Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis

A Long-Term, Open-Label, Safety, Tolerability and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients With Cystinosis

The purpose of this study is to gather information about the effectiveness (how well it works to treat cystinosis) and safety of a new form of cysteamine bitartrate called RP103, compared to the already-approved drug cystinosis patients are taking called Cystagon®.

In cystinosis, the body builds up cystine. When taken regularly, the active ingredient of 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. To decide if RP103 is better than Cystagon®, the study will look at 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.

RP103 is 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®.

Some cystinosis patients have bad breath (halitosis) when they take Cystagon®. Study participants who experience bad breath with Cystagon® will be asked if they would like to participate in an optional "halitosis substudy" to investigate this issue by collecting some extra PK blood samples.

Study Overview

• Status: Completed
• Conditions: Cystinosis
• Intervention / Treatment: Drug: RP103; Drug: Cystagon®

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • University Hospital of Leuven
• France
  • Lyon, France
    • Hospices Civils de Lyon
  • Paris, France
    • Hopital Robert Debre
  • Paris, France
    • Hôpital Necker-Enfants Malades
• Italy
  • Rome, Italy
    • Ospedale Pediatrico Bambino Gesù
• Netherlands
  • Nijmegen, Netherlands
    • Radboud University Nijmegen Medical Center
• United Kingdom
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital Birmingham
  • London, United Kingdom
    • Guy's Hospital
  • London, United Kingdom
    • Great Ormond Street
• United States
  • California
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center (CPMC) Research Institute
    • Stanford, California, United States, 94305
      • Stanford University Medical School
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine / Texas Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA:

• Male or female with a documented diagnosis of cystinosis
• On a stable dose of Cystagon® at least 21 days prior to Screening
• WBC cystine level > 1 nmol 1/2 cystine/mg of protein, on average over at least 2 measurements collected during the 2 years prior to Screening
• No clinically significant change in liver function tests, i.e. 1.5 times upper limit of normal (ULN) for alanine aminotransferase and aspartate aminotransferase, 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/1.73m^2 (using the equation from Schwartz 2009 J Am Soc Nephrol 20:629-647)
• Female subjects 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), intrauterine device, or a partner who has been vasectomized for at least 6 months.
• Subject or their parent or guardian must provide written informed consent, assent (where applicable), prior to participation in the study

EXCLUSION CRITERIA:

• Younger than 12 years of age

• 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 < 9 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 cysteamine and penicillamine
• Female subjects who are nursing, planning a pregnancy, or are known or suspected to be pregnant
• Subjects who, in the opinion of the investigator, are not able or willing to comply with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All Participants; Cystagon® Phase: From Screening and during Months 1, 2, 3 participants receive their usual dose of Cystagon® every 6 hours (Q6H). RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants receive RP103 every 12 hours (Q12H). Long Term Phase: On or after Month 7, for the remainder of study participants receive RP103 Q12H.	Drug: RP103; Other Names: cysteamine bitartrate delayed-release capsules; PROCYSBI®; Drug: Cystagon®; Other Names: cysteamine bitartrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values	The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.	While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs	AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; 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, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs	From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.
Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine	Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.	While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine	Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.	While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine	Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.	While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
Halitosis Substudy: Expired Air DMS Concentrations	Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.	While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose 30 min post-dose, 2, 3, 4 and 6 hours post-dose. While taking RP103 (Month 4, 5, or 7): Within 15 min. prior to morning dose. 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post dose

Collaborators and Investigators

• Sponsor: Horizon Pharma USA, Inc.

Publications and helpful links

General Publications

• Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.

Helpful Links

• RP103 (marketed as PROCYSBI) is now approved by the US FDA for management of nephropathic cystinosis in patients 6 years and older.

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2013
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): July 10, 2017

Study Registration Dates

• First Submitted: November 16, 2012
• First Submitted That Met QC Criteria: November 20, 2012
• First Posted (Estimate): November 27, 2012

Study Record Updates

• Last Update Posted (Actual): August 13, 2018
• Last Update Submitted That Met QC Criteria: July 10, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Nephropathic Cystinosis; Cysteamine; CTNS Protein, Human; Orphan Disease; Delayed-Release Cysteamine
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Cystinosis; Molecular Mechanisms of Pharmacological Action; Cystine Depleting Agents; Cysteamine
• Other Study ID Numbers: RP103-07; 2012-002773-64 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided