contact in the event of trial-related injury. 
R. 
The foreseeable circumstances or reasons under which the subject's 
participation in the trial may be terminated. 
S. 
The expected duration of the subject's participation in the trial. 
T. 
The approximate number of subjects involved in the trial. 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 85 of 91 
14.5. Instructions for Calculating Body Mass Index and Surface Area 
 
 Screening height will be used for all body mass index (BMI) calculations. 
The formula for calculating BMI is: 
 
BMI = weight (kg) ÷ height (m)2 
 
Example:  The BMI of a subject 1.7 m tall who weighs 90 kg is: 
BMI = 90 ÷ 1.7 m2 = 31.1 kg/m2 
 
 To calculate body surface area (m2) the method of Haycock is being used 
[Haycock GB, et al, 1978] 
m2 = [Height (cm) 0.3964 x Weight (kg) 0.5378] 0.024265 
Note: 2.2 lb = 1 kg; 1 in = 0.0254 m = 2.54 cm 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 86 of 91 
14.6. Pharmacokinetic Sample Collection and Processing 
 
14.6.1. Collection 
 
Blood samples (approximately 1 mL) for analysis of cysteamine will be collected in 
chilled (+2°C to +8°C) 1 or 2 mL green-top Vacutainer evacuated collection tubes 
containing sodium heparin. 
 
Each sample tube should bear the following information on the label: 
 
 RP103-04 
 Subject identification number and/or initials 
 Nominal time 
 Date 
 
After collection, tubes will be mixed by gently by inverting 2 to 3 times and stored in 
an ice water bath until they are centrifuged (i.e., within 1 hour of collection). 
 
14.6.2. Processing 
 
Blood samples will be centrifuged at 2000g and 4C for at least 10 minutes. Samples 
must be processed within 1 hour of collection. The plasma will be split into two 
approximately equal volumes and placed into CryoTubes and frozen at approximately 
–70C or below.   
 
All CryoTubes will be properly labeled and stored at approximately –70C or below 
until transfer. Each CryoTube should bear the following information on the label: 
 
 RP103-04 
 Subject identification number and/or initials 
 Nominal time 
 Date 
 Tube number of the total number of plastic CryoTubes 
 
1. One of the two aliquots will be shipped to the central bioanalytical laboratory 
with sufficient dry ice to last the duration of transit. The second aliquot should 
be shipped separately.  
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 87 of 91 
14.7. Pharmacodynamic Sample Collection and Processing 
 
14.7.1. Collection 
 
Blood samples (4 mL) for analysis of WBC cystine will be collected in a 4 mL green-
top Vacutainer evacuated collection tubes containing sodium heparin. 
 
Each sample tube should bear the following information on the label: 
 
 RP103-04 
 Subject identification number and/or initials 
 Nominal time 
 Date 
 
After collection, tubes will be mixed by gently by inverting 2 to 3 times and stored at 
room temperature and should be processed as soon as possible (i.e., within 30-60 
minutes of collection). 
 
14.7.2. Processing 
 
The following processing procedure was taken from the University of California, San 
Diego Cystine Determination Laboratory website.   
 
