Clinical Trial Results:
An open-label, behavioral-treatment-controlled evaluation of the effects of extended release methylphenidate (Ritalin® LA) on the frequency of cytogenetic abnormalities in children 6 – 12 years of age with attention deficit hyperactivity disorder (ADHD) followed by an observation phase up to 24-months
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Summary
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EudraCT number |
2015-004444-19 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
05 Mar 2008
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Dec 2016
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First version publication date |
21 Dec 2016
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Other versions |
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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 |
CRIT124D2201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00409708 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
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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 |
05 Mar 2008
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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 |
05 Mar 2008
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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 was to compare the frequency of chromosomal abnormalities (chromosomal
aberrations per 100 cells excluding gaps and micronuclei per 1000 binucleated cells) before and after three months of treatment with Ritalin® LA (extended release MPH) and behavioral treatment,
compared to behavioral treatment alone.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP)
Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Nov 2006
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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: 109
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Worldwide total number of subjects |
109
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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) |
104
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Adolescents (12-17 years) |
5
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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 |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 142 participants were screened for the study but only 109 were randomized to treatment | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ritalin LA Plus Behavior Therapy | ||||||||||||||||||||||||||||||
Arm description |
10-60 mg/day | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
methylphenidate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/day to 60 mg/day
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Arm title
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Behavior Therapy | ||||||||||||||||||||||||||||||
Arm description |
0 mg/day Ritalin LA | ||||||||||||||||||||||||||||||
Arm type |
Behavioral therapy | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 2
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Period 2 title |
Washout
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ritalin LA Plus Behavior Therapy | ||||||||||||||||||||||||||||||
Arm description |
10-60 mg/day | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
methylphenidate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/day to 60 mg/day
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Arm title
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Behavior Therapy | ||||||||||||||||||||||||||||||
Arm description |
0 mg/day Ritalin LA | ||||||||||||||||||||||||||||||
Arm type |
Behavioral Therapy | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Ritalin LA Plus Behavior Therapy
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Reporting group description |
10-60 mg/day | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Behavior Therapy
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Reporting group description |
0 mg/day Ritalin LA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Ritalin LA plus behavior therapy
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
10-60 mg/day
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Subject analysis set title |
Behavior therapy
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
0 mg/day Ritalin LA
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End points reporting groups
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Reporting group title |
Ritalin LA Plus Behavior Therapy
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Reporting group description |
10-60 mg/day | ||
Reporting group title |
Behavior Therapy
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Reporting group description |
0 mg/day Ritalin LA | ||
Reporting group title |
Ritalin LA Plus Behavior Therapy
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Reporting group description |
10-60 mg/day | ||
Reporting group title |
Behavior Therapy
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Reporting group description |
0 mg/day Ritalin LA | ||
Subject analysis set title |
Ritalin LA plus behavior therapy
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
10-60 mg/day
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Subject analysis set title |
Behavior therapy
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
0 mg/day Ritalin LA
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End point title |
The number of chromosomal aberrations per 100 cells excluding gaps at baseline and at the end of treatment i.e day 84 (week 12) | ||||||||||||||||||
End point description |
The number of chromosomal aberrations per 100 cells excluding gaps at Baseline (n=33, n=32) and at Week 12 (n=33, n=32) was counted in blood samples cultured for 48 hours using a standard protocol. The types of abnormalities included translocations (reciprocal and non-reciprocal), insertions, dicentrics, fragments, inversions, chromatid exchanges (quadriradials and triradials), breaks, and other unusual observations, eg, aneuploidy, tetraploidy or endoreduplication.
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End point type |
Primary
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End point timeframe |
baseline and at end of treatment (Week 12)
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Statistical analysis title |
Ratio of Day 84 (Week 12) to Baseline | ||||||||||||||||||
Statistical analysis description |
Inferential analysis of change from baseline reported in least square means for cytogenetic endpoints by visit by treatment
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Comparison groups |
Ritalin LA plus behavior therapy v Behavior therapy
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Number of subjects included in analysis |
104
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||||||||
Method |
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Parameter type |
Poisson model | ||||||||||||||||||
Point estimate |
1.34
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
0.53 | ||||||||||||||||||
upper limit |
3.4 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.64
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| Notes [1] - Ratio less than 1 indicates a decrease from Baseline to Day 84 (Week 12). Least squares means of the ratio of Day 84 (Week 12) to Baseline in either group were estimated by a Poisson model using GEE estimation techniques that included factors for time, treatment by time interaction, sex and age group as covariates. |
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End point title |
The Number of Micronuclei per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) [2] | ||||||||||||||||||
End point description |
The number of micronuclei per 1000 binucleated cells was measured at Baseline ( n=34 , n=29 ) and at the end of treatment, Week 12 (n =34, n= 29), in blood cultured for 48 hours using a standard protocol.
