Clinical Trial Results:
A Randomized, Crossover Pharmacokinetic and Pharmacodynamic Study to Determine the Safety and Efficacy of Cysteamine Bitartrate Delayed-release Capsules (RP103), Compared to Cystagon® in Patients with Nephropathic Cystinosis
Summary
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EudraCT number |
2009-017882-42 |
Trial protocol |
FR NL |
Global end of trial date |
03 Jun 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
20 May 2017
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First version publication date |
20 May 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RP103-03
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01000961 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Horizon Pharma USA, Inc.
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Sponsor organisation address |
150 S. Saunders Road, Lake Forest, Illinois, United States, 60045
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Public contact |
Evelyn Olson, BS, Horizon Pharma USA, Inc., clinicaltrials@horizonpharma.com
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Scientific contact |
Evelyn Olson, BS, Horizon Pharma USA, Inc., clinicaltrials@horizonpharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Jun 2011
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Jun 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Cystinosis is an inherited disease that if untreated, results in kidney failure as early as the first decade of life. The current marketed therapy is Cystagon® (cysteamine bitartrate) which must be taken every six hours for the rest of the patient's life to prevent complications of cystinosis. RP103 is a formulation of cysteamine bitartrate that is being studied to see if it may be able to be given less frequently, once every 12 hours, and have similar results to four times a day Cystagon®.
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Protection of trial subjects |
The protocol and consent/assent forms were submitted by each investigator to an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. The study was conducted in accordance with legal and regulatory requirements including Guidance for Good Clinical Practice (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association 2008). Only subjects who met the inclusion criteria and none of the exclusion criteria were enrolled to this study. Written informed consent was to be obtained from the subject’s legally acceptable representative and assent by the minor subject, as applicable, before screening or baseline assessments. Instructions were given to the subject's legally acceptable representative in case of emergency or other questions.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Jun 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 26
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Country: Number of subjects enrolled |
France: 14
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Country: Number of subjects enrolled |
Netherlands: 4
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Worldwide total number of subjects |
44
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EEA total number of subjects |
18
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
24
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Adolescents (12-17 years) |
16
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Adults (18-64 years) |
4
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
Pre-assignment
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Screening details |
Participants randomized to each per sequence Arm are expected to remain in the same Arm throughout all intervention periods. | ||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
44 | ||||||||||||||||||
Number of subjects completed |
43 | ||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Physician decision: 1 | ||||||||||||||||||
Period 1
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Period 1 title |
Run-in Period of 2-3 weeks on Cystagon
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cystagon first, then Cystagon, then RP103 | ||||||||||||||||||
Arm description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cystagon®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Prior to treatment, eligible subjects underwent a 2 to 3 week Run-in Period of their stable dose of Cystagon® administered every 6 hours.
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Arm title
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Cystagon first, then RP103, then Cystagon | ||||||||||||||||||
Arm description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cystagon®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Prior to treatment, eligible subjects underwent a 2 to 3 week Run-in Period of their stable dose of Cystagon® administered every 6 hours.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One subject was withdrawn prior to randomization, and is accounted for in the Pre-assignment Milestones table. |
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Period 2
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Period 2 title |
First Intervention (3 weeks)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cystagon first, then Cystagon, then RP103 | ||||||||||||||||||
Arm description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cystagon®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
3 weeks (±3 days) treatment with Cystagon® every 6 hours
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Arm title
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Cystagon first, then RP103, then Cystagon | ||||||||||||||||||
Arm description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cysteamine bitartrate
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Investigational medicinal product code |
RP103
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Other name |
PROCYSBI®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
3 weeks (±3 days) of RP103 administered every 12 hours
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Period 3
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Period 3 title |
Second Intervention (3 weeks)
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cystagon first, then Cystagon, then RP103 | ||||||||||||||||||
Arm description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cysteamine bitartrate
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Investigational medicinal product code |
RP103
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Other name |
PROCYSBI®
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
3 weeks (±3 days) of RP103 administered every 12 hours
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Arm title
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Cystagon first, then RP103, then Cystagon | ||||||||||||||||||
Arm description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Cystagon®
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
3 weeks (±3 days) treatment with Cystagon® every 6 hours
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Baseline characteristics reporting groups
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Reporting group title |
Run-in Period of 2-3 weeks on Cystagon
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Reporting group description |
- | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cystagon first, then Cystagon, then RP103
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Reporting group description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||
Reporting group title |
Cystagon first, then RP103, then Cystagon
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Reporting group description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||
Reporting group title |
Cystagon first, then Cystagon, then RP103
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Reporting group description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||
Reporting group title |
Cystagon first, then RP103, then Cystagon
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Reporting group description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||
Reporting group title |
Cystagon first, then Cystagon, then RP103
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Reporting group description |
Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in first intervention (after Run-in period) and RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in second intervention period. | ||
Reporting group title |
Cystagon first, then RP103, then Cystagon
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Reporting group description |
RP103 dose in 25 mg and 75 mg capsule formulations administered every 12 hours in first intervention (after Run-in period) and Cystagon® dose in 50 mg and 150 mg capsule formulations administered every 6 hours in second intervention period. | ||
Subject analysis set title |
RP103 and Cystagon® crossover
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Per Protocol Population
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Subject analysis set title |
RP103
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per Protocol Population
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Subject analysis set title |
Cystagon®
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per Protocol Population
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End point title |
The Steady-State White Blood Cell Cystine Levels of RP103 Compared to Cystagon® | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
4 weeks after the last subject has completed the study
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
16-subject study will have 90% power to reject the null hypothesis of non-inferiority at the 0.025 level of significance with a non-inferiority margin of 0.3. Final analysis was performed at a nominal significance level of 0.02104.
