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| Name | Class |
|---|---|
| Seattle Children's Hospital | OTHER |
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This study evaluates the effects of receiving and then discontinuing methylphenidate (MPH) in children with ADHD. After receiving MPH for 8 weeks, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks.
The stimulant methylphenidate (MPH) is the most commonly prescribed psychoactive medication in children. An abundance of studies attest to the efficacy of MPH for attenuating inattentive, hyperactive, and impulsive symptoms in children with ADHD. Despite its efficacy, most children with ADHD who are prescribed MPH have poor continuity of treatment for a variety of reasons, including forgetting to administer the medication and delays obtaining refills. In addition, it is an accepted clinical practice for physicians to omit MPH for periods of time, such as during the summer or on weekends (i.e., drug holidays). Since MPH discontinuation is considered to be benign, many clinicians do not employ any special procedures or inform families of any special precautions in regard to its cessation. However, increasing evidence suggests that the pharmacological effects of MPH cause lasting changes in brain neurochemistry that persist beyond medication discontinuation. Moreover, these neurobiological effects of discontinuation appear to have neurobehavioral consequences. There is a critical need to better understand the breadth and magnitude of the neurobehavioral effects caused by MPH discontinuation as well as to better understand the temporal trajectory of these deleterious effects. Hence, the primary goal of the proposed research is to conduct the first randomized, double-blind, placebo-controlled trial specifically designed to study the negative effects of MPH discontinuation at multiple time points. 180 children diagnosed with ADHD will participate across two recruitment sites. After undergoing a 4-week MPH titration trial and 4-week MPH maintenance phase, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks. Comprehensive multi-time point, multi-informant (parents, teachers, study staff) and multi-modal (behavior/mood/affect ratings scales, direct behavior observations, standardized testing) assessments will be used to assess a broad range of neurobehavioral outcomes. We will examine the magnitude and time course of effects of MPH discontinuation on behavioral as well as cognitive and academic functioning in children with ADHD. Furthermore, we will examine moderators of the adverse effects of MPH discontinuation on these outcomes to aid in the identification of those who are at increased risk.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MPH Discontinuation | Placebo Comparator |
|
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| Sustained MPH | Active Comparator |
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| OROS-Methylphenidate (MPH) | Drug | OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Parent ADHD Total Symptom Scores | Parent Vanderbilt ADHD Rating Scale Total Symptom Score, minimum=0, maximum=54, higher scores indicate more/worse ADHD symptoms | baseline, study weeks 8, 9, 10, 12 |
| Inhibitory Control Reaction Time Variability (SD of the Reaction Time) | Assessed via the Go/No-Go computerized measure of inhibitory control reaction time variability (with standard deviation of the reaction time being the indicator variability variability). Unit of measure is msec. Minimum is 0, Maximum is 500. Higher scores indicate more variability (higher standard deviation) in reaction time, indicating worse outcome (more characteristic of individuals with ADHD and less characteristic of typically developing individuals). | baseline, study weeks 8, 9, 10 & 12 |
| Math Computation - Number of Problems Completed Correctly | Math Computation Curriculum-Based Measure - Number of Problems Completed Correctly. Minimum=0, Maximum=600. Higher scores indicate improved/better performance | baseline, study weeks 8, 9, 10 & 12 |
| % Time on Task | Participants were videotaped while completing the 20-minute Analogue Math task. Their behavior was coded in 20-second intervals by trained coders who determined if the children were on-task or off-task during each interval. The amount of time coded as on-task was divided by the total amount of time and then multiplied by 100 to generate the % of time on task variable. | baseline, study weeks 8, 9, 10, 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Barkley Sluggish Cognitive Tempo (SCT) Ratings | assessed via parent-completed Barkley Sluggish Cognitive Tempo Scale. Minimum=12, Max=48, higher scores indicate worse outcome. | baseline, study weeks 8, 9, 10 &12 |
| Parent Ratings of Emotional Regulation |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tanya E. Froehlich, MD | Children's Hospital Medical Center, Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States | ||
| Seattle Children's Hospital |
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The number Enrolled (those who signed informed consent) differs from the number who Started in the Participant Flow module because: 1) some children who signed informed consent were determined to be ineligible after having formal assessment for study inclusion, 2) some children were unable to learn to swallow the study pill so could not start protocol participation, 3) some families changed their minds about participating after signing informed consent but before starting study procedures.
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| ID | Title | Description |
|---|---|---|
| FG000 | MPH Discontinuation |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
| FG001 | Sustained MPH |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | MPH Discontinuation |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Parent ADHD Total Symptom Scores | Parent Vanderbilt ADHD Rating Scale Total Symptom Score, minimum=0, maximum=54, higher scores indicate more/worse ADHD symptoms | There was some attrition and missing data at different data collection points. | Posted | Mean | Standard Deviation | score on a scale | baseline, study weeks 8, 9, 10, 12 |
|
Duration of trial (3 months)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | MPH Discontinuation |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal Ideation | Psychiatric disorders | Systematic Assessment | Participant had suicidal ideation (SI) that the treating psychiatry team deemed related to gender identity issues and bullying and were not judged to be related to study participation. Participant withdrew from study to receive care for SI. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Decreased appetite | Gastrointestinal disorders | Systematic Assessment |
Note that the school direct observations outcome was not collected due to data collection not being feasible due to schools' privacy concerns about other students in the classroom. All other outcome measures that were pre-specified Primary or Secondary Outcome Measures have been reported in this ClinicalTrials.gov entry.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Tanya Froehlich, MD | Cincinnati Children's Hospital Medical Center | 5136361154 | tanya.froehlich@cchmc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 18, 2020 | Nov 30, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| D013035 | Spasm |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
| D020879 | Neuromuscular Manifestations |
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| ID | Term |
|---|---|
| D008774 | Methylphenidate |
| ID | Term |
|---|---|
| D010648 | Phenylacetates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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|
assessed via parent-completed Emotion Regulation Checklist (ERC). Outcome assessed is ERC total mean score: minimum value=1, max value=4, higher scores indicate worse outcome |
| baseline, study weeks 8, 9, 10 &12 |
| Spatial Working Memory | Spatial working memory was assessed via the Corsi Computerized Spatial Span Task, which requires the participant to reproduce a sequence of movements by tapping a series of blocks on a computer screen in the same order demonstrated by the examiner. Outcome of interest is total trials correct. Minimum score=0, max score=10. Higher scores indicate better performance. | baseline, study weeks 8, 9, 10 &12 |
| Math Reasoning | Math reasoning was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Math Concepts and Applications. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 1, 8, 9, 10 &12 |
| Reading Comprehension | Reading Comprehension was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Reading Comprehension. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 8, 9, 10 &12 |
| Written Expression | Assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Written Expression, with the measure assessing number of words written by the child after receiving a prompt. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score (# of words written) on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 1, 8, 9, 10 &12 |
| Seattle |
| Washington |
| 98105 |
| United States |
| BG001 | Sustained MPH |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Parent Vanderbilt ADHD Total Symptom Score | Parent Vanderbilt ADHD Rating Scale Total Symptom Score: minimum=0, maximum=54, higher scores indicate more/worse symptoms | Mean | Standard Deviation | score on a scale |
|
| OG001 | Sustained MPH |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. |
|
|
|
| Primary | Inhibitory Control Reaction Time Variability (SD of the Reaction Time) | Assessed via the Go/No-Go computerized measure of inhibitory control reaction time variability (with standard deviation of the reaction time being the indicator variability variability). Unit of measure is msec. Minimum is 0, Maximum is 500. Higher scores indicate more variability (higher standard deviation) in reaction time, indicating worse outcome (more characteristic of individuals with ADHD and less characteristic of typically developing individuals). | There was some attrition and missing data at different data collection points. | Posted | Mean | Standard Error | msec | baseline, study weeks 8, 9, 10 & 12 |
|
|
|
|
| Primary | Math Computation - Number of Problems Completed Correctly | Math Computation Curriculum-Based Measure - Number of Problems Completed Correctly. Minimum=0, Maximum=600. Higher scores indicate improved/better performance | There was some attrition and missing data at different data collection points. | Posted | Mean | Standard Deviation | Number of problems completed correctly | baseline, study weeks 8, 9, 10 & 12 |
|
|
|
|
| Primary | % Time on Task | Participants were videotaped while completing the 20-minute Analogue Math task. Their behavior was coded in 20-second intervals by trained coders who determined if the children were on-task or off-task during each interval. The amount of time coded as on-task was divided by the total amount of time and then multiplied by 100 to generate the % of time on task variable. | There was some attrition and missing data at different data collection points. | Posted | Mean | Standard Error | percentage of time spent on task | baseline, study weeks 8, 9, 10, 12 |
|
|
|
| Secondary | Barkley Sluggish Cognitive Tempo (SCT) Ratings | assessed via parent-completed Barkley Sluggish Cognitive Tempo Scale. Minimum=12, Max=48, higher scores indicate worse outcome. | Note: There was some missing data as well as attrition. the numbers of participants with available data for this outcome has been verified. | Posted | Mean | Standard Error | score on a scale | baseline, study weeks 8, 9, 10 &12 |
|
|
|
| Secondary | Parent Ratings of Emotional Regulation | assessed via parent-completed Emotion Regulation Checklist (ERC). Outcome assessed is ERC total mean score: minimum value=1, max value=4, higher scores indicate worse outcome | There was some attrition and some missing data. # of participants with available data has been verified. | Posted | Mean | Standard Error | score on a scale | baseline, study weeks 8, 9, 10 &12 |
|
|
|
