This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Effects of Methylphenidate on Cellular Abnormalities in Children With Attention Deficit Hyperactivity Disorder (ADHD) (NCT00409708), a randomized phase 2 study. The primary outcome is The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00409708 |
| Phase | Phase 2 |
| Condition | Attention Deficit Hyperactivity Disorder |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 142 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis |
| Results posted | Yes |
2. Clinical Question
The trial addresses whether the frequency of chromosomal abnormalities in circulating lymphocytes changes over treatment in children with ADHD receiving extended release methylphenidate alongside behavior therapy, compared with children receiving behavior therapy. The registry record describes participants as treatment-naive and gives the age range as 6–12 years. The planned treatment period was 3 months, with the primary endpoint assessed at baseline and the end of treatment, identified as Day 84 (Week 12).
Population
Treatment-naive children 6–12 years of age with attention deficit hyperactivity disorder. The primary endpoint description uses the Per-Protocol-1 population, defined by randomization and cytogenetic data for at least one primary endpoint at baseline and Week 12.
Intervention
Extended release methylphenidate plus behavior therapy, with chromosomal abnormalities assessed in circulating lymphocytes.
Comparator
Behavior therapy without the listed methylphenidate intervention.
Primary question
How does the number of chromosomal aberrations per 100 cells, excluding gaps, compare at baseline and the end of treatment across the treatment groups?
This is a question about a laboratory measure, not a direct comparison of clinical symptoms as the primary endpoint. The registry also lists symptom and clinical-global-rating measures as secondary outcomes, including the Conners' ADHD/DSM-IV Scale for Parents and Clinical Global Impression ratings. Numerical primary-outcome results and a single between-group primary comparison are not reported in the registry record, so the question can be described from the design but not answered quantitatively from the posted results.
3. Trial Design
The registry record identifies this as a randomized, open-label, parallel-group Phase 2 study. It lists an enrollment of 142 and describes the comparison as extended release methylphenidate plus behavior therapy versus behavior therapy. The planned treatment duration was 3 months. The study is marked completed, with a start date of 2006-11 and primary completion in 2008-03.
Random allocation is intended to make treatment assignment independent of participant characteristics on average, although the record does not report the allocation procedure or whether any restrictions were used. The open-label designation means masking was not used; the registry does not explain whether laboratory personnel or outcome assessors were masked separately. This matters when interpreting outcomes that may involve subjective assessment. The primary measure is a laboratory count, but the record does not state whether those who counted or classified abnormalities were unaware of treatment assignment.
The parallel design assigns participants to a treatment group for the study comparison rather than describing a crossover. The registry record does not provide arm-specific descriptions beyond naming the interventions, nor does it describe treatment adherence, treatment changes, or the behavior therapy protocol. Those details are therefore not reported in the registry record.
The primary endpoint is specified at baseline and at the end of treatment, Day 84 (Week 12). The endpoint description reports cytogenetic data for the Per-Protocol-1 population, whose membership required randomization and cytogenetic data for at least one primary endpoint at baseline and Week 12. The description gives group counts of n=33 and n=32 for baseline and again n=33 and n=32 at Week 12. These are endpoint-specific counts; the record does not provide an accounting of all randomized participants by arm or explain the difference between enrollment and the endpoint population. The number analyzed for other outcomes is not reported in the registry record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Treatment
| Stage | Ritalin LA Plus Behavior Therapy | Behavior Therapy |
|---|---|---|
| STARTED | 53 | 56 |
| COMPLETED | 38 | 39 |
| NOT COMPLETED | 15 | 17 |
Reasons for not completing this period:
| Reason | Ritalin LA Plus Behavior Therapy | Behavior Therapy |
|---|---|---|
| Abnormal test procedure result(s) | 1 | 0 |
| Lack of Efficacy | 0 | 1 |
| Protocol Violation | 6 | 2 |
| Withdrawal by Subject | 3 | 8 |
| Lost to Follow-up | 0 | 6 |
| Administrative problems | 5 | 0 |
Washout
| Stage | Ritalin LA Plus Behavior Therapy | Behavior Therapy |
|---|---|---|
| STARTED | 38 | 39 |
| COMPLETED | 17 | 29 |
| NOT COMPLETED | 21 | 10 |
Reasons for not completing this period:
| Reason | Ritalin LA Plus Behavior Therapy | Behavior Therapy |
|---|---|---|
| Lack of Efficacy | 9 | 1 |
| Protocol Violation | 0 | 1 |
| Withdrawal by Subject | 11 | 5 |
| Lost to Follow-up | 1 | 3 |
Analysis population for the primary outcome, as defined in the registry: 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.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Ritalin LA Plus Behavior Therapy | Behavior Therapy | Total |
|---|---|---|---|---|
| Participants analysed | 52 | 52 | 104 | |
| Age, Categorical: <=18 years | Participants | 52 | 52 | 104 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 | 0 | 0 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Age Continuous | years | 8.3 (SD 1.75) | 8.5 (SD 1.91) | 8.4 (SD 1.83) |
| Sex: Female, Male: Female | Participants | 21 | 17 | 38 |
| Sex: Female, Male: Male | Participants | 31 | 35 | 66 |
6. Primary Endpoint
The registry lists the primary outcome as The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of Treatment i.e Day 84 (Week 12), measured over baseline and at end of treatment (Week 12).