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Comparison groups |
RP103 v Cystagon®
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.0001 | ||||||||||||
Method |
t-test, 1-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
0.0785
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Confidence interval |
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level |
95.8% | ||||||||||||
sides |
2-sided
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lower limit |
0.0107 | ||||||||||||
upper limit |
0.1464 | ||||||||||||
Notes [1] - The non-inferiority endpoint of the clinical trial would be achieved if the upper limit of the 95.8% CI of the difference between RP103 and Cystagon® was less than the a-priori 0.3 non-inferiority margin, which would correspond to an observed p-value less than or equal to 0.02104 |
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End point title |
Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon® | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
4 weeks after the last subject has completed the study
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
RP103 v Cystagon®
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
1.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.17 | ||||||||||||
upper limit |
1.67 |
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End point title |
Comparison of Cysteamine PK profiles, Steady State Tmax, Between RP103 and Cystagon® | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
4 weeks after the last subject has completed the study
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Cystagon® v RP103
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
105
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
90 | ||||||||||||
upper limit |
150 |
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End point title |
Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon® | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
6 hours post dosing for Cystagon®; 12 hours post dosing for RP103.
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Cystagon® v RP103
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.03
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
1.75 | ||||||||||||
upper limit |
2.39 |
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Adverse events information
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Timeframe for reporting adverse events |
Treatment periods
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Adverse event reporting additional description |
Safety population AE reporting.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.0
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Reporting groups
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Reporting group title |
Cystagon®
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Reporting group description |
Safety population during treatment periods | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RP103
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Reporting group description |
Safety Population during treatment periods | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 Feb 2010 |
Per the CSR, the rationale for Amendment 1 (21 February 2010) was to revise aspects of the protocol design to incorporate input from the FDA. The most significant of these was to update and clarify study endpoints and analysis plans, update and finalize sample size estimate, and add collection of PK data to the study design. In addition, the study schedule and procedures were changed to reduce discomfort and impact to the subject and their family. Minor editorial changes were made to clarify statements and instructions and correct typographical and formatting errors in the protocol. |
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03 May 2010 |
Per the CSR, as was the case for Amendment 1, Amendment 2 (03 May 2010) was intended to incorporate input from the FDA. The most significant revisions included the addition of a Run-in Period and randomized parallel crossover which allowed for Cystagon® dose adjustment. Inclusion and exclusion criteria were modified to establish entry criteria for subjects with low WBC cystine levels, specify subject age and weight restrictions, and provide specific parameters for clinically significant changes in liver and renal function. Study objectives, endpoints, and analysis plans were updated. Minor editorial changes were made to clarify statements and instructions and correct typographical and formatting errors in the protocol. |
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22 Jul 2010 |
Per the CSR, Amendment 3 (22 July 2010) was intended to incorporate input from the FDA. The most significant revisions included restricting study participation to those subjects with a 3-day average WBC cystine level ≤2 nmol ½ cystine/mg protein during Week 2 of the Run-in Period; adjustment of RP103 PD sampling timepoints to ensure appropriate collection; including stratification of subjects according to baseline WBC cystine levels; eliminating one week from the Run-in Period; and setting the minimum sample size to 30 subjects. Inclusion criteria were modified to include subjects with WBC cystine levels ≤2 nmol ½ cystine/mg protein. Minor editorial changes were made to clarify statements and instructions and correct typographical and formatting errors in the protocol. |
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22 Oct 2010 |
Per the CSR, Amendment 4 (22 October 2010) was intended primarily to change the starting total daily dose of RP103 from 70% to 80% at the end of the Run-in Period Cystagon® total daily dose and allow a maximum RP103 dose increase to 100% at the end of the Run-in Period Cystagon® total daily dose, with additional information on the background and rationale for the change in RP103 starting dose. Minor editorial changes were made to clarify statements and instructions and correct typographical and formatting errors in the protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |