A Long Term Post-Marketing Study on the EffIcacy and Safety of Osmotic Release Oral System (OROS) Methylphenidate on the Cognitive Functions of Attention Deficit Hyperactivity Disorder (ADHD) Participants

Study Overview
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Brief Summary
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The purpose of this long term post-marketing study is to evaluate the effectiveness and safety of osmotic release oral system methylphenidate hydrochloride (OROS-MPH) in participants with Attention Deficit Hyperactivity Disorder (ADHD).

Detailed Description
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This is an open-label (all people know the identity of the intervention), prospective (study following participants forward in time), self-controlled, long-term post-marketing study in participants with ADHD. The study consists of 3 periods: screening period, wash-out period/run-in period (3 days), and open-label treatment period (12 weeks) which is divided into 2 periods that is dosage adjustment period and dose-optimization period. The total duration of the study is 12 weeks. During the dosage adjustment period, the dose of methylphenidate hydrochloride was adjusted to the optimal dose within 1-3 weeks starting with initial dosage of 18 milligram per day (mg/d) which can be increased to 36 mg/d up to a maximum dosage of 54 mg/d according to the therapeutic effect and tolerance or maintained at 36 mg or re-adjusted to 18 mg due to intolerance. Participants will receive the optimal dose determined during dose adjustment period for 9 weeks during the dose-optimization period. In the study, 2 types of participants will be enrolled in 2 groups (according to condition): OROS-MPH group (participants with ADHD) and the normal children group (healthy participants). The efficacy will be assessed primarily by Digit Span Test and Inattention /Over activity With Aggression (IOWA) Conners evaluation scale. Participants' safety will be monitored throughout the study.

Official Title
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An Open, Self-Controlled, Prospective Study of Concerta on Cognitive Functions, Efficacy and Tolerance in the Pediatric Patients With Attention Deficit Hyperactivity Disorder (ADHD)

Conditions
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Attention Deficit Hyperactivity Disorder (ADHD)

Intervention / Treatment
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* Drug: Osmotic Release Oral System Methylphenidate Hydrochloride (OROS-MPH)
* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ADHD children must sign the consent form in person, and their parents or guardian must endorse, in the consent form, participation of the child in the designated research program Through personal interaction and assessment questionnaire, examine to determine compliance of DSM-IV ADHD diagnostic criteria According to the judgment of researchers, the ADHD children should have normal intelligence. Normal intelligence is defined as no obvious evidence of mental retardation in general (specific learning disabilities will not be considered mental retardation in general), formal IQ test to be conducted and 85 marks or above ought to be scored ADHD children should not have been subjected to psychotropic drug treatment within 6 months. Those ADHD children on whom methylphenidate immediate-release tablets treatment is effective (with maximum daily dosage of 60 mg), may be admitted Normal children with IQ greater than or equal to 85 Exclusion Criteria: Unable to fully comply with the cognitive function test in the laboratory Known to be allergic to methylphenidate Consumption of psychoactive drugs currently or in the past 30 days, including use of monoamine oxidase inhibitors, clonidine, other alpha 2 adrenergic receptor agonists, tricyclic antidepressants, theophylline, bishydroxycoumarin etc History of alcohol, drugs or substances abuse Have medical history of type I or II bipolar affective disorder, anxiety disorder, schizophrenia or pervasive developmental disorder

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OROS-MPH Group<br>Participants with ADHD will receive OROS -MPH starting at initial dosage of 18 milligram per day (mg/d) which can be increased to 36 mg/d up to a maximum dosage of 54 mg/d according to the therapeutic effect and tolerance or maintained at 36 mg or re-adjusted to 18 mg due to intolerance. | Drug: Osmotic Release Oral System Methylphenidate Hydrochloride (OROS-MPH)<br>* Osmotic release oral system methylphenidate hydrochloride (OROS-MPH) starting at initial dosage of 18 milligram per day (mg/d) which can be increased to 36mg/d up to a maximum dosage of 54mg/d according to the therapeutic effect and tolerance or maintained at 36 mg or re-adjusted to 18mg due to intolerance.<br>|
| Active Comparator: Normal Group<br>Participants did not receive any study drug in this group. Participants were assessed for changes in the cognitive functions and the efficacy was compared with ADHD children. | Other: No intervention<br>* Participants did not receive any study drug in this group. Participants were assessed for changes in the cognitive functions and the efficacy was compared with ADHD children.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Digit Span Test Total Score at Week 12 | The digit span test is mainly used to measure the ability of short-term memory and attention. The participant will be given a string of digits and asked to repeat them forward, and then a second string of digits to repeat backward. The score is the number of correct responses, where the digits were repeated correctly. One point will be given for each correctly repeated string of digits. The maximum subscore in the Digits Forward is 16, and the maximum subscore in the Digits Backward is 14, summed for a total score of 30. A higher score is indicative of better recall and attention. | Baseline and Week 12 | 
| Change From Baseline in Inattention/Overactivity With Aggression (IOWA) Conners Behavior Rating Scale - I/O Score at Week 1 | IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and Week 1 | 
| Change From Baseline in IOWA Conners Behavior Rating Scale - I/O Score at Week 2 | IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and Week 2 | 
| Change From Baseline in IOWA Conners Behavior Rating Scale - I/O Score at Week 3 | IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and Week 3 | 
| Change From Baseline in IOWA Conners Behavior Rating Scale - I/O Score at Week 7 | IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and Week 7 | 
| Change From Baseline in IOWA Conners Behavior Rating Scale - I/O Score at Week 12 | IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Total Score of IO Sub-scale Less Than or Equal to 5 in IOWA Conners Measurement Scale. | Remission rate is the percentage of participants with total score of IO sub-scale less than or equal to 5 in IOWA Conners measurement scale | End of Week 1, 2, 3, 7 and 12 | 
| Stroop Color Word Naming Test | This is a psychological test to observe the interference in which disparity between the meaning and color affects reading speed. A participant will be given 3 tasks of recognition: reading the printed colored ink (Color Test), reading color words in black ink (Word Test), and interference, reading color words printed in different colored ink (Word-Color Test). The test is scored on the number of correct answers. There are 100 items for each of the three categories and if they made it through the 100 words with time remaining, they would repeat the list. Median naming time in the Stroop color word naming test will be assessed. Stroop color word naming test 1 ,2 ,3 and 4 stand for gradually increased difficulty and each test has a corresponding baseline and endpoint. | Baseline and End of Week 12 | 
| Wisconsin Card Sorting Test (WCST): Administered Responses (Ra) of Completed Examination | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. During number of trials administered or administered responses, participants were administered 128 cards and asked to sort the cards until all the 6 sorting categories was completed. Response number used to complete all 6 categories ranges from 50 to 128, lesser the better. | Baseline and End of Week 12 | 
| WCST: Completed Categories (Cc) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. In completed categoriies, number of categories completed out of 6 sorting categories after the test was evaluated. Ranges from 0 to 6. The more the number of categories completed the better is the response. | Baseline and End of Week 12 | 
| WCST: Correct Responses (Rc) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. The number of correct responses which meets all the requirements according to the response principles was evaluated. Ranges from 0-116, the more the better. | Baseline and End of Week 12 | 
| WCST: Error Responses (Re) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Number of error responses which did not comply with the response principles was evaluated. Ranges from 0 to 128, the less the better. | Baseline and End of Week 12 | 
| WCST: Percentage of Correct Responses (Rc%) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Percentage of correct responses which meets all the requirements according to the response principles was evaluated. Ranges from 0 to 100 percent (%), the more the better. | Baseline and End of Week 12 | 
| WCST: First Response (Rf) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Number of responses needed to complete the first color classification was evaluated. Ranges from 9 to 128, the lesser the better. | Baseline and End of Week 12 | 
| WCST: Percentage of Conceptual Level Responses (Rf%) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Percentage of the responses completed with 3-10 continuous correct during the entire measuring process was evaluated. Ranges from 0 to 100%, the more the better. | Baseline and End of Week 12 | 
| WCST: Perseverative Responses (Rp) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Number of perseverative responses were the responses which applied continuity principle for matching answers was evaluated. Ranges from 0 to 100, the less the better. | Baseline and End of Week 12 | 
| WCST: Perseverative Error Responses (Rpe) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Perseverative error responses are the number of responses which applied continuity principle for matching answers and also had the wrong answer was evaluated. Ranges from 0 to 128, the less the better. | Baseline and End of Week 12 | 
| WCST: Percentage of Perseverative Error Responses (Rpe%) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative (pvt) errors; nonperseverative errors; failure to maintain set; learning to learn. Percentage of persistent errors out of total number of responses was evaluated. Ranges from 0 to 100%, the less the better. | Baseline and End of Week 12 | 