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End point type |
Primary
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End point timeframe |
baseline and at end of treatment (Week 12)
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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: Only summary analysis performed per groups |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Sister Chromatoid Exchanges Per Cell | ||||||||||||||||||
End point description |
Blood collected at baseline (n=20, n=14) and at the end of treatment, Week 12, (n= 20, n= 14) was cultured for 48 hours using a standard protocol. Giemsa staining and/or fluorescent in situ hybridization (FISH) chromosome painting was done on the cells in metaphase and the number of chromatoid exchanges per cell was recorded by blinded raters.
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End point type |
Secondary
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End point timeframe |
baseline and at end of treatment (Week 12)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Pharmacokinetic/pharmacodynamic relationship of methylphenidate blood levels and cytogenetic changes | |||||||||
End point description |
Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics.
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End point type |
Secondary
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End point timeframe |
End of treatment (Week 12)
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| Notes [3] - analysis not completed as per protocol [4] - analysis not completed as per protocol |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from baseline to end of treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) | ||||||||||||
End point description |
Parents completed the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) consisting of the ADHD Index (12 items) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)( 18 items). Parents rated their child's behavior of the previous week from a list of common problems. When asked "How much of a problem has this been in the last week?” parents selected 0 = none, not at all, seldom, or very infrequently; 3 = very much true, or it occurs very often or frequently; or 1 or 2 for ratings in between. A score of 50 is considered normal and more than 70 markedly atypical.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment (Week 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline to the end of treatment (Week 12) on the global improvement rating of the Clinical Global Impression scale (CGI-I) | ||||||||||||
End point description |
The Clinical Global Impression scale (CGI-I) is a clinician-rated instrument designed to assess the overall change of illness relative to baseline. The CGI-I consists of 7 ratings as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. CGI-I assessments are relative to the patient’s status at the Baseline visit.
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End point type |
Secondary
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End point timeframe |
From baseline to the end of treatment (Week 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from baseline to the end of treatment (Week 12) on the severity of illness rating of the Clinical Global Impression scale (CGI-S) | ||||||||||||
End point description |
The Clinical Global Impression scale (CGI-S) is a clinician-rated instrument designed to assess the severity of illness. The CGI-S rating indicates illness severity at each time-point on a scale as follows: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = extremely ill. CGI-S assessments are relative to the patient’s status at the Baseline visit.
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End point type |
Secondary
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End point timeframe |
From baseline to the end of treatment (Week 12)
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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 |
Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last
Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV.
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Adverse event reporting additional description |
AE additional description
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
11.0
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Reporting groups
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Reporting group title |
Behavior
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Reporting group description |
Behavior | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ritalin+Behavior
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Reporting group description |
Ritalin+Behavior | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Oct 2006 |
To separate the efficacy assessment of the two treatment arms and specify the parameters
to be analyzed
• To add an additional efficacy questionnaire (SDQ) to the study as exploratory objective
• To add GGT to the exclusion criteria
• To define the age for the stratification groups
• To clarify the different study phases with the different phase- and study-completion visits
• To allow patients with co-morbid Oppositional Defiant Disorder (ODD) and with nonsevere
Conduct Disorder (CD) into the study
• To align the names of the assessments with the names of the corresponding CRF pages
and add missing ones to the assessment table
• To add and clarify some assessment time-points
• To correct the fact that the study data are recorded on paper CRF and not on electronic
CRF
• To add explanation of the ECG assessments
• To correct the strengths of the investigational drug to be dispensed
• To add further clarifications to the analysis
• To correct that patients, who show chromosomal changes will be followed until it can be
determined whether their health is affected
• To expand the behavior therapy |
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22 Feb 2007 |
The main purpose of this amendment was to
include an observation-phase to follow up those patients who finished the core study 2201
before the last patient was completed. This amendment was designed to obtain additional
data concerning potential cytogenetic changes and concurrent medical, social and
environmental factors in these patients.
These amendments (both before database lock) were not felt to affect the interpretation of
study results, as the changes were minor, and occurred at a time when all centers were still
recruiting patients into both treatment groups. |
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23 Jan 2008 |
The main purpose of this amendment was to reflect the manner in which cytogenetic data are typically presented in the peer-reviewed literature (Koppen et al, 2007; Lazutka et al. 1999; El-Zein et al, 2005; Neri et al, 2005; Walitza et al, 2007), the final results would be reported as the "number of chromosomal aberrations per 100 cells excluding gaps", and the "number of micronuclei per 1000 binucleated cells". No change was made to sister chromatid exchanges. This amended approach recognized the relatively infrequent cells that contain more than one abnormal event. The actual difference in the means between the two approaches was expected to be modest and probably not biologically meaningful. However, this amended approach was more scientifically accurate. An interim analysis confirmed that the power of the sample size calculation based on number of abnormal events per number of cells (ie: number of CAs/200 cells, number of MNs/2000 binucleated cells) was similar compared to the original calculation, that was based on the number of cells with aberrations. |
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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. | |||
| Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics. | |||
