Effects of Methylphenidate on Cellular Abnormalities in Children With Attention Deficit Hyperactivity Disorder (ADHD)

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00409708
• Collaborator: (none)
• Enrollment: 142
• Location: 1
• Arms: 2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Attention Deficit Hyperactivity Disorder	Drug: Extended Release Methylphenidate (Ritalin LA ) plus Behavior Therapy; Behavioral: Behavior Therapy	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Behavioral-treatment-controlled Evaluation of the Effects of Extended Release Methylphenidate on the Frequency of Cytogenetic Abnormalities in Children 6 - 12 Years of Age With Attention Deficit Hyperactivity Disorder (ADHD)
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1	Drug: Extended Release Methylphenidate (Ritalin LA ) plus Behavior Therapy; Other Names: Ritalin LA
Other: 2	Behavioral: Behavior Therapy

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Pharmaceuticals Investigational site	Houston	Texas	United States	77007

Sponsors and Collaborators

• Novartis

Investigators

• Study Chair: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00409708
• Other Study ID Numbers: CRIT124D2201
• First Posted: Dec 11, 2006
• Last Update Posted: May 17, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Attention Deficit Hyperactivity Disorder,; ADHD; Cytogenetic abnormalities,; extended-release methylphenidate,
• Additional relevant MeSH terms: Hyperkinesis; Congenital Abnormalities; Disease; Attention Deficit Disorder with Hyperactivity; Methylphenidate

Study Results

Participant Flow

Arm/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Period Title: Treatment
STARTED	53	56
COMPLETED	38	39
NOT COMPLETED	15	17
Period Title: Treatment
STARTED	38	39
COMPLETED	17	29
NOT COMPLETED	21	10

Baseline Characteristics

Arm/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy	Total
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA	Total of all reporting groups
Overall Participants	52	52	104
Age (Count of Participants)
<=18 years	52 100%	52 100%	104 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.3 (1.75)	8.5 (1.91)	8.4 (1.83)
Sex: Female, Male (Count of Participants)
Female	21 40.4%	17 32.7%	38 36.5%
Male	31 59.6%	35 67.3%	66 63.5%

Outcome Measures

1. Primary Outcome

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)
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.
Time Frame	baseline and at end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	36	35
Baseline	1.05 (1.246)	0.75 (1.008)
At the end of treatment i.e. week12: Mean	0.53 (1.132)	0.41 (0.665)

2. Secondary Outcome

Title	Number of Sister Chromatoid Exchanges Per Cell
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.
Time Frame	baseline and at end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

Per-Protocol-2 population: The PP2 population consisted of all subjects who were randomized and provided at least one post-baseline efficacy assessment.

Arm/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	38	37
Baseline	7.807 (0.9228)	7.533 (1.2160)
At the end of treatment i.e. Week12	7.213 (1.0408)	7.303 (0.6165)

3. Secondary Outcome

Title	Pharmacokinetic/Pharmacodynamic Relationship of Methylphenidate Blood Levels and Cytogenetic Changes
Description	Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics.
Time Frame	End of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	0	0

4. Secondary Outcome

Title	Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P)
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.
Time Frame	Baseline to end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	38	37
Mean (Standard Deviation) [Units on a rating scale]	-17.0 (11.23)	-7.0 (9.97)

5. Secondary Outcome

Title	Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I)
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.
Time Frame	From baseline to the end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	38	37
Mean (Standard Deviation) [Units on a rating scale]	1.9 (0.81)	3.0 (0.97)

6. Secondary Outcome

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)
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.
Time Frame	From baseline to the end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	38	37
Mean (Standard Deviation) [Units on a rating scale]	-1.9 (0.98)	-0.6 (1.01)

7. Primary Outcome

Title	The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12)
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.
Time Frame	baseline and at end of treatment (Week 12)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ritalin LA Plus Behavior Therapy	Behavior Therapy
Arm/Group Description	10-60 mg/day	0 mg/day Ritalin LA
Measure Participants	36	35
At Baseline	5.76 (2.336)	5.71 (4.535)
At the end of treatment i.e. Week 12	3.63 (2.053)	4.19 (2.737)

Adverse Events

Arm/Group Title	Ritalin+Behavior		Behavior
Arm/Group Description	Ritalin+Behavior		Behavior
All Cause Mortality
	Ritalin+Behavior		Behavior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ritalin+Behavior		Behavior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/52 (0%)
Other (Not Including Serious) Adverse Events
	Ritalin+Behavior		Behavior
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/52 (53.8%)		13/52 (25%)
Gastrointestinal disorders
Abdominal Pain Upper	5/52 (9.6%)		2/52 (3.8%)
Vomiting	5/52 (9.6%)		1/52 (1.9%)
General disorders
Fatigue	4/52 (7.7%)		0/52 (0%)
Pyrexia	2/52 (3.8%)		3/52 (5.8%)
Infections and infestations
Nasopharyngitis	4/52 (7.7%)		4/52 (7.7%)
Upper Respiratory Tract Infection	6/52 (11.5%)		5/52 (9.6%)
Metabolism and nutrition disorders
Decreased Appetite	10/52 (19.2%)		0/52 (0%)
Nervous system disorders
Headache	7/52 (13.5%)		1/52 (1.9%)
Psychiatric disorders
Initial Insomnia	3/52 (5.8%)		0/52 (0%)
Insomnia	5/52 (9.6%)		0/52 (0%)
Tearfulness	3/52 (5.8%)		0/52 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	4/52 (7.7%)		1/52 (1.9%)

Limitations/Caveats

Since no cytogenetic effects were observed, blood samples were not analyzed for pharmacokinetics/pharmacodynamics.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.