Refer to the study manual for the actual procedure.  A summary of this procedure is 
provided below.  If any discrepancies exist then defer to the study laboratory manual 
for precise instructions. 
2. ACD-Dextran should be at room temperature before using. The 0.9% NaCl, 3.6% 
NaCl, and distilled water should be placed on ice. Determine the correct setting for 
your centrifuge from the chart provided in your laboratory manual. 
3. Draw 4 mL of heparinized blood (0.1 mL heparin, Na or Li in syringe or a green 
top vacutainer). 
4. As soon as possible transfer blood from vacutainer to the 15 mL centrifuge tube, 
add an equal volume of ACD-Dextran, cap and invert to mix. Then remove cap or 
trapped blood may dribble down later. Set on ice for 30-45 minutes. 
5. Transfer supernatant to a clean 15 mL centrifuge tube. Centrifuge for 10 minutes at 
5° C at your centrifuge setting. 
6. Discard supernatant. The white cell pellet will look red. 
7. Add 0.8 mL of 0.9% NaCl and 2.4 mL of distilled water. Start timing and vortex 
continuously at moderate speed for 90 seconds and then add 0.8 mL of 3.6% NaCl. 
If there is a small red cell clot, remove it. Spin for 3 minutes at 5° C at your 
centrifuge setting. 
8. Discard supernatant and repeat step 6. 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 88 of 91 
9. Add 3.0 mL of 0.9% NaCl. Gently resuspend pellet by vortexing. Pellet does not 
have to be completely resuspended. Spin for 3 minutes at 5° C at your centrifuge 
setting. 
10. After discarding supernatant, add as accurately as possible, 0.3 mL of distilled 
water. Re-suspend gently and transfer all of the cell suspension to a clean, labeled, 
Eppendorf tube. If the pellet is gummy and resists suspension, it may help to cut 
off the end of a clean blue tip for use in transferring. Transfer EVERYTHING to 
the Eppendorf tube, even if it remains a glob. 
11. Lyse the white cells by freezing in a dry ice/ethanol bath and then place in a warm 
water bath until just thawed and no longer. Tube may be supported in the bath. 
Repeat two more times. 
12. Wipe off the tube. Immediately transfer all (0.1 mL) of the 12% sulfosalicylic acid 
(SSA) solution to the Eppendorf containing the lysed cells and vortex. Label with 
subject identification number and/or initials, date, and nominal time.  
13. Freeze sample to -70°C or below. The sample can remain frozen for at least two 
weeks. 
The sample(s) will be sent to the central bioanalytical laboratory with sufficient dry ice 
to last the duration of transit. 
 




Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 90 of 91 
14.9. RP103 DOSING INSTRUCTIONS 
14.9.1. RP103 DOSE AND FOOD TIMING 
 Subjects should not eat for at least 2 hours before taking and at least 30 
minutes after taking RP103. 
 Subjects who are unable to take RP103 without eating should eat only a small 
amount (approximately 4 ounces or ½ cup) of food between 1 hour before and 
1 hour after taking RP103. 
 Dairy products should be withheld between 1 hour before and 1 hour after 
taking RP103. 
14.9.2. RP103 DOSING IN FOOD 
Below are instructions for subjects unable or unwilling to take whole, intact RP103 
capsules and prefer to dose in food. 
OPTION 1 – EATING: 
- 
Open all the capsules for either the morning or evening dose and sprinkle the 
contents onto approximately 4 ounces of an acceptable soft food. 
- 
Gently stir the medication beads into the soft food, creating an RP103-food 
mixture. 
- 
Eat the entire amount of RP103-food mixture.  This may be followed by 8 ounces 
(1 cup) of an acceptable liquid. 
OPTION 2 – ADMINISTRATION BY G-TUBE, NG-TUBE OR GJ-TUBE: 
- 
Open all the capsules for either the morning or evening dose and sprinkle the 
contents onto approximately 4 ounces of applesauce (NOT liquid). 
- 
Gently stir the medication beads into the soft food, creating an RP103-applesauce 
mixture. 
- 
Place the syringe tip at the bottom of the container of RP103-applesauce mixture; 
draw up a third of the mixture. 
- 
Keeping the syringe tip at the bottom of the container, mix for a few seconds, 
then draw up another one-third of the RP103-applesauce mixture.  Repeat this 
step and draw up the final one-third of the RP103-applesauce mixture. This 
method prevents air from entering the syringe. 
- 
Place syringe on the feeding tube and slowing dispense until the RP103-
applesauce mixture is at the end.  This removes any air from the tube. 
- 
Place the tube on the button.  Deliver the RP103-applesauce mixture at a rate of 
10mL/10 seconds, until the syringe is fully dispensed into the tube. 
- 
Take a syringe of acidic juice or other acceptable liquid and deliver through the 
tube to ensure the entire RP103-applesauce mixture has been administered into 
the body, and no beads are left in the tube. 
 
