Clinical Trial Results:
A Multicenter, Open-Label, 2-Group, Dose Escalation Study of Monotherapy Administration of Rotigotine in Pediatric Subjects With Idiopathic Restless Legs Syndrome
Summary
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EudraCT number |
2014-004383-37 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
30 Apr 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jun 2016
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First version publication date |
03 Jul 2015
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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 |
SP1004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01495793 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
UCB Biosciences Inc.
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Sponsor organisation address |
8010 Arco Corporate Drive, Raleigh, United States, NC 27617
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Public contact |
CTRRD, UCB Biosciences GmbH, +49 2173481515, clinicaltrials@ucb.com
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Scientific contact |
CTRRD, UCB Biosciences GmbH, +49 2173481515, clinicaltrials@ucb.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 |
13 Aug 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Apr 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Apr 2014
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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 |
The primary objective of this study was to determine the pharmacokinetic (PK) properties of rotigotine in adolescents with idiopathic restless legs syndrome (RLS) after multiple patch administrations.
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Protection of trial subjects |
Close monitoring of subjects safety status, including checks of mental health e.g. by CSSR-S questionnaire.
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Background therapy |
If nausea or vomiting occurred during the study, antiemetic therapy with ondansetron was allowed. Ondansetron was not to be used prophylactically. Use of a topical anesthetic was permitted to treat the venous puncture or indwelling venous catheter site prior to the needle stick. If medication is medically indicated, the subject must inform the investigator immediately. All concomitant medication and treatment was recorded in the appropriate study documents (i.e. eCRF and source document). | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
01 Dec 2011
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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: 24
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Worldwide total number of subjects |
24
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EEA total number of subjects |
0
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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) |
0
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Adolescents (12-17 years) |
24
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Adults (18-64 years) |
0
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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 |
This was a multicenter study in which 42 subjects were enrolled and 24 treated at 8 sites in the USA. | ||||||||||||
Pre-assignment
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Screening details |
In total 42 subjects signed the informed consent and were enrolled into the study (Enrolled Set). 24 of these subjects were treated with medication. The sample size of 24 subjects was sufficient to target a 95% confidence interval and the calculation was based on a previous study. Participant Flow refers to the 24 treated subjects (Safety Set). | ||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Arms
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Arm title
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Rotigotine | ||||||||||||
Arm description |
In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Neupro 0.5 mg/24 h
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Investigational medicinal product code |
Prod 1
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Other name |
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.
Dose (size): 0.5 mg/24 h (2.5 cm^2)
The patch has to be applied continuously for 24h. After 24h, the patch has to be removed and a new one applied.
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Investigational medicinal product name |
Neupro 1 mg/24 h
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Investigational medicinal product code |
Prod 2
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Other name |
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
In the Titration Period a subject received the first dose of rotigotine than the dose was increased weekly by a dose step over 4 weeks.
Dose (size): 1 mg/24 h (5 cm^2)
The patch has to be worn continuously for 24h. After 24h, the patch has to be removed and a new one applied.
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Investigational medicinal product name |
Neupro 3 mg/24 h
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Investigational medicinal product code |
Prod 4
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Other name |
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
In the Titration Period a subject received the first dose of rotigotine than the dose was increased weekly by a dose step over 4 weeks.
Dose (size): 3 mg/24 h (15 cm^2)
The patch has to be worn continuously for 24h. After 24h, the patch has to be removed and a new one applied.
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Investigational medicinal product name |
Neupro 2 mg/24 h
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Investigational medicinal product code |
Prod 3
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Other name |
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
In the Titration Period a subject received the first dose of rotigotine than the dose was increased weekly by a dose step over 4 weeks.
Dose (size): 2 mg/24 h (10 cm^2
The patch has to be worn continuously for 24h. After 24h, the patch has to be removed and a new one applied.
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Baseline characteristics reporting groups
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Reporting group title |
Rotigotine
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Reporting group description |
In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rotigotine
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Reporting group description |
In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks. | ||
Subject analysis set title |
Rotigotine (PKPPS)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The Pharmacokinetic Per Protocol Set (PKPPS) includes all enrolled subjects who were included in the Safety Set, who had no protocol deviations that were considered to impact the subject's validity for analysis of the primary study objective and who for at least 1 dose step fulfilled specific predefined conditions.
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End point title |
Apparent Total Body Clearance (Cl/f) of unconjugated rotigotine 0.5 mg/24 h (2.5 cm^2) [1] | ||||||||||
End point description |
CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Apparent Total Body Clearance (Cl/f) of unconjugated rotigotine 1 mg/24 h (5 cm^2) [2] | ||||||||||
End point description |
CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Apparent Total Body Clearance (Cl/f) of unconjugated rotigotine 2 mg/24 h (10 cm^2) [3] | ||||||||||
End point description |
CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Apparent Total Body Clearance (Cl/f) of unconjugated rotigotine 3 mg/24 h (15 cm^2) [4] | ||||||||||
End point description |
CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Volume of Distribution at steady state (VSS/f) of unconjugated rotigotine 0.5 mg/24 h (2.5 cm^2) [5] | ||||||||||
End point description |
VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Volume of Distribution at steady state (VSS/f) of unconjugated rotigotine 1 mg/24 h (5 cm^2) [6] | ||||||||||
End point description |
VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Volume of Distribution at steady state (VSS/f) of unconjugated rotigotine 2 mg/24 h (10 cm^2) [7] | ||||||||||
End point description |
VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Volume of Distribution at steady state (VSS/f) of unconjugated rotigotine 3 mg/24 h (15 cm^2) [8] | ||||||||||
End point description |
VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma.
For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.
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End point type |
Primary
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End point timeframe |
0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
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Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
This summary includes TEAEs from the Titration period, Taper period and Safety Follow-up (Day 1 up to 69 days).
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
9.1
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Reporting groups
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Reporting group title |
Rotigotine
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Reporting group description |
In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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31 Mar 2011 |
The main purpose of this substantial amendment was to include the suicidality risk assessment (Columbia-Suicide Severity Rating Scale [C-SSRS]). In accordance with the FDA draft Guidance for Industry, which went into effect on 29 Oct 2010. In addition, a list of anticipated serious adverse events (SAEs) was included in this amendment in compliance with the recent FDA guidance on safety reporting requirements for studies conducted under an open Investigational New Drug Application. The Beck Depression Inventory II and the Beck Anxiety Inventory were removed from the study assessments.
Other changes included in this amendment were as follows:
- Procedures for subjects wishing to enter the open-label, LTFU study (SP1005) following dose de-escalation but prior to the SFU Visit were added.
- Definition of clinically relevant renal dysfunction at Visit 1/Screening Period as an exclusion criterion was increased from serum creatinine >1.0mg/dL to >1.5mg/dL since the previous serum creatinine level >1.0mg/dL was within the central laboratory’s normal range.
Physical examination was removed as a safety variable.
- The version number of the Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale was added.
- For clarity, a dose de-escalation table (Table 3-3) was added.
- Storage requirements for the rotigotine patch were updated.
- Use of a topical anesthetic prior to the needle stick was permitted.
- Corrections were made to the definitions of some PK parameters, as well as the preparation and handling of the blood and saliva PK samples.
- Reference to patch size was removed from all sections, except Section 7.1 of the protocol, Description of investigational medicinal product (IMP).
- Vital sign parameters to be measured were specified as pulse rate, SBP, DBP, and orthostatic hypertension assessments.
- Sponsor Clinical Project Manager contact information was updated.
- Typographic errors and changes of an editorial nature were made. |
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19 Sep 2011 |
The purpose of this substantial amendment was to increase the minimum weight for enrollment in the study from 30kg to 40kg.
An additional change clarifying that subjects must tolerate the first dose step to be able to transition into the open-label, LTFU study was also made. |
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02 May 2012 |
The main purpose of this substantial amendment was to ensure consistency between the protocol and the FDA Pediatric Development Plan for the RLS indication in subjects 13 to <18 years of age. Since the subject’s dosing was no longer dependent on body weight, the dosing schedules for each study period were revised. The primary PK variables were changed to reflect those that were requested by the FDA for the revised sample size calculation. In addition, PK saliva sampling was removed from the study. Data from a recently completed PK study (RL0002) suggest that saliva concentrations of rotigotine cannot be used as a surrogate for plasma concentrations of rotigotine.
Other changes included in this amendment were as follows:
- Updated contact information for SAE reporting and procedures for reporting SAEs to be consistent with the current protocol template.
- Updated the regulatory status of rotigotine for the treatment of RLS in adults in the US.
- Removed the requirement for the PK blood samples to be centrifuged at a controlled temperature.
- Corrected typographic errors and minor inconsistencies of an editorial nature. |
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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 |