Safety/Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Cysteamine Treatment Naive Patients With Cystinosis

Study Overview
=================
Brief Summary
-----------------
This was a long-term, open-label study of the safety, tolerability and effectiveness of RP103 in cystinosis patients who were naïve to any form of cysteamine treatment. Participants received RP103 treatment for at least 12 months. U.S. participants transitioned to the commercially approved drug PROCYSBI®. In Brazil, after at least 12 months of study participation and upon approval by the Brazilian regulatory authorities, participants were eligible to transition to a post-study drug supply program, and continue to receive the drug at no personal cost.

Detailed Description
-----------------
The purpose of this study was to gather information about the safety and effectiveness (how well it works to treat cystinosis) of a new drug called RP103. In cystinosis, the body builds up cystine. When taken regularly, the active ingredient of an older, already approved drug called Cystagon® (cysteamine bitartrate) reduces cystine in the body. RP103 has the same active ingredient as Cystagon® and is designed to reduce cystine in a similar way that Cystagon® does. RP103 is also different from Cystagon®: Instead of the cysteamine bitartrate being absorbed from the stomach, RP103 is designed to be absorbed from the small intestine. This may make the effects of the drug last longer, so that it can be taken twice a day instead of four times a day like Cystagon®. To decide if RP103 is effective, the study used two types of blood tests. One test is pharmacodynamics (PD), which measures the amount of white blood cell (WBC) cystine after taking study drug. WBC cystine is a laboratory test used to find out if cysteamine bitartrate is reducing cystine levels in the body. The second test is pharmacokinetics (PK), which measures the amount of cysteamine in the blood after taking the drug.

Official Title
-----------------
An Open-Label, Safety and Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Cysteamine Treatment Naïve Patients With Cystinosis

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

Intervention / Treatment
-----------------
* Drug: RP103


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female with a documented diagnosis of cystinosis No clinically significant change in liver function tests, i.e. 1.5 times upper limit of normal (ULN) for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and/or 1.5 times ULN for total bilirubin, within 6 months prior to Screening No clinically significant change in renal function, i.e. estimated glomerular filtration rate (GFR) within 6 months prior to Screening Must have an estimated GFR > 20 mL/minute/1.73m² (using the equation from Schwartz 2009 J Am Soc Nephrol 20:629-647) Female participants who are sexually active and of childbearing potential, i.e. not surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy) or at least 2 years naturally postmenopausal must agree to use an acceptable form of contraception from Screening through completion of the study. 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 or diaphragm with spermicide), IUD, or a partner who has been vasectomized for at least 6 months. Childbearing potential was defined as a female who had reached menarche. Participant or their parent or guardian must provide written informed consent and assent (where applicable) prior to participation in the study Had not taken any form of cysteamine bitartrate in the past Exclusion Criteria: Current history of the following conditions or any other health issues that make it, in the opinion of the Investigator, unsafe for study participation: Inflammatory bowel disease if currently active, or prior resection of the small intestine Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias, or poorly controlled hypertension) within 90 days prior to Screening Active bleeding disorder within 90 days prior to Screening History of malignant disease within 2 years prior to Screening Hemoglobin level of < 10 g/dL at Screening or, in the opinion of the investigator, a hemoglobin level that would make it unsafe for study participation Known hypersensitivity to penicillamine Female subjects who were nursing, planning a pregnancy, or were known or suspected to be pregnant Participants who, in the opinion of the investigator, were not able or willing to comply with study requirements Had received a kidney transplant or was currently on dialysis Was 6 years of age or older at the time of the Screening visit

Ages Eligible for Study
-----------------
Maximum Age: 6 Years

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: RP103<br>From Day 1 and throughout the duration of participation, RP103 (Cysteamine Bitartrate Delayed-release Capsules) was administered every 12 hours (Q12H), supplied as 75 mg and 25 mg capsules. | Drug: RP103<br>* Cysteamine Bitartrate Delayed-release Capsules (RP103) were administered twice daily, orally or via gastrostomy tube (G-tube), after a 2-hour fast. The starting dose was one-quarter of the RP103 targeted maintenance dose based on age, weight, and body surface area. The recommended targeted maintenance dose for children up to 6 years old was 1 gram/m²/day, in 2 divided doses given Q12H. The dose was gradually escalated, in 10% steps, based on monitoring of WBC cystine levels 30 minutes after the morning RP103 dose collected every 2 weeks, until the participant's WBC cystine level was <1 nmol ½ cystine/mg protein.<br>* Other names: Cysteamine Delayed-release Capsules;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean White Blood Cell (WBC) Cystine Concentration at Each Visit | Blood samples were taken 30 minutes after the morning RP103 dose at each study visit to determine White Blood Cell (WBC) cystine concentration. WBC cystine concentrations were determined using liquid chromatography. | Day 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Month 6, Month 9, Month 12, Month 15, Month 18, Study Exit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs). An AE/adverse experience was any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. For additional information regarding adverse events, please see the safety section of the record. | Day 1 through study exit | 
| Maximum Observed Plasma Concentration (Cmax) of Cysteamine | Blood samples were collected and plasma cysteamine concentration was determined using liquid chromatography. The maximum observed plasma concentration (Cmax) of cysteamine was determined directly from the data. | 30 minutes after the morning RP103 dose at Month 6 (prior to Protocol Amendment 1) or 0 (pre-dose), 30 minutes, 2, 3, 4, 6, 8, 10, and 12 hours after the morning RP103 dose at Month 6 for those enrolled under Protocol Amendment 1 or later | 
| Time of the Maximum Observed Plasma Concentration (Tmax) of Cysteamine | Blood samples were collected and plasma cysteamine concentration was determined using liquid chromatography. The time of the maximum observed plasma concentration (Tmax) of cysteamine was determined directly from the data. | 30 minutes after the morning RP103 dose at Month 6 (prior to Protocol Amendment 1) or 0 (pre-dose), 30 minutes, 2, 3, 4, 6, 8, 10, and 12 hours after the morning RP103 dose at Month 6 for those enrolled under Protocol Amendment 1 or later | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of Cysteamine | Blood samples were collected and plasma cysteamine concentration was determined using liquid chromatography. AUC values were estimated using non-compartmental analysis methods. AUClast was defined as the area under the plasma concentration versus time curve, from time 0 to the time of the last measurable concentration (720 minutes). AUCinf was defined as the area under the plasma concentration-versus-time curve from time 0 to infinity. | 30 minutes after the morning RP103 dose at Month 6 (prior to Protocol Amendment 1) or 0 (pre-dose), 30 minutes, 2, 3, 4, 6, 8, 10, and 12 hours after the morning RP103 dose at Month 6 for those enrolled under Protocol Amendment 1 or later | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nephropathic Cystinosis, Cysteamine, Delayed-release Cysteamine, CTNS Protein, Human, Orphan Disease