Back to resultsOpen-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis
Primary Purpose
Cystinosis
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
RP103
Cystagon®
Sponsored by
About this trial
This is an interventional treatment trial for Cystinosis focused on measuring Nephropathic Cystinosis, Cysteamine, Delayed-Release Cysteamine, Orphan Disease, CTNS Protein, Human
Eligibility 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.
Sites / Locations
- California Pacific Medical Center (CPMC) Research Institute
- Stanford University Medical School
- Emory Children's Center
- Ann & Robert H. Lurie Children's Hospital of Chicago
- Baylor College of Medicine / Texas Childrens Hospital
- University Hospital of Leuven
- Hospices Civils de Lyon
- Hôpital Necker-Enfants Malades
- Hôpital Robert Debré
- Ospedale Pediatrico Bambino Gesù
- Radboud University Nijmegen Medical Center
- Queen Elizabeth Hospital Birmingham
- Great Ormond Street
- Guy's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
All Participants
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
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.
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.
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.
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.
Full Information
NCT ID
NCT01733316
First Posted
November 16, 2012
Last Updated
July 10, 2018
Sponsor
Horizon Pharma USA, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT01733316
Brief Title
Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis
Official Title
A Long-Term, Open-Label, Safety, Tolerability and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients With Cystinosis
Study Type
Interventional
2. Study Status
Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
January 31, 2013 (Actual)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
July 10, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Pharma USA, Inc.
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystinosis
Keywords
Nephropathic Cystinosis, Cysteamine, Delayed-Release Cysteamine, Orphan Disease, CTNS Protein, Human
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
41 (Actual)
8. Arms, Groups, and Interventions
Arm Title
All Participants
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
RP103
Other Intervention Name(s)
cysteamine bitartrate delayed-release capsules, PROCYSBI®
Intervention Type
Drug
Intervention Name(s)
Cystagon®
Other Intervention Name(s)
cysteamine bitartrate
Primary Outcome Measure Information:
Title
Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values
Description
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.
Time Frame
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 Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs
Description
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
Time Frame
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.
Title
Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine
Description
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.
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
Title
Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine
Description
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.
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
Title
Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine
Description
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.
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
Title
Halitosis Substudy: Expired Air DMS Concentrations
Description
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.
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Evelyn Olson, BS
Organizational Affiliation
Horizon Pharma USA, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
California Pacific Medical Center (CPMC) Research Institute
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Stanford University Medical School
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Emory Children's Center
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Baylor College of Medicine / Texas Childrens Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University Hospital of Leuven
City
Leuven
Country
Belgium
Facility Name
Hospices Civils de Lyon
City
Lyon
Country
France
Facility Name
Hôpital Necker-Enfants Malades
City
Paris
Country
France
Facility Name
Hôpital Robert Debré
City
Paris
Country
France
Facility Name
Ospedale Pediatrico Bambino Gesù
City
Rome
Country
Italy
Facility Name
Radboud University Nijmegen Medical Center
City
Nijmegen
Country
Netherlands
Facility Name
Queen Elizabeth Hospital Birmingham
City
Birmingham
Country
United Kingdom
Facility Name
Great Ormond Street
City
London
Country
United Kingdom
Facility Name
Guy's Hospital
City
London
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
19158356
Citation
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.
Results Reference
background
Links:
URL
http://procysbi.com/
Description
RP103 (marketed as PROCYSBI) is now approved by the US FDA for management of nephropathic cystinosis in patients 6 years and older.
Learn more about this trial
Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis
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