* 
The RP103-food/RP103-applesauce mixture must be eaten or administered within 
2 hours after preparation. 
 


Raptor Pharmaceuticals Inc.   
 Cysteamine Bitartrate Delayed-release Capsules (RP103) 
CONFIDENTIAL PROTOCOL 
 
IND 103,694: Study RP103-04 
 
 
Amendment 9:  18 November 2015 
 
Page 91 of 91 
14.9.3. RP103 DOSING IN LIQUID 
Below are instructions for subjects unable or unwilling to take whole, intact RP103 
capsules and prefer to dose with liquid. 
OPTION 1 – ADMINISTRATION BY ORAL DOSING SYRINGE: 
- 
Open all the capsules for either the morning or evening dose and sprinkle the 
contents into 4-6 ounces of an acceptable liquid. 
- 
Mix gently for 5 minutes, then draw up the RP103-liquid mixture into a dosing 
syringe.  Administer the entire dose by mouth. Do NOT administer the RP103-
liquid mixture by G-tube, NG-tube or GJ-tube. 
- 
Eat the entire amount of RP103-food mixture.  This may be followed by 8 ounces 
(1 cup) of an acceptable liquid. 
OPTION 2 – DRINKING: 
- 
Open all the capsules for either the morning or evening dose and sprinkle the 
contents into 4-6 ounces of an acceptable liquid. 
- 
Mix gently for 5 minutes in an uncovered cup, or – shake gently for 5 minutes in 
a covered cup (e.g., “sippy cup”).  Drink all of the RP103-liquid mixture. 
 
* 
The RP103-liquid mixture must be drunk or administered within 30 minutes after 
preparation. 
 
14.9.4. ACCEPTABLE/UNACCEPTABLE FOODS AND LIQUIDS 
Acceptable soft foods for RP103 dosing: 
Applesauce (not compote, not chunky), non-dairy pudding, or berry jelly. 
 
Acceptable liquids for RP103 dosing: 
Fruit juice, e.g., orange juice (preferred), apple juice or any acidic fruit juice, PolyCitra, 
PolyCitra-K, non-caffeinated soda (allow bubbles to disperse so that soda is somewhat 
flat), or bottled or tap water with lemon concentrate added (¼  teaspoon concentrate per 
¼ ounce water / 1mL lemon concentrate per 7mL water). 
 
Unacceptable foods and liquids for RP103 dosing: 
Milk, dairy products, alcoholic beverages, liquids or foods with a pH from neutral to 
basic (e.g., bottled or tap water without lemon concentrate added). 

SAP_001.pdf: 




Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol RP103-04 
 
A Long-Term, Open-Label, Safety and Efficacy Study of Cysteamine Bitartrate Delayed- 
released Capsules (RP103) in Patients with Cystinosis 
 
 
Protocol Number: 
(Version Date) 
RP103-04 
21 November 2010 (Original) 
 
18 November 2015 (Amendment 9) 
Name of Test Drug: 
RP103 
Phase: 
3 Long-Term Safety / Efficacy 
Methodology: 
Open label 
 
Sponsor: 
Horizon Pharma USA, Inc. 
150 S. Saunders Road 
Lake Forest, IL 60045  
 
Sponsor Representative: 
 
  
 
Chief Medical Officer & Executive 
Vice President Research and 
Development 
Horizon Pharma Inc. 
 
 
Document Date: 
 
 
 07AUG2017 
Document Version: 
Version 2.0 


Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
CONFIDENTIAL
2
 
 
 
 
SIGNATURE PAGE 
 
 
Protocol Title: 
A Long-Term, Open-Label, Safety and Efficacy Study 
of  Cysteamine Bitartrate Delayed-release Capsules 
(RP103) in Patients with Cystinosis 
 
 
Sponsor: 
Horizon Pharma USA, Inc. 
150 S. Saunders Road 
Lake Forest, IL 60045 
Protocol Number: 
RP103-04 
Document Date/Version: 
07August 2017 / v2.0 
Cytel, Inc. Signatory: 
 
Cytel Inc. 
955 Chesterbrook Blvd. Suite 
Chesterbrook, PA 19087 
 
 
 
 
Signature:   
 
Date:  
  
Sponsor Approval 
 
Sponsor Signatory: 
 
Associate Director, Biostatistics 
Horizon Pharma Inc. 
150 S. Saunders Road 
Lake Forest, Il 60045 
 
 
Senior Medical Director 
Horizon Pharma Inc. 
150 S. Saunders Road 
Lake Forest, Il 60045 
 
Signature:____________________________________ 
Date:________________________________________ 
 
 
 
 
Signature:____________________________________ 
 
Date:________________________________________ 




Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
CONFIDENTIAL
4
 
 
5. 
SUBJECT DISPOSITION 
................................................................................................... 18 
6. 
PROTOCOL DEVIATIONS 
............................................................................................... 18 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
.......................................... 18
 
8. 
PHARMACOKINETIC, PHARAMCODYNAMIC AND EXPLORATORY 
EVALUATIONS .................................................................................................................. 19 
8.1.  Pharmacodynamics
 .............................................................................................................. 19
 
8.2.  Pharmacokinetics
 .................................................................................................................
 19
 
 
 
 
 
 
 
 
 
 
 21
 
9. 
SAFETY ANALYSES 
.......................................................................................................... 22 
9.1.  Study Drug Exposure 
........................................................................................................... 22
 
9.2.  Adverse Events 
.....................................................................................................................
 22
 
9.3.  Laboratory Data 
...................................................................................................................
 23
 
9.4.  Vital Signs and Physical Examinations 
.............................................................................. 24 
9.5.  Electrocardiogram ...............................................................................................................
 24
 
9.6.  Concomitant Medications 
.................................................................................................... 24 
10. 
CHANGES TO PLANNED ANALYSES 
........................................................................... 25 
11. 
TABLES AND LISTINGS CONVENTIONS 
.................................................................... 25 
12. 
LIST OF STATISTICAL TABLES, LISTINGS, AND FIGURES TO BE 
PROGRAMMED ................................................................................................................. 26 
12.1. Tables ....................................................................................................................................
 26
 
12.2. Listings
 ..................................................................................................................................
 34
 
12.3. Figures
 ...................................................................................................................................
 34
 
 
 
 
 
 
 
 
 
 
 
 


Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
CONFIDENTIAL
5
 
 
 
ABBREVIATIONS 
 
Abbreviation 
Definition 
AE
 Adverse
 
Event
 
ATC-4 
Anatomical Therapeutic Chemical 4th Level 
BMI
 Body
 
Mass
 
Index
 
BSA 
Body Surface Area 
CSR
 Clinical
 
Study
 
Report
 
ECG
 Electrocardiogram
 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
ICH 
International Conference on Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
NDS 
New Drug Submission 
 
 
PK
 Pharmacokinetic
 
PD
 Pharmacodynamic
 
PT
 Preferred
 
Term
 
SAP
 Statistical
 
Analysis
 
Plan
 
SD
 Standard
 
Deviation
 
 
 
SOC 
System Organ Class 
 
 
WHO 
World Health Organization 




Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
CONFIDENTIAL
7
 
 
 
 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
 
 
This is a long-term, open-label study of the safety, tolerability and steady-state 
pharmacokinetics and pharmacodynamics of RP103 in pediatric and adult subjects with 
cystinosis. Initially only subjects who completed the previous phase III Study (RP103-03) will 
be offered the opportunity to enroll in this extension Study. 
 
Additional subjects, who did not complete Study RP103-03 but qualify for RP103-04 based on 
current inclusion and exclusion criteria, may be enrolled after completion of the analysis of the 
RP103-03 study where the non-inferior efficacious and safe dose of RP103 versus Cystagon
® has 
been determined. 
 
Study visits consist of: 
 
For subjects who completed Study RP103-03: 
 
 Screening Visit:  The RP103-04 Screening visit occurred simultaneously with the 
RP103- 03 Period 2 Day 7 End of Study (EOS) visit.  These subjects continued RP103 
Q12H treatment at the last dose level prescribed during their participation in Study 
RP103- 03. 
 