| WCST: Non-Persistent Error Responses (nRpe) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. Non perseverative error responses are the errors remaining after subtracting persistent errors from total errors. Ranges from 0 to 128 and was not linear (cannot be considered to be good or bad just judged by the number, analyzed with other factors case by case). | Baseline and End of Week 12 | 
| WCST: Failure to Maintain Set (Fm) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. The 13 indicators are as follows: number of trials administered; number of categories completed; response corrects; percent corrects; total number of errors; trials to complete first category; percent conceptual level responses; perseverative responses; perseverative errors; percent perseverative errors; nonperseverative errors; failure to maintain set; learning to learn. The frequency (number of times) of responses completed with 5 to 9 continuous correct was evaluated. Ranges from 0 to 26 and was not linear (cannot be considered to be good or bad just judged by the number, analyzed with other factors case by case). | Baseline and End of Week 12 | 
| WCST: Learning to Learn (L-C) | WCST is used to evaluate participants' abilities of abstract generalization, working memory, and distraction-cognitive clinically, which reflects participants' cognitive function objectively and comprehensively. WCST consists of 13 test indicators and all indicators will be analyzed separately. Learning to learn indicator was a measure of decrement in the number of responses needed to achieve each successive category. The raw score ranged from 0 to 100. The high, negative value suggests the participants could not effectively learn the task presented by the WCST. Only calculated in those completed 3 or more categories and not linear (cannot be considered to be good or bad just judged by the number, analyzed with other factors case by case). | Baseline and End of Week 12 | 
| Coding Test | The coding Test is a common test indicator for perceptual speed. The test presents a series of corresponding relationship between graphics and symbols to the participant, and then participants will be required to fill out the appropriate symbol following single symbol in the test part. The test is limited within 150 seconds and evaluated the number of symbols been replaced correctly by the participants. | Baseline and End of Week 12 | 
| Academic Achievement | Mathematics and language scores will be obtained from their corresponding examinations at school. Scores ranges from 0-100 respectively. Mathematics and language would be summarized separately. | Baseline and End of Week 12 | 
| Number of Participants With Clinical Global Impression - CGI Scale Score | CGI is an overall rating scale. Clinical Global Impression (Improvement of Diseases) is divided into seven grades: 1=very significant improvement, 24=significant improvement or advanced, 3=improvement or slightly advanced, 4=no change, 5=slight aggravation, 6=significant aggravation, and 7=very significant aggravation or seriously aggravated. Number of participants in each category of grade were assessed. | End of Week 1, 2, 3, 7 and 12 | 
| Change From Baseline in I/O Score of IOWA Conners Behavior Rating Scale at Week 12 | IOWA conners behavior rating scale score in different dosage groups will be accessed to evaluate relationship between therapeutic effect and dosage. IOWA Conners Behavior Rating Scale evaluated by parents provides accurate measurement standards for behavioral change and therapeutic response. It includes 2 sub-scales: Inattention/Overactivity (I/O) subscale and Attacks (A), also known as Opposition/Defiant (O/D) sub-scale. IO (primary measurement ) will be assessed using 5-items and all Items will be scored on a 4-point scale (from 0=not at all to 3=very much). Total score range is from 0 to 15. Higher scores indicate worsening. | Baseline and End of Week 12 | 
| Change From Baseline in Total Scores of Digit Span Test at Week 12 | The digit span test total score will be accessed in different dosage groups to evaluate the relationship between therapeutic effect and dosage. The digit span test is mainly used to measure the ability of short-term memory and attention. The participant will be given a string of digits and asked to repeat them forward, and then a second string of digits to repeat backward. The score is the number of correct responses, where the digits were repeated correctly. One point will be given for each correctly repeated string of digits. The maximum subscore in the Digits Forward is16, and the maximum subscore in the Digits Backward is 14, for a total score of 30. A higher score was indicative of better recall and attention. | Baseline and End of Week 12 | 
| Change From Baseline in Completion Time of Stroop Color-word Test at Week 12 | Completion time of stroop color-word test in different dosage groups will be accessed to evaluate the relationship between therapeutic effect and dosage. This is a psychological test to observe the interference in which disparity between the meaning and color affects reading speed. A participant will be given 3 tasks of recognition: reading the printed colored ink (Color Test), reading color words in black ink (Word Test), and interference, reading color words printed in different colored ink (Word-Color Test). The test will be scored on the number of correct answers. There are 100 items for each of the three categories and if they made it through the 100 words with time remaining, they would repeat the list. Median time of the naming time in the Stroop color word naming test will be accessed. Stroop color word naming test 1 ,2 ,3 and 4 stand for gradually increased difficulty and each test has a corresponding baseline and endpoint. | Baseline and End of Week 12 | 
| Percentage of Participants With Total Score of IO Sub-scale Less Than or Equal to 5 in IOWA Conners Measurement Scale at Week 12 | Remission rate in different dosage groups will be accessed to evaluate the relationship between therapeutic effect and dosage. Remission rate is the percentage of participants with total score of IO sub-scale less than or equal to 5 in IOWA Conners measurement scale. | Week 12 | 
| Number of Participants Compliant With Treatment | Number of Participants who are Compliant with Treatment will be accessed. Less than 80 percent and more than 120 percent compliance signifies bad compliance, 80 to 120 percent compliance signifies good compliance . The compliance was calculated by the percentage of dose (actual dose multiplied by 100/theoretical dose).The theoretical dose means the dose prescribed by the Investigator. | End of Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Attention Deficit Hyperactivity Disorder, Methylphenidate Hydrochloride, CONCERTA