Attention Deficit Hyperactivity Disorder
Conditions
Keywords
Attention Deficit Hyperactivity Disorder,, ADHD, Cytogenetic abnormalities,, extended-release methylphenidate,
Brief summary
This study will assess the frequency of chromosomal abnormalities measured in circulating lymphocytes in treatment-naive children with Attention Deficit Hyperactivity Disorder (ADHD) treated for 3 months with either extended release methylphenidate or behavioral therapy.
Detailed description
This study will determine whether the administration of extended-release methylphenidate in treatment-naïve children with Attention Deficit Hyperactivity Disorder (ADHD) affects the frequency of chromosomal abnormalities.
Interventions
DRUGExtended Release Methylphenidate (Ritalin LA ) plus Behavior Therapy
BEHAVIORALBehavior Therapy
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Children of both genders, 6-12 years old * Written informed consent by the parent and the patient (over 7) * Diagnosis of ADHD * Age-appropriate cognitive functioning * All patients who had at least one post-baseline cytogenetic assessment in the core study can enter the observation phase.
Exclusion criteria
* History of malignant neoplasm * History of seizures (except childhood febrile seizures) * Hyperthyroidism * Concurrent medical condition which may interfere with study Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12) | baseline and at end of treatment (Week 12) | 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. |
| The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) | baseline and at end of treatment (Week 12) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) | Baseline to end of treatment (Week 12) | 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. |
| Number of Sister Chromatoid Exchanges Per Cell | baseline and at end of treatment (Week 12) | 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. |
| Change From Baseline to the End of Treatment (Week 12) on the Severity of Illness Rating of the Clinical Global Impression Scale (CGI-S) | From baseline to the end of treatment (Week 12) | 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. |
| Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I) | From baseline to the end of treatment (Week 12) | 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. |
| Pharmacokinetic/Pharmacodynamic Relationship of Methylphenidate Blood Levels and Cytogenetic Changes | End of treatment (Week 12) | Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ritalin LA Plus Behavior Therapy 10-60 mg/day | 52 |
| Behavior Therapy 0 mg/day Ritalin LA | 52 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment | Abnormal test procedure result(s) | 1 | 0 |
| Treatment | Administrative problems | 5 | 0 |
| Treatment | Lack of Efficacy | 0 | 1 |
| Treatment | Lost to Follow-up | 0 | 6 |
| Treatment | Protocol Violation | 6 | 2 |
| Treatment | Withdrawal by Subject | 3 | 8 |
| Washout | Lack of Efficacy | 9 | 1 |
| Washout | Lost to Follow-up | 1 | 3 |
| Washout | Protocol Violation | 0 | 1 |
| Washout | Withdrawal by Subject | 11 | 5 |
Baseline characteristics
| Characteristic | Ritalin LA Plus Behavior Therapy | Behavior Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 52 Participants | 52 Participants | 104 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 8.3 years STANDARD_DEVIATION 1.75 | 8.5 years STANDARD_DEVIATION 1.91 | 8.4 years STANDARD_DEVIATION 1.83 |
| Sex: Female, Male Female | 21 Participants | 17 Participants | 38 Participants |
| Sex: Female, Male Male | 31 Participants | 35 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 52 | 13 / 52 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 |
Outcome results
Primary
The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12)
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.
Time frame: baseline and at end of treatment (Week 12)
Population: Per-Protocol-1 (PP1) population: The PP1 population consisted of all patients who were randomized and provided cytogenetic data for at least one of the primary endpoints at baseline and at the Week 12 evaluation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12) | Baseline | 1.05 number of abnormalities | Standard Deviation 1.246 |
| Ritalin LA Plus Behavior Therapy | The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At the end of treatment i.e. week12: Mean | 0.53 number of abnormalities | Standard Deviation 1.132 |
| Behavior Therapy | The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12) | Baseline | 0.75 number of abnormalities | Standard Deviation 1.008 |
| Behavior Therapy | The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At the end of treatment i.e. week12: Mean | 0.41 number of abnormalities | Standard Deviation 0.665 |
Primary
The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12)
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.
Time frame: baseline and at end of treatment (Week 12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At Baseline | 5.76 number of micronuclei per 1000 binucleat | Standard Deviation 2.336 |
| Ritalin LA Plus Behavior Therapy | The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At the end of treatment i.e. Week 12 | 3.63 number of micronuclei per 1000 binucleat | Standard Deviation 2.053 |
| Behavior Therapy | The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At the end of treatment i.e. Week 12 | 4.19 number of micronuclei per 1000 binucleat | Standard Deviation 2.737 |
| Behavior Therapy | The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) | At Baseline | 5.71 number of micronuclei per 1000 binucleat | Standard Deviation 4.535 |
Secondary
Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P)
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.
Time frame: Baseline to end of treatment (Week 12)
Population: Per-Protocol-2 (PP2) Population: The PP2 population consisted of all subjects who were randomized and provided at least one post-baseline efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) | -17.0 Units on a rating scale | Standard Deviation 11.23 |
| Behavior Therapy | Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) | -7.0 Units on a rating scale | Standard Deviation 9.97 |
Secondary
Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I)
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.
Time frame: From baseline to the end of treatment (Week 12)
Population: Per-Protocol-2 (PP2) Population: The PP2 population consisted of all subjects who were randomized and provided at least one post-baseline efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I) | 1.9 Units on a rating scale | Standard Deviation 0.81 |
| Behavior Therapy | Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I) | 3.0 Units on a rating scale | Standard Deviation 0.97 |
Secondary
Change From Baseline to the End of Treatment (Week 12) on the Severity of Illness Rating of the Clinical Global Impression Scale (CGI-S)
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.
Time frame: From baseline to the end of treatment (Week 12)
Population: Per-Protocol-2 (PP2) Population: The PP2 population consisted of all subjects who were randomized and provided at least one post-baseline efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | Change From Baseline to the End of Treatment (Week 12) on the Severity of Illness Rating of the Clinical Global Impression Scale (CGI-S) | -1.9 Units on a rating scale | Standard Deviation 0.98 |
| Behavior Therapy | Change From Baseline to the End of Treatment (Week 12) on the Severity of Illness Rating of the Clinical Global Impression Scale (CGI-S) | -0.6 Units on a rating scale | Standard Deviation 1.01 |
Secondary
Number of Sister Chromatoid Exchanges Per Cell
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.
Time frame: baseline and at end of treatment (Week 12)
Population: Per-Protocol-2 population: The PP2 population consisted of all subjects who were randomized and provided at least one post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ritalin LA Plus Behavior Therapy | Number of Sister Chromatoid Exchanges Per Cell | Baseline | 7.807 number of sister chromatoid exchanges | Standard Deviation 0.9228 |
| Ritalin LA Plus Behavior Therapy | Number of Sister Chromatoid Exchanges Per Cell | At the end of treatment i.e. Week12 | 7.213 number of sister chromatoid exchanges | Standard Deviation 1.0408 |
| Behavior Therapy | Number of Sister Chromatoid Exchanges Per Cell | Baseline | 7.533 number of sister chromatoid exchanges | Standard Deviation 1.216 |
| Behavior Therapy | Number of Sister Chromatoid Exchanges Per Cell | At the end of treatment i.e. Week12 | 7.303 number of sister chromatoid exchanges | Standard Deviation 0.6165 |
Secondary
Pharmacokinetic/Pharmacodynamic Relationship of Methylphenidate Blood Levels and Cytogenetic Changes
Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics.
Time frame: End of treatment (Week 12)