 
 Monthly Study Visits are only for subjects who completed Study RP103-03 and 
began within 1 month (± 7 days) after study entry.  Each subject completes a 
minimum of six (6) consecutive monthly visits. 
 
 Quarterly Study Visits commence for each subject ≥ 1 month and < 4 months after the 
subject has completed at least six (6) consecutive Monthly visits. Each Quarterly visit 
takes place by the middle of the first month (± 7 days) of each calendar quarter (i.e. 
January 15, April 15, July 15 and October 15).   
 
 End of Study (EOS) Visit is conducted within 7 (± 2) days from the last completed study 
visit or from the date of decision to terminate. 
 
For subjects who did not complete Study RP103-03: 
 
 Screening Visit which may occur up to 28 days prior to Day 1. 


Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07AUG2017
CONFIDENTIAL
8
 
 
 
 
 Dose Confirmation Period (Days 1-5) which includes three (3) study visits over five (5) 
days. 
 
o Day 1 includes a morning study visit while the subject is fasted, with pre-dose 
blood samples collected for trough cysteamine and peak white blood cell (WBC) 
cystine determination while the subject is still taking Cystagon
®. RP103 
treatment regimen begins at the clinic on the morning of Day 1, administered 
Q12H at a starting total daily RP103 dose equal to 70% of the Screening total 
daily Cystagon® dose. Subjects 
leave 
the 
clinic for Days 2-3 and take RP103 as 
instructed. 
o Days 4 and 5 each include a morning study visit; RP103 Q12H treatment 
regimen continues. 
 
 Quarterly Study Visits commence for each subject ≥ 1 month and < 4 months after 
enrollment in the study.  Each quarterly visit takes place by the middle of the first month 
(± 7 days) of each calendar quarter (i.e., January 15, April 15, July 15 and October 15). 
 
 
 End of Study (EOS) Visit will be conducted within 7 (± 2 days) from the last completed 
study visit or from the date of decision to terminate. 
 
 
 
2.2. 
Randomization Methodology 
 
 
This is a single-arm study.  Subjects are not randomized. 
 
 
2.3. 
Stopping Rules and Unblinding 
 
 
This is an open-label, long-term safety study with no stopping rules. 
 
 
2.4. 
Study Procedures 
 
 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1.1 and Table 
1.2. 






11
 
 
dose on Monthly and Quarterly Visits, thereafter and at the End of Study (EOS) visit. For subjects who have transitioned back to Cystagon®, the EOS visit PD blood sample 
will be collected immediately prior to their next Cystagon® dose. 
q. A PK (plasma cysteamine) sample will be collected at: Screening (if subject did not complete Study RP103-03) at 5-6 hours after the last Cystagon
® dose, on Day 1 (if 
subject did not complete Study RP103-03) immediately prior (≤ 15 minutes) to morning dose administration of RP103, and for all subjects at 0.5 hour (30 minutes) post 
RP103 dose on Monthly and Quarterly Visits, thereafter and at the End of Study (EOS) visit. For subjects who have transitioned back to Cystagon® PK blood sample at the 
EOS visit will be collected immediately prior to their next Cystagon® dose. 
r. Investigator will perform a review of available safety, PK and PD date prior to or at study visits (i.e., Monthly/Quarterly).  A dose adjustment may be indicated, as described 
in Section 8.5of the protocol. For subjects who did not complete Study RP103-03, the first potential dose adjustment should be as soon as the Investigator receives WBC 
cystine results for the Dose Confirmation Period, so that any RP103 dose adjustment may be implemented before the subject returns for their next study visit (Quarterly 
Visit 1). 
s. Food should try to avoid eating food for at least 2 hours before and 30 minutes after RP103 administration. In case subjects cannot comply with this recommendation, they 
should ingest at least a small amount of food around the time of RP103 dosing (from 1 hour before to 1 hour afterwards). 
 
 
 
 
 
 






Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07Aug 2017 
14
 
 
 
 
3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
 
 
Two populations for this study are planned for analysis as described below. 
 
Safety Population:  The Safety Population consists of all subjects who received at least 
one dose of study drug (RP103). 
 
PK/PD Population: All subjects who have at least one PK/PD measurement are included in the 
PK/PD population. 
 
Each one of these 2 populations is then partitioned in 3 subpopulations:  
  A: Subjects who completed Study RP103-03 
B: Subjects ≤ 6 years old  
     C: Renal Transplant subjects 
 
3.2. 
Protocol Violations/Deviations 
 
Failure to meet any inclusion or exclusion criteria (see Sections 7.1 and 7.2 of the protocol) 
during participation in the study constitutes a protocol violation.  Other unforeseen situations may 
result in a protocol violation and is reported accordingly.  No protocol violations are used to 
exclude subjects from the safety analysis. 
 
 
4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
 
 
 
The sample size for this study is determined by the number of subjects who participated in the 
previous phase III Study (RP103-03) and any additional subjects, who did not complete 
the RP103-03 study, who enroll after all subjects that participated in RP103-03 completed and 
data have been analyzed. 
 
 
4.2. 
General Statistical Methods and Data Handling 
 
4.2.1. 
General Methods 
 
All data displays and analyses will adhere to the International Conference on Harmonisation 
(ICH) recommendations, and will be formatted to the appropriate page size(s). 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage 
within each category (with a category for missing data) of the parameter will be presented.  For 
continuous variables, N, the mean, median, standard deviation, minimum and maximum values 


Protocol RP103-04
Statistical Analysis Plan
Version 2.0, 07Aug 2017 
15
 
 
will be presented. 
 
Relative days will be calculated relative to the first dose of study drug.  Day 1 will be the first day 
of study drug administration in the study, and the day prior to the first dose of study drug 
administration will be Day -1.  There will be no Day 0. 
 
Any statistical testing will be considered exploratory; two-sided p-values will use alpha = 0.050. 
 
Baseline is defined, unless otherwise specified, as the last non-missing measurement before the 
first dose of study drug, unless otherwise specified. For subjects who completed Study RP103-03, 
baseline results could come from the Screening Visit (which is the RP103- 03 Period 2 Day 7 End 
of Study (EOS) visit).   
 
 
4.2.2. 
Computing Environment 
 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.2 
or later), unless otherwise noted.  Medical history and adverse events will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), Version 13.0. Concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary (June 2010). 
 
 
 
4.2.3. 
Methods of Pooling Data  
Not applicable to the present study. 
 
 
4.2.4. 
Adjustments for Covariates 
 
There are no planned adjustments for covariates in this study. 
 
 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
 
No formal statistical adjustments are planned for multiplicity. 
 
 
 
4.2.6. 
Subpopulations 
 
Data will be summarized by the subpopulations described in Section 3.1:   
 
  A: Subjects who completed Study RP103-03 
B: Subjects ≤ 6 years old 
C: Renal Transplant subjects 
 
 
 
 
 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 


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There are no planned exclusions due to withdrawals, dropouts, or loss to follow-up. 
 
 
4.2.8. 
Missing, Unused and Spurious Data 
 
Imputation of missing data is not planned. 
 
4.2.9. 
Visit Windows 
 
The visit schedule in Study RP103-04 differed according to whether a subject entered the study 
after completing Study RP103-03 or entered the study without having previously participated in 
Study RP103-03 (i.e., Subjects ≤ 6years of age and kidney transplant recipients). This difference in 
visit schedule resulted in each Quarterly visit for subjects from Study RP103-03 occurring, on 
average, approximately 6 months later in the study than the corresponding Quarterly visit for 
subjects who did not previously participate in Study RP103-03. For example, the Quarterly 1 visit 
of a subject from Study RP103-03 generally occurred at approximately 0.75 years in the study, 
while the Quarterly 1 visit for a subject not previously participating in Study RP103-03 generally 
occurred at approximately 0.25 years in the study. Two approaches were taken in the analysis to 
aligning visits for summarization over time: 
1. Collected Visits: Scheduled Visits (i.e., the visit as recorded on the case report form) were 
assigned to what is referred to as “Collected Visits” (see  
2. Table 2). Summarization using Collected Visits will help to address the approximate 6-
month difference between the Quarterly visits for subjects from Study RP103-03 compared 
to subjects who had not participated in Study RP103-03.  
 
Table 2:  
Definition of “Collected Visits” for Subjects Not Previously Participating in 
Study RP103-03 (Subjects ≤ 6 Years of Age and Kidney Transplant Recipients) 
Scheduled Visit 
Assigned “Collected Visit” (Label) 
Scheduled Visit 
Number 
Scheduled Visit 
Name 
14 
Quarterly 1 
Monthly 3  
15 
Quarterly 2 
Monthly 6  
16 
Quarterly 3 
Quarterly 1  
17 
Quarterly 4 
Quarterly 2  
18 
Quarterly 5 
Quarterly 3  
19 
Quarterly 6 
Quarterly 4  
20 
Quarterly 7 
Quarterly 5  
21 
Quarterly 8 
Quarterly 6  
22 
Quarterly 9 
Quarterly 7  
23 
Quarterly 10 
Quarterly 8  
24 
Quarterly 11 
Quarterly 9  




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4.3 
Interim Analyses 
 
There have been three interim analyses performed to support interim CSRs.  The first interim 
CSR was dated 14 February 2012 (amended 10 January 2013).   A second interim CSR was dated 
17 September 2013 (amended 06 March 2015).  The third interim CSR was dated  11 November 
2015. 
 
5. 
SUBJECT DISPOSITION 
 
Subject disposition will be tabulated overall and for each subpopulation.  The number of 
subjects screened and in each analysis population will be summarized.  The number and 
percentage of subjects who complete the study will be summarized, along with the number and 
percentage of subjects who do not complete the study for each discontinuation reason as 
specified on the eCRFs. 
 
 
6. 
PROTOCOL DEVIATIONS  
 
The number and percentage of subjects who have major protocol deviations during the study will 
be summarized overall and for each deviation reason for the Safety Population. 
Protocol deviations will be presented by subject in a data listing. 
 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
Demographic and baseline characteristics at study entry will be summarized by subpopulation and 
overall for the Safety Population.   
Variables to be summarized are: 
 Continuous variables  
- Age (years) 
- Weight (kg) 
- Height (cm) 
- Body mass index (BMI) (kg/m2) 
- Body surface area (BSA) (m2) 
- Previous daily dose of Cystagon (mg/m2/day) 
- Total daily dose of RP103 (average % of previous Cystagon dose) 
- WBC cystine level (nmol ½ cystine/mg) 
 Categorical variables  
- Age category (young child, child, adolescent, adult) 
- Gender  
- Race  










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 Subjects reporting at least one Grade ≥ 3 AE 
 Subjects reporting at least one AE leading to discontinuation of study 
 
The number and percentage of subjects who experienced at least one AE will be summarized 
overall and for each SOC and each PT.  The percentage will be based on the number of subjects 
in the Safety Population.  Each subject will contribute at most one count per summarization 
category.  In other words, if a subject has more than one AE with same PT, the subject will be 
counted only once for that PT.  Similarly, if a subject has more than one AE for a SOC, the 
subject will be counted only once in that SOC and PT. SOCs (and PTs within each SOC) will be 
sorted in summary tables by descending frequency of each.  
 
Similarly, the number and percentage of subjects with any treatment-emergent SAEs, with any 
treatment-emergent adverse events assessed by the Investigator as related to treatment, and with 
any treatment-emergent adverse events leading to discontinuation of study and with any SAE 
will be summarized by SOC and PT.   
 
The number and percentage of subjects with any treatment-emergent adverse events will be 
summarized by relationship to study drug (not related, unlikely related, possibly related, probably 
related, definitely related, unknown) and severity (mild, moderate, severe, life-threatening, death, 
unknown) by SOC and PT. In these tabulations, each subject will contribute only once (i.e., the 
most related occurrence or the most intense occurrence) to each of the incidence rates in the 
descriptive analysis, regardless of the number of episodes – e.g. worst grade, per subject, per 
toxicity. 
 
In addition, summaries of the incidence of subjects with AEs, and SAEs, by study year of onset 
(Year 1, Year 2 and Year 3 or later) will be generated.  Treatment-emergent gastro-intestinal 
adverse events, i.e. adverse events with SOC of “gastrointestinal disorders”, will also be 
summarized by frequency of episodes (1-3 occurrences vs 4 or more) by PT. Similarly, treatment-
emergent treatment-related gastro-intestinal adverse events will be summarized.  
 
All adverse events occurring on study will be listed in subject data listings. 
By-subject listings also will be provided for the following:  serious adverse events, adverse 
events for laboratory abnormalities, and adverse events leading to study discontinuation. 
 
 
 
9.3. 
Laboratory Data 
 
Clinical laboratory values will be expressed using SI units.  
 
Hematology, chemistry, and urinalysis results will be summarized for each lab parameter at 
baseline, each collected postbaseline visit, and change from baseline using descriptive 
statistics (number of subjects, mean, median, SD, and minimum and maximum values).  In 
the event of repeat values, the last non-missing value per visit, per timepoint will be used.  If 
there are multiple records for the same visit and timepoint, the average of the values will be 
used. 
 
Analysis of individual subject changes will be summarized by shift tables, which will be 
generated for hematology and serum chemistry parameters.  These tables will show the number 
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high at each collected visit. 
 
All laboratory data will be provided in data listings. Values outside of the reference range will be 
flagged. 
 
 
 
9.4. 
Vital Signs and Physical Examinations 
 
Vital signs data will include temperature, respiratory rate, weight, BMI, BSA, systolic and 
diastolic blood pressures (BPs) and heart rate.  Results will be summarized at baseline, each 
collected postbaseline visit, and change from baseline using descriptive statistics (number of 
subjects, mean, median, SD, and minimum and maximum values). For subjects who 
completed study RP103-03, baseline height is taken from the RP103-03 Screening Visit. For 
subjects who did not complete study RP103-03, baseline height is the last available 
observation prior to the first dose of study drug in RP103-04. 
 
By-subject listings of vital sign measurements and physical examinations will be presented in 
data listings. 
 
 
 
9.5. 
Electrocardiogram 
 
Electrocardiogram data will include heart rate, QRS duration, QRS axis, QT and PR intervals, and 
QT interval corrected for heart rate using Fridericia method (QTcF).  ECG data will be 
summarized for baseline, each collected postbaseline visit  and for the change from baseline to 
each visit using descriptive statistics (number of subjects, mean, median, SD, and minimum and 
maximum values) by treatment.  
 
Overall interpretation results for the ECG are classified into 1 of 3 categories:  normal, 
abnormal – not clinically significant, or abnormal – clinically significant. Shift tables will 
show the number of subjects who had results that shifted from normal, abnormal – not 
clinically significant, or abnormal – clinically significant at baseline to normal, abnormal – 
not clinically significant, or abnormal – clinically significant at each collected post-baseline 
visit. 
 
All ECG data for each subject will be provided in data listings. 
 
 
9.6. 
Concomitant Medications 
 
Concomitant medications are coded using the WHO Drug dictionary (June 2010) . Results will 
be summarized by Anatomic Therapeutic Class 4th level (ATC-4) and preferred name.  If the 4th 
level term is not available, the next available level (e.g., ATC-3) will be used.  All medications 
with a stop date prior to the first dose of study drug will be considered “prior”. All medications 
taken on or after the first RP103 dose, regardless of the start date, will be considered 
“concomitant.” 
 
 
Gastric-acid reducing (GAR) medications were recorded on a separate eCRF from concomitant 
medications, and will be summarized by ATC-4 and preferred name.  The number of occurrences