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | number of abnormalities |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the number of chromosomal aberrations per 100 cells, excluding gaps, measured at baseline and at the end of treatment (Day 84, Week 12). It is reported as a mean with a standard deviation, so the intended summary describes the average count and the spread of counts in the analyzed population. The endpoint description says blood samples were cultured for 48 hours using a standard protocol.
The counted abnormalities could include reciprocal and non-reciprocal translocations, insertions, dicentrics, fragments, inversions, chromatid exchanges (quadriradials and triradials), breaks, and other unusual observations such as aneuploidy, tetraploidy, or endoreduplication. Gaps are explicitly excluded from the primary count. This definition matters because a count depends on which observations are classified as abnormalities and which are left out.
A cytogenetic count is used as a laboratory measure of cellular abnormalities. It is distinct from the registry's listed symptom and clinical-global-rating measures, which are secondary outcomes. The record does not explain why this endpoint was selected, how its clinical relevance was evaluated, or whether a particular change would be considered meaningful. Those rationales are not reported in the registry record.
Although the endpoint is specified at baseline and Week 12, the registry record does not report the group means, standard deviations, change estimates, confidence intervals, or a single primary comparison. Therefore, the endpoint definition is clear enough to describe what was intended to be measured, but the posted results do not establish the magnitude or precision of any treatment-group difference.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record gives a clearly named laboratory endpoint and specifies its measurement at baseline and Week 12. It also identifies the endpoint as a mean with standard deviation and describes a Per-Protocol-1 population. However, the record does not report a single numerical primary-outcome comparison. It therefore does not permit an estimate of how much the endpoint changed within either group or how the groups differed at the end of treatment.
The reported endpoint counts are n=33 and n=32 at baseline and n=33 and n=32 at Week 12. They describe the cytogenetic observations included in the endpoint description, not the full enrollment. The registry record does not provide the corresponding group means or standard deviations, so these counts cannot be used to reconstruct the observed effect or its uncertainty. No unadjusted recalculation is possible from the posted information.
Interpretation also depends on the endpoint's structure. The title and description cover values at baseline and end of treatment, rather than presenting a single change contrast in the posted results. A comparison of endpoint values, a comparison of changes from baseline, and a model that accounts for repeated measurements are different analyses. The registry record does not identify which of these was used for the primary analysis, and the primary outcome is not reduced to one comparison in the posted record. Thus it would be inappropriate to select an analysis and present it as the trial's result.
The study is described as randomized, which supports a causal comparison in principle, but randomization alone does not establish that the treatment groups were similar in the analyzed population or resolve missing endpoint data. The primary endpoint is described for a per-protocol population, rather than explicitly as an analysis of all randomized participants. The record does not report an intention-to-treat analysis, reasons for exclusion, or how missing cytogenetic measurements were handled. These omissions limit assessment of potential selection and attrition effects.
The posted adverse-event information can be read separately from the primary endpoint. The record reports zero serious adverse events in each group and records other adverse events in 28 participants in the methylphenidate-plus-behavior group and 13 in the behavior group, with 52 at risk in each group. Those counts do not provide information about the primary cytogenetic comparison. Deaths are not reported in the registry record.
The appropriate conclusion is about reporting, not treatment effect: the registry describes the design and endpoint but does not provide the numerical primary result needed to assess its direction, magnitude, or precision. A missing estimate is not evidence of no difference, and it also cannot be interpreted as evidence of a difference. The registry's secondary outcome list does not substitute for a reported primary analysis.
