Long-Term Safety Follow-up Study of Cysteamine Bitartrate Delayed-release Capsules (RP103)

Study Overview
=================
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.

Official Title
-----------------
A Long-Term, Open-Label, Safety and Efficacy Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients With Cystinosis

Conditions
-----------------
Cystinosis

Intervention / Treatment
-----------------
* Drug: Cysteamine Bitartrate Delayed-release Capsules


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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: Male and female subjects must have cystinosis. Subjects must be on a stable dose of Cystagon® at least 21 days prior to Screening. Within the last 6 months, no clinically significant change from normal in liver function tests (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin) and renal function (i.e., estimated glomerular filtration rate [eGFR]) at Screening as determined by the Investigator. Subjects with an eGFR corrected for body surface area > 30 mL/min/1.73m². 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. Subjects must be willing and able to comply with the study restrictions and requirements. Subjects or their parent or guardian must provide written informed consent and assent (where applicable) prior to participation in the study. Exclusion Criteria: 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: Subjects less than 1 year old Subjects with a known history, currently of the following conditions or other health issues that make it, in the opinion of the investigator, unsafe for them to participate: inflammatory bowel disease (if currently active) or have had 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; Malignant disease within the last 2 years. Patients with a hemoglobin level < 10 g/dL at Screening or a level that, in the opinion of the investigator, makes it unsafe for the subject to participate. Subjects with known hypersensitivity to cysteamine or penicillamine. Female subjects who are nursing, planning a pregnancy, known or suspected to be pregnant, or have a positive serum pregnancy screen. Subjects who, in the opinion of the Investigator, are not able or willing to comply with the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cysteamine Bitartrate<br>Cysteamine bitartrate delayed-release capsules were administered twice daily for up to 96 months. | Drug: Cysteamine Bitartrate Delayed-release Capsules<br>* 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.<br>* Other names: PROCYSBI®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events | Drug-related adverse events (AEs) are AEs the investigator assessed as having relation to drug of 'possibly', 'probably' or 'definitely'. The severity of AEs was categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 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 occurred. | From first dose of study drug to 7 days after the last dose; median duration of treatment was 1461 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough Plasma Cysteamine Concentration | Plasma cysteamine concentration was determined using methods employing Hydrophilic Interaction Liquid Chromatography (HILC) high pressure liquid chromatography (HPLC) tandem mass spectrometry (HPLC-MS/MS). | Day 1 (predose) and Month 6, Years 1, 1.5, 2, 3, 4 and 5 at 0.5 hours post-dose | 
| White Blood Cell Cystine Concentration | White blood cell (WBC) cystine concentration was determined using high performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). | Day 1 (predose) and Month 6, Years 1, 1.5, 2, 3, 4 and 5 at 0.5 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cystinosis, cysteamine, inheritable disease, orphan disease, CTNS protein, human, metabolic disease, nephropathic cystinosis