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Phase 3 Study of Cysteamine Bitartrate Delayed-release (RP103) Compared to Cystagon® in Patients With Cystinosis

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ClinicalTrials.gov Identifier: NCT01000961
Recruitment Status : Completed
First Posted : October 23, 2009
Results First Posted : November 19, 2014
Last Update Posted : May 19, 2017
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma USA, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cystinosis
Interventions Drug: Cystagon® (Cysteamine Bitartrate)
Drug: Cysteamine Bitartrate Delayed-release Capsules (RP103)
Enrollment 43
Recruitment Details  
Pre-assignment Details Participants randomized to each per sequence Arm are expected to remain in the same Arm throughout all intervention periods.
Arm/Group Title Cystagon First, Then Cystagon, Then RP103 Cystagon First, Then RP103, Then Cystagon
Hide Arm/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. 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.
Period Title: Run-in Period of 2-3 Weeks on Cystagon
Started 21 [1] 22 [1]
Completed 21 22
Not Completed 0 0
[1]
Part of the Safety analysis set
Period Title: First Intervention (3 Weeks)
Started 21 22
Completed 21 20
Not Completed 0 2
Reason Not Completed
Withdrawal by Subject             0             1
Infection after pre-planned surgery             0             1
Period Title: Second Intervention (3 Weeks)
Started 21 20
Completed 21 [1] 20 [1]
Not Completed 0 0
[1]
Part of Efficacy analysis set
Arm/Group Title RP103 and Cystagon® Crossover
Hide Arm/Group Description Per Protocol Population
Overall Number of Baseline Participants 39
Hide Baseline Analysis Population Description
There were 39 participants analyzed for Cystagon®; and there were 37 participants analyzed for RP103.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
<=18 years
36
  92.3%
Between 18 and 65 years
3
   7.7%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 39 participants
11.9  (4.33)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
Female
16
  41.0%
Male
23
  59.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants
France 13
United States 22
Netherlands 4
1.Primary Outcome
Title The Steady-state White Blood Cell Cystine Levels of RP103 Compared to Cystagon®
Hide Description [Not Specified]
Time Frame 4 weeks after the last subject has completed the study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title RP103 Cystagon®
Hide Arm/Group Description:
Per Protocol Population
Per Protocol Population
Overall Number of Participants Analyzed 39 39
Least Squares Mean (Standard Error)
Unit of Measure: nmol ½ Cystine / mg protein
0.5152  (0.05555) 0.4367  (0.05555)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection RP103, Cystagon®
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method t-test, 1 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0785
Confidence Interval (2-Sided) 95.8%
0.0107 to 0.1464
Estimation Comments 95.8% confidence interval was used instead of 95% to take into account a sample size re-estimation calculation that was performed after 20 patients were enrolled.
2.Secondary Outcome
Title Comparison of Cysteamine PK Profiles, Steady State Cmax, Between RP103 and Cystagon®.
Hide Description [Not Specified]
Time Frame 4 weeks after the last subject has completed the study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cystagon® RP103
Hide Arm/Group Description:
Per Protocol Population
Per Protocol Population
Overall Number of Participants Analyzed 39 37
Least Squares Mean (Standard Deviation)
Unit of Measure: Cmax (mg/L)
2.73  (1.36) 3.70  (1.72)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cystagon®, RP103
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 1.40
Confidence Interval (2-Sided) 95%
1.17 to 1.67
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Comparison of Cysteamine PK Profiles, Steady State Tmax, Between RP103 and Cystagon®.
Hide Description [Not Specified]
Time Frame 4 weeks after the last subject has completed the study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cystagon® RP103
Hide Arm/Group Description:
Per Protocol Population
Per Protocol Population
Overall Number of Participants Analyzed 39 37
Least Squares Mean (Standard Deviation)
Unit of Measure: Tmax (minute)
72  (31) 187  (89)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cystagon®, RP103
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 105
Confidence Interval (2-Sided) 95%
90 to 150
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Comparison of Cysteamine PK Profiles, AUC(0-t), Between RP103 and Cystagon®.
Hide Description [Not Specified]
Time Frame 6 hours post dosing for Cystagon®; 12 hours post dosing for RP103.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cystagon® RP103
Hide Arm/Group Description:
Per Protocol Population
Per Protocol Population
Overall Number of Participants Analyzed 39 37
Least Squares Mean (Standard Deviation)
Unit of Measure: AUC(0-t) (min*mg/L)
357  (150) 739  (334)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cystagon®, RP103
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.03
Confidence Interval (2-Sided) 95%
1.75 to 2.39
Estimation Comments [Not Specified]
Time Frame Treatment periods
Adverse Event Reporting Description Safety population AE reporting
 
Arm/Group Title RP103 Cystagon®
Hide Arm/Group Description Safety Population during treatment periods Safety population during treatment periods
All-Cause Mortality
RP103 Cystagon®
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
RP103 Cystagon®
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/43 (13.95%)      1/41 (2.44%)    
Gastrointestinal disorders     
Abdominal Discomfort  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Vomiting  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Infections and infestations     
Gastroenteritis  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Injury, poisoning and procedural complications     
Femur Fracture  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Metabolism and nutrition disorders     
Hypovolaemia  1  0/43 (0.00%)  0 1/41 (2.44%)  1
Hypokalaemia  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Knee deformity  1  1/43 (2.33%)  1 0/41 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
RP103 Cystagon®
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   16/43 (37.21%)      5/41 (12.20%)    
Gastrointestinal disorders     
Vomiting  1  5/43 (11.63%)  8 3/41 (7.32%)  5
Nausea  1  5/43 (11.63%)  7 2/41 (4.88%)  3
Abdominal Pain  1  3/43 (6.98%)  4 0/41 (0.00%)  0
Metabolism and nutrition disorders     
Hypokalaemia  1  3/43 (6.98%)  3 0/41 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Investigators may publish or disclose study data, with the restriction that sponsor may embargo such communications for a period up to 60 days from the time submitted to sponsor. As a multi-center study, first publication of results will take place in conjunction with all investigators. If such a multi-center publication is not forthcoming within 18 months of study completion, individual investigators may publish as restricted according to limitations expressed above (60 day embargo).
Results Point of Contact
Name/Title: Evelyn Olson, Director
Organization: Horizon Pharma USA, Inc.
Phone: 224-383-3000
Responsible Party: Horizon Pharma USA, Inc.
ClinicalTrials.gov Identifier: NCT01000961     History of Changes
Other Study ID Numbers: RP103-03
First Submitted: October 22, 2009
First Posted: October 23, 2009
Results First Submitted: November 2, 2012
Results First Posted: November 19, 2014
Last Update Posted: May 19, 2017