9. Statistical Methods Explained
The registry describes a continuous primary measure summarized as a mean and standard deviation. A mean represents the average of the observed counts in a group. A standard deviation describes how dispersed individual observations are around that average; it is not the uncertainty in the estimated mean. These summaries help characterize the data, but they do not by themselves establish whether a difference between groups is compatible with chance variation.
What would a treatment comparison require?
A treatment comparison needs a defined contrast, such as a difference between group means at Week 12 or a difference between the groups in change from baseline. Those contrasts answer related but distinct questions. Comparing Week 12 values alone does not account for baseline differences in the same way as comparing changes. A repeated-measures analysis could use measurements from both time points and model their relationship. The registry record does not specify which contrast or model was used, and it does not report a single primary-outcome comparison. It is therefore not possible to describe the sponsor's statistical test or independently reproduce it.
A confidence interval, in general, expresses the precision of an estimated effect by giving a range of values compatible with the data and the method used to calculate the interval. A narrow interval indicates greater precision than a wide interval, but interpretation also depends on whether the range includes effects that would matter scientifically or clinically. No primary effect estimate or confidence interval is reported in the registry record, so neither precision nor the range of plausible effects can be assessed.
What does the endpoint count represent?
The outcome counts chromosomal aberrations per 100 cells, excluding gaps. It is not a count of affected children or a clinical symptom score. The listed categories include several kinds of structural and other cytogenetic observations. Any count depends on a consistent laboratory protocol and classification process. The record states that blood samples were cultured for 48 hours using a standard protocol, but does not report laboratory blinding, reproducibility checks, or rules for handling ambiguous observations. Those methods are not reported in the registry record.
For count outcomes, a simple mean-and-standard-deviation summary may not describe every feature of the distribution. Counts can be concentrated at low values or vary more than a basic statistical model expects. In general, over-dispersion means that variation in the data exceeds what a model assumes; if it is ignored, standard errors and confidence intervals may be poorly calibrated. The registry record does not provide the distribution of the cytogenetic counts or name a count-data model, so it is not possible to determine whether over-dispersion was assessed or how it influenced inference.
Why do analysis population and missing data matter?
The endpoint description defines the Per-Protocol-1 population as participants who were randomized and provided cytogenetic data for at least one primary endpoint at baseline and the Week 12 evaluation. This definition indicates that endpoint availability was required for inclusion, but the record does not give a complete flow from randomization to analysis or reasons that data were unavailable. An analysis restricted to participants with measurements may be affected if availability is related to treatment assignment or outcome. In general, missing-data methods rely on assumptions about why measurements are missing; different assumptions can lead to different estimates.
The registry does not state whether missing outcomes were imputed, whether participants with partial measurements contributed to a model, or whether sensitivity analyses were conducted. It also does not report the primary statistical model, covariates, significance threshold, confidence-interval method, or any adjustment for multiple comparisons. These methods are not reported in the registry record and should not be inferred from the endpoint description.
How should planning calculations be read?
Any sample-size illustration is a planning calculation, not an observed trial result and not observed power. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and a target effect expressed as a stated fraction of the observed effect. The planning note says that non-time-to-event illustrations are expressed as participants per arm. However, the primary endpoint was not reduced to a single comparison, and no numerical observed effect is reported in the record. Without that effect and a defined comparison, a reader cannot use the planning assumptions to infer how many participants would be required for this endpoint or to judge the study's achieved power.
In general, post hoc power calculations based on an observed effect do not resolve uncertainty about that effect; the effect estimate and its confidence interval are more informative. A planning illustration can show how assumed effect size and design choices relate to a target sample size, but it does not establish that the study had adequate power or that a nonsignificant result would indicate no effect. The registry record does not report the sample-size justification used when the trial was designed, so the displayed planning assumptions should not be treated as the original design plan.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 7 outcome measures, including the primary cytogenetic endpoint and secondary outcomes related to sister chromatid exchanges, methylphenidate blood levels and cytogenetic changes, parent-rated ADHD symptoms, and clinical-global ratings. Considering multiple outcomes or multiple time points raises the general issue of multiplicity: the more comparisons examined, the greater the chance that some appear unusual by chance alone. This is a general statistical concern, not evidence that any particular result in this trial is false.
