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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier:
NCT01733316
First received: November 16, 2012
Last updated: July 26, 2017
Last verified: July 2017
  Purpose

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.


Condition Intervention Phase
Cystinosis Drug: RP103 Drug: Cystagon® Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Long-Term, Open-Label, Safety, Tolerability and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients With Cystinosis

Resource links provided by NLM:


Further study details as provided by Horizon Pharma USA, Inc.:

Primary Outcome Measures:
  • Average Difference Between Morning and Non-Morning Log WBC Cystine Values [ Time Frame: While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-AM and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-PM dose. ]
    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.


Secondary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs [ Time Frame: Day 1 through interim data cutoff (of 10 April 2015). Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 168 days (range 1-511) during the long-term RP-103 phase. ]
    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. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.

  • Number of Participants With Clinical Laboratory Abnormalities (Hematology, Blood Chemistry, Urinalysis) Reported as AEs [ Time Frame: Day 1 through interim data cutoff (of 10 April 2015). Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 168 days (range 1-511) during the long-term RP-103 phase. ]
    Investigators monitored clinical laboratory test findings. If any laboratory test on or after the first study drug treatment was abnormal, it was followed at the discretion of the Investigator. Abnormal laboratory tests considered clinically significant were reported as AEs. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.

  • Number of Participants With Electrocardiogram (ECG) Abnormalities Classified as Clinically Significant [ Time Frame: Day 1 through interim data cutoff (of 10 April 2015). Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 168 days (range 1-511) during the long-term RP-103 phase. ]
    Standard 12-lead ECGs were used for the ECG evaluation. Abnormal ECGs considered clinically significant by the Investigator are reported. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.

  • Number of Participants With Clinically Relevant Trends or Mean Changes From Baseline in Vital Signs [ Time Frame: Day 1 through interim data cutoff (of 10 April 2015). Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 168 days (range 1-511) during the long-term RP-103 phase. ]
    Vital signs (including body mass index, body surface area, weight, systolic blood pressure, diastolic blood pressure, pulse and respiratory rates) over the course of the study were evaluated for clinically relevant trends or changes over the course of the study. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.

  • Number of Participants With Physical Examination Findings Reported as AEs Related to Study Drug [ Time Frame: Day 1 through interim data cutoff (of 10 April 2015). Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 168 days (range 1-511) during the long-term RP-103 phase. ]
    The physical examinations included assessments of the following: general appearance, eyes, ears, nose and throat, chest (heart, lungs), abdomen (palpation, gastrointestinal sounds), extremities and skin. The Investigator also conducted a basic neurological examination. Findings were evaluated for treatment-related AEs over the course of the study. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.

  • Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine [ Time Frame: 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 ]
    Participants who report halitosis ("bad breath") as a side effect while receiving Cystagon® will be asked to participate in a substudy that will 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 will be collected over a 6 hour period when Cystagon® is administered and over a 12 hour period when RP103 is administered. Data will be summarized in final analysis.

  • Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine [ Time Frame: 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 ]
    Participants who report halitosis ("bad breath") as a side effect while receiving Cystagon® will be asked to participate in a substudy that will 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 will be collected over a 6 hour period when Cystagon® is administered and over a 12 hour period when RP103 is administered. Data will be summarized in final analysis.

  • Halitosis Substudy: Area Under the Plasma Concentration Time Curve (AUC) for Plasma Cysteamine [ Time Frame: 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 ]
    Participants who report halitosis ("bad breath") as a side effect while receiving Cystagon® will be asked to participate in a substudy that will 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 will be collected over a 6 hour period when Cystagon® is administered and over a 12 hour period when RP103 is administered. Data will be summarized in final analysis.

  • Halitosis Substudy: Expired Air DMS Concentrations [ Time Frame: 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 ]
    Participants who report halitosis ("bad breath") as a side effect while receiving Cystagon® will be asked to participate in a substudy that will 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 will be collected over a 6 hour period when Cystagon® is administered and over a 12 hour period when RP103 is administered. Data will be summarized in final analysis.


Enrollment: 41
Actual Study Start Date: January 13, 2013
Study Completion Date: July 10, 2017
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cystagon® Q6H
From Screening and during Months 1, 2, 3: Participants receive their usual dose of Cystagon® every 6 hours (Q6H).
Drug: Cystagon®
Other Name: cysteamine bitartrate
Experimental: RP103 Q12H
From Months 3.5, 4, 5, 6, 7 and the remainder of study participation: RP103 every 12 hours (Q12H) started at a total daily dose of 70% of participants' Cystagon® dose.
Drug: RP103
Other Names:
  • cysteamine bitartrate delayed-release capsules
  • PROCYSBI®

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01733316

Locations
United States, California
California Pacific Medical Center (CPMC) Research Institute
San Francisco, California, United States, 94115
Stanford University Medical School
Stanford, California, United States, 94305
United States, Georgia
Emory Children's Center
Atlanta, Georgia, United States, 30322
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60614
United States, Texas
Baylor College of Medicine / Texas Childrens Hospital
Houston, Texas, United States, 77030
Belgium
University Hospital of Leuven
Leuven, Belgium
France
Hospices Civils de Lyon
Lyon, France
Hôpital Robert Debré
Paris, France
Italy
Ospedale Pediatrico Bambino Gesù
Rome, Italy
Netherlands
Radboud University Nijmegen Medical Center
Nijmegen, Netherlands
United Kingdom
Queen Elizabeth Hospital Birmingham
Birmingham, United Kingdom
Great Ormond Street
London, United Kingdom
Guy's Hospital
London, United Kingdom
Sponsors and Collaborators
Horizon Pharma USA, Inc.
Investigators
Study Director: Evelyn Olson, BS Horizon Pharma USA, Inc.
  More Information

Additional Information:
Publications:
Responsible Party: Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier: NCT01733316     History of Changes
Other Study ID Numbers: RP103-07
2012-002773-64 ( EudraCT Number )
Study First Received: November 16, 2012
Results First Received: April 10, 2017
Last Updated: July 26, 2017

Keywords provided by Horizon Pharma USA, Inc.:
Nephropathic Cystinosis
Cysteamine
Delayed-Release Cysteamine
Orphan Disease
CTNS Protein, Human

Additional relevant MeSH terms:
Cystinosis
Lysosomal Storage Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Cysteamine
Cystine Depleting Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 22, 2017