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

Primary Purpose

Cystinosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
RP103
Sponsored by
Horizon Pharma USA, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystinosis focused on measuring Nephropathic Cystinosis, Cysteamine, Delayed-release Cysteamine, CTNS Protein, Human, Orphan Disease

Eligibility Criteria

undefined - 6 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RP103

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
December 5, 2012
Last Updated
January 17, 2018
Sponsor
Horizon Pharma USA, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01744782
Brief Title
Safety/Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Cysteamine Treatment Naive Patients With Cystinosis
Official Title
An Open-Label, Safety and Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Cysteamine Treatment Naïve Patients With Cystinosis
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
December 20, 2012 (Actual)
Primary Completion Date
December 13, 2016 (Actual)
Study Completion Date
December 13, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Pharma USA, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

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, CTNS Protein, Human, Orphan Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)

8. Arms, Groups, and Interventions

Arm Title
RP103
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
RP103
Other Intervention Name(s)
Cysteamine Delayed-release Capsules
Intervention Description
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.
Primary Outcome Measure Information:
Title
Mean White Blood Cell (WBC) Cystine Concentration at Each Visit
Description
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.
Time Frame
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 Measure Information:
Title
Number of Participants With Adverse Events
Description
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.
Time Frame
Day 1 through study exit
Title
Maximum Observed Plasma Concentration (Cmax) of Cysteamine
Description
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.
Time Frame
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
Title
Time of the Maximum Observed Plasma Concentration (Tmax) of Cysteamine
Description
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.
Time Frame
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
Title
Area Under the Plasma Concentration Versus Time Curve (AUC) of Cysteamine
Description
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.
Time Frame
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

10. Eligibility

Sex
All
Maximum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
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
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
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo
City
Sao Paulo
State/Province
SP
Country
Brazil

12. IPD Sharing Statement

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://www.horizonpharma.com/medicines/rare-diseases/procysbi/
Description
Related Info

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

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