The registry record does not report a multiplicity adjustment, a hierarchy of outcomes, or a statistical analysis plan specifying which comparisons were confirmatory. It reports 0 analyses in the analysis listings, and the primary outcome was not reduced to one comparison. The intended handling of multiple outcome categories or time points is therefore not reported in the registry record. No claim about adjustment, prespecification, or interim analyses can be made from the available record.
Missing-data reporting is also limited. The primary endpoint description gives cytogenetic counts for the Per-Protocol-1 population and reports n=33 and n=32 at baseline and Week 12. It does not explain how many randomized participants lacked each measurement, why measurements were unavailable, whether the same participants contributed at both times, or whether incomplete data were imputed. The registry does not report a complete participant-flow account for the primary analysis.
Because the analysis population requires cytogenetic data, results from that population could differ from results among all randomized participants if inclusion depends on treatment assignment, prognosis, or outcome. That is a general limitation of complete-case or per-protocol analysis, not a finding that such bias occurred. The registry record does not report an all-randomized analysis, missing-data sensitivity analyses, or the assumptions used to address missing observations.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Ritalin+Behavior | 0 | 52 | 0.0% |
| Behavior | 0 | 52 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Ritalin+Behavior | 28 of 52 |
| Behavior | 13 of 52 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Ritalin+Behavior | Behavior |
|---|---|---|---|
| Upper Respiratory Tract Infection | Infections and infestations | 6 of 52 | 5 of 52 |
| Decreased Appetite | Metabolism and nutrition disorders | 10 of 52 | 0 of 52 |
| Nasopharyngitis | Infections and infestations | 4 of 52 | 4 of 52 |
| Headache | Nervous system disorders | 7 of 52 | 1 of 52 |
| Abdominal Pain Upper | Gastrointestinal disorders | 5 of 52 | 2 of 52 |
| Vomiting | Gastrointestinal disorders | 5 of 52 | 1 of 52 |
| Pyrexia | General disorders | 2 of 52 | 3 of 52 |
| Insomnia | Psychiatric disorders | 5 of 52 | 0 of 52 |
| Cough | Respiratory, thoracic and mediastinal disorders | 4 of 52 | 1 of 52 |
| Fatigue | General disorders | 4 of 52 | 0 of 52 |
The registry reports zero serious adverse events among the 52 participants at risk in the extended release methylphenidate plus behavior therapy group, and zero among the 52 at risk in the behavior therapy group. It also reports other adverse events for 28 participants in the former group and 13 in the latter. These are counts as recorded in the registry, not a complete description of event type, timing, severity, or duration.
Zero reported serious adverse events does not establish that serious events could not occur; it describes the registry entry for this study. The count of other adverse events does not show whether events were related to treatment, whether participants experienced more than one event, or how the events were judged. Those details are not reported in the registry record. Deaths are not reported in the registry record.
These safety counts should be kept separate from the primary cytogenetic endpoint. They do not show whether chromosomal-aberration counts changed, and they cannot be used to infer the effect of treatment on that laboratory measure. The registry record also does not provide a detailed safety analysis or comparisons adjusted for differences in follow-up or exposure.
12. What the Result Does, and Does Not, Mean
The trial record identifies a randomized, open-label, parallel-group study in children with ADHD and states that the primary measure was chromosomal aberrations per 100 cells, excluding gaps, at baseline and the end of treatment. It names the intervention as extended release methylphenidate plus behavior therapy and the comparator as behavior therapy. The record also describes the laboratory procedure and the analysis population for the endpoint.
What the record does not establish is the size or direction of a primary treatment-group difference. Numerical means, standard deviations, change estimates, confidence intervals, and a single primary comparison are not reported in the registry record. As a result, the posted information cannot show whether the measured count increased, decreased, or differed between groups, or how precisely any effect was estimated. An unreported result should not be read as a result of no difference.
The endpoint is a laboratory measure of cytogenetic abnormalities. It is not itself a measure of ADHD symptoms, functioning, or a clinical outcome. Although the registry lists parent-rated symptoms and clinical-global ratings as secondary outcomes, their presence in the outcome list does not establish their results. Those numerical results and their analyses are not reported in the registry record.
Likewise, the listed safety counts are descriptive registry entries and do not answer the primary endpoint question. Zero serious adverse events in the recorded groups does not prove an absence of risk, and the other adverse-event counts do not establish causation. The registry provides no detailed event descriptions or death counts.