| Secondary | Spatial Working Memory | Spatial working memory was assessed via the Corsi Computerized Spatial Span Task, which requires the participant to reproduce a sequence of movements by tapping a series of blocks on a computer screen in the same order demonstrated by the examiner. Outcome of interest is total trials correct. Minimum score=0, max score=10. Higher scores indicate better performance. | some missing data due to attrition, non-valid trials/responses, and equipment failure. # of participants with available data has been verified. | Posted | Mean | Standard Error | total number of correct trials | baseline, study weeks 8, 9, 10 &12 |
|
|
|
| Secondary | Math Reasoning | Math reasoning was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Math Concepts and Applications. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | some missing data due to factors such as attrition and the test not being appropriate to administer all grade levels (e.g., not designed for participants who were in 1st grade) grade. # of participants with available data has been verified. | Posted | Mean | Standard Error | percentage of expected improvement | baseline, study weeks 1, 8, 9, 10 &12 |
|
|
|
| Secondary | Reading Comprehension | Reading Comprehension was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Reading Comprehension. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | some missing data due to attrition, non-valid test administration. Numbers of participants with available data has been verified. | Posted | Mean | Standard Error | percentage of expected improvement | baseline, study weeks 8, 9, 10 &12 |
|
|
|
| Secondary | Written Expression | Assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Written Expression, with the measure assessing number of words written by the child after receiving a prompt. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score (# of words written) on the test by the score predicted at that time point after applying the measure's normed "rate of improvement (ROI)" metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | some missing data due to attrition, non-valid responses, etc. # of participants with available data verified. | Posted | Mean | Standard Error | percentage of expected improvement | baseline, study weeks 1, 8, 9, 10 &12 |
|
|
|
| 0 |
| 92 |
| 1 |
| 92 |
| 55 |
| 92 |
| EG001 | Sustained MPH |
OROS-Methylphenidate (MPH): OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA. | 0 | 17 | 0 | 17 | 15 | 17 |
|
| Headache | Nervous system disorders | Systematic Assessment |
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| Stomachache | Gastrointestinal disorders | Systematic Assessment |
|
| Trouble Sleeping | General disorders | Systematic Assessment |
|
| Irritability | Psychiatric disorders | Systematic Assessment |
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| Social Withdrawal | Psychiatric disorders | Systematic Assessment |
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| Sadness | Psychiatric disorders | Systematic Assessment |
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| Dull, tired, listless | General disorders | Systematic Assessment |
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| Skin-picking | Psychiatric disorders | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
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| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010880 |
| Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Maintenance Visit (week 8) |
|
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| Randomization 1 (week 9) |
|
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| Randomization 2 (week 10) |
|
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| Randomization 3 (week 12) |
|
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| t-test, 2 sided |
| .90 |
| Mean Difference (Final Values) |
| 4.38 |
| Standard Error of the Mean |
| 30.1 |
| 2-Sided |
| Superiority |
| Compared at Randomization Phase 1 (week 9) | t-test, 2 sided | .007 | Mean Difference (Final Values) | 100.81 | Standard Error of the Mean | 37.5 | 2-Sided | Superiority |
| Compared at Randomization Phase 2 (week 10) | t-test, 2 sided | .26 | Mean Difference (Final Values) | 49.07 | Standard Error of the Mean | 56.6 | 2-Sided | Superiority |
| Compared at Randomization Phase 3 (week 12) | t-test, 2 sided | .01 | Mean Difference (Final Values) | 123.90 | Standard Error of the Mean | 37.6 | 2-Sided | Superiority |
| Maintenance Visit (week 8) |
|
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| Randomization 1 (week 9) |
|
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| Randomization 2 (week 10) |
|
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| Randomization 3 (week 12) |
|
|
| t-test, 2 sided |
| .06 |
| Mean Difference (Final Values) |
| 56.86 |
| Standard Error of the Mean |
| 29.5 |
| 2-Sided |
| Superiority |
| Comparison at Randomization Phase 1 (week 9) | t-test, 2 sided | .05 | Mean Difference (Final Values) | 108.78 | Standard Error of the Mean | 46.8 | 2-Sided | Superiority |
| Comparison at Randomization Phase 2 (week 10) | t-test, 2 sided | .008 | Mean Difference (Final Values) | 118.12 | Standard Error of the Mean | 44.2 | 2-Sided | Superiority |
| Comparison at Randomization Phase 3 (week 12) | t-test, 2 sided | .07 | Mean Difference (Final Values) | 77.09 | Standard Error of the Mean | 42.9 | 2-Sided | Superiority |
| Week 8 (MPH Maintenance dose) |
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| Week 9 |
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| Week 10 |
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| Week 12 |
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| Randomization 1 (week 9) |
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| Randomization 2 (week 10) |
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| Randomization 3 (week 12) |
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| Randomization 1 (wk 9) |
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| Randomization 2 (wk 10) |
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| Randomization 3 (wk 12) |
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| week 9 |
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| week 10 |
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| week 12 |
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| week 9 |
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| week 10 |
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| week 12 |
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| week 9 |
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| week 10 |
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| week 12 |
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| week 9 |
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| week 10 |
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| week 12 |
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