In general, a randomized comparison can support an estimate of treatment effect when the analysis, outcome data, and uncertainty are reported and interpreted in light of missingness and design limitations. Here, important statistical details—including the primary comparison, analysis model, multiplicity approach, and missing-data handling—are not reported in the registry record. The defensible interpretation is therefore limited to the study's stated question, design, and descriptive information, rather than a conclusion that the intervention did or did not change the cytogenetic endpoint.
13. Why This Trial Matters Statistically
This trial is statistically notable because its primary question concerns a defined laboratory count measured at baseline and after treatment, while the registry record does not provide a single numerical comparison. That gap separates knowing what a study intended to measure from being able to assess what the data show. An endpoint definition and group counts are not substitutes for effect estimates and uncertainty.
The study also illustrates why analysis populations matter. The cytogenetic endpoint is described for a Per-Protocol-1 population requiring data at baseline and Week 12 for at least one primary endpoint. That population definition informs which participants contribute to the stated endpoint, but the record does not provide a full flow or explain missing observations. Readers therefore cannot assess how inclusion in the analysis relates to randomization or treatment assignment.
Multiplicity is relevant because the registry lists several outcomes and the primary endpoint spans baseline and end-of-treatment assessments. Without a stated hierarchy or analysis plan, it is not possible to determine which comparisons were treated as primary for inference or whether multiple testing was addressed. The record's lack of a single primary comparison also means no recalculated effect can be responsibly derived from the posted numbers.
Finally, planning calculations must be distinguished from observed evidence. The record describes assumptions for sample-size illustrations based on an observed effect, but does not report a single primary effect on which to base a reconstruction. Such illustrations, where available, are not observed power and do not replace reporting the trial's effect estimate and confidence interval. The case shows why transparent reporting of analysis choices, missing data, and precision is essential to interpreting a clinical trial.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
Several trial-specific limitations are apparent from the registry record. The study is open-label, and the record does not say whether laboratory staff or outcome assessors were masked to treatment assignment. Although the primary endpoint is a laboratory count, classification and counting can involve decisions; the absence of reported masking and reproducibility information leaves uncertainty about how measurement bias was minimized.
The endpoint is assessed at baseline and Week 12, but no primary contrast or analysis model is specified in the posted results. A difference in Week 12 values and a difference in change from baseline are not interchangeable, particularly if baseline values differ. The record does not supply group means, standard deviations, effect estimates, or confidence intervals, so readers cannot examine baseline balance, treatment effect, or precision.
The primary endpoint is reported for the Per-Protocol-1 population rather than explicitly for all randomized participants. The registry does not provide a full accounting of exclusions, missing cytogenetic measurements, or reasons for missingness. It also does not report an intention-to-treat analysis or sensitivity analyses. These gaps prevent assessment of how selection into the endpoint population could affect the results.
The record lists multiple outcomes, but does not report a statistical analysis plan, outcome hierarchy, multiplicity strategy, or interim analyses. It also does not describe the behavior therapy protocol, treatment adherence, or laboratory quality-control procedures. Those details are not reported in the registry record and should not be assumed.
Finally, the study's primary measure is a cytogenetic laboratory endpoint. The registry record does not state how a change in this measure relates to clinical importance. The listed secondary symptom and clinical-global outcomes do not resolve that question without their results and analyses.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effects of Methylphenidate on Cellular Abnormalities in Children With Attention Deficit Hyperactivity Disorder (ADHD) — NCT00409708.
- Registry record last updated 2011-05-17; status last verified 2011-04.
- Results first posted 2011-05-17.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT00409708 is a completed, randomized, open-label, parallel-group Phase 2 study sponsored by Novartis. The record lists enrollment of 142 and describes treatment-naive children 6–12 years of age with ADHD. The comparison was extended release methylphenidate plus behavior therapy versus behavior therapy, with treatment planned for 3 months.
The primary endpoint was the mean number of chromosomal aberrations per 100 cells, excluding gaps, measured at baseline and Day 84 (Week 12), with standard deviation as the dispersion measure. The endpoint description concerns the Per-Protocol-1 population and gives counts of n=33 and n=32 at baseline and Week 12.
The registry record does not report a single primary-outcome comparison or its numerical estimates. It lists 7 outcome measures and 0 analyses. Safety entries report zero serious adverse events in each group and other adverse events in 28 participants in the methylphenidate-plus-behavior group and 13 in the behavior group; deaths are not reported in the registry record.