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 Efficacy and Safety of RAD001 in Treating Plexiform Neurofibromas (PN) Associated With Neurofibromatosis (NF1) (NCT01365468), a non-randomized phase 2 study. The primary outcome is Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01365468 |
| Phase | Phase 2 |
| Condition | Plexiform Neurofibroma Associated With Neurofibromatosis Type 1 |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 9 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Children and adults with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN). The study description distinguishes patients with inoperable, documented progressive PN from patients with inoperable PN without documented radiographic progression at entry. The record reports enrollment of 9 participants, but does not report how many were children or adults.
Intervention
Everolimus, also called RAD001, administered orally once daily on a continuous dosing schedule. The open-label treatment description gives a recommended starting dose based on body surface area, ranging from 2.5 mg once daily to 7.5 mg once daily.
Comparator
No separate comparator is described. The study is recorded as non-randomized and single-group, so the two strata should not be read as randomized treatment arms or as a like-for-like control comparison.
Primary question
The listed primary outcome counts patients with adverse events assessed using CTCAE version 4.0. The study description also states efficacy aims: assessing time to progression by volumetric MRI in the progressive-PN stratum and objective radiographic response by volumetric MRI in the other stratum. Results for those efficacy questions are not reported in the registry record.
The clinical question therefore has a safety focus in the registered primary outcome, alongside two intended radiographic efficacy questions. These are distinct questions and would require different outcome definitions and analyses. Time to progression concerns when a progression event occurs, whereas objective response concerns whether a specified radiographic response is observed. The registry description identifies volumetric MRI as the basis for both, but does not provide response criteria, progression definitions, or outcome results. It also does not state how participants were assigned to the two strata beyond describing their disease status at study entry.
3. Trial Design
This was a Phase II, non-randomized, single-group study of everolimus (RAD001) in people with plexiform neurofibromas associated with NF1. The registry lists enrollment of 9 and records the study as terminated. The listed dates are a start in 2012-04 and primary completion in 2015-04. The reason for termination is not reported in the registry record.
Treatment was open label: participants and study staff were not masked according to the record. Participants received everolimus, with a recommended starting dose dependent on body surface area and a range from 2.5 mg once daily to 7.5 mg once daily. The summary describes a continuous daily dosing schedule. Dose changes, treatment duration by participant, adherence, and reasons for stopping treatment are not reported in the registry record.
The planned efficacy questions distinguished two groups by disease status. Stratum 1 comprised children and adults with NF1, inoperable documented progressive PN, and an intended assessment of time to progression using volumetric MRI. Stratum 2 comprised children and adults with NF1 and inoperable PN without documented radiographic progression at entry, with an intended assessment of objective radiographic response. The record does not report the number of participants in each efficacy stratum or confirm the status of each enrolled participant. The adverse-event results are reported by stratum, with 4 participants at risk in Stratum 1 and 5 in Stratum 2.
Because there was no randomized comparator, the design does not support a direct randomized treatment contrast. Differences between the two strata would also be difficult to interpret as treatment effects because the groups were defined by different disease status. The registry does not report a protocol-level statistical analysis plan, so the intended inferential methods for either efficacy question are 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.
Overall Study
| Stage | Stratum 1 | Stratum 2 |
|---|---|---|
| STARTED | 4 | 5 |
| COMPLETED | 0 | 5 |
| NOT COMPLETED | 4 | 0 |
Reasons for not completing this period:
| Reason | Stratum 1 | Stratum 2 |
|---|---|---|
| Physician Decision | 1 | 0 |
| Disease progression | 1 | 0 |
| Lost to Follow-up | 2 | 0 |
Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) consisted of all enrolled patients.
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 | Stratum 1 | Stratum 2 | Total |
|---|---|---|---|---|
| Participants analysed | 4 | 5 | 9 | |
| Age, Continuous | Years | 22.7 (SD 14.3) | 16.9 (SD 9.8) | 19.5 (SD 11.6) |
| Sex: Female, Male: Female | Participants | 3 | 1 | 4 |
| Sex: Female, Male: Male | Participants | 1 | 4 | 5 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04, measured over From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Patients |
| Endpoint classification | Binary Endpoint |
The listed primary outcome is the number of patients with adverse events assessed by Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. The observation window begins when informed consent was signed and continues until 28 days after the end of treatment, up to a maximum of 25 months. The safety population is described as participants who received at least one dose of study treatment and had at least one post-baseline safety assessment.
This endpoint is used to describe the occurrence of adverse events during treatment and the stated follow-up window. Counting participants with events gives a patient-level summary: it indicates whether a participant experienced an event, rather than how many separate event episodes occurred. The record also explains that, when CTCAE grading did not exist for an event, severity categories of mild, moderate, severe, and life-threatening corresponded to grades 1 through 4. Grade 5, death, was not used in this study.
As a safety measure, this count addresses tolerability and toxicity, but it does not by itself describe event duration, recurrence, timing, or clinical consequences. The posted primary outcome is not a measure of tumor response or time to progression. Although those efficacy aims appear in the study summary, their observed results are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes 9 enrolled participants in a non-randomized, single-group study, with adverse-event summaries separated into Stratum 1 and Stratum 2. For serious adverse events, 1 of the 4 participants at risk in Stratum 1 was affected, while none of the 5 participants at risk in Stratum 2 was affected. For other adverse events, all 4 participants at risk in Stratum 1 and all 5 at risk in Stratum 2 were affected. These are descriptive counts within small groups; they do not establish a comparative treatment effect.
The record also lists hypersensitivity at 25.0% among the top serious terms. It does not specify the denominator for that percentage in the posted summary, so the percentage should not be converted into an event count or used to infer how many participants experienced hypersensitivity. The registry describes its safety population as those receiving at least one dose and having at least one post-baseline safety assessment. The number meeting that definition is not reported in the registry record.
No numerical results for time to progression, objective radiographic response, or volumetric MRI change are reported in the registry record. Consequently, the stated efficacy aims cannot be interpreted from these posted results. The study’s termination is recorded, but its reason is not reported in the registry record; termination alone does not indicate why the study ended or what its findings were.
General statistical interpretation: counts from small groups are imprecise descriptions of the participants observed. A confidence interval, if reported, would communicate a range of values compatible with the data under its statistical assumptions; no confidence intervals or inferential analyses are reported for these adverse-event counts. The absence of a randomized comparator also means there is no concurrent control group in this record against which to separate treatment-associated events from events that might occur in the underlying population or over time.
The sample-size planning illustration is explicitly based on the observed effect and uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it considers the stated fraction of the observed effect. Such assumptions describe a planning exercise, not the actual single-group design. The illustration is not observed power, and the numerical planning outputs are not reported in the registry record. The registered design and the assumptions used for that illustration answer different questions.
9. Statistical Methods Explained
What the registered design permits. This is a non-randomized, single-group study, with treatment administered open label. In general, random allocation helps balance measured and unmeasured characteristics between treatment groups. Without a randomized comparison, a change or event observed during follow-up cannot be attributed to treatment by comparing it with a randomized control group. The registry record does not describe a control group. The two disease strata are defined by different progression status and have separate intended efficacy questions; they are not interchangeable treatment arms.
Patient counts and event counts. The primary outcome is the number of patients with adverse events, a patient-level count of participants who experienced an event during the defined safety period. A patient can experience more than one event, so a count of affected patients is not the same as a count of all event episodes. General statistical explanation: patient-level summaries are useful for communicating how many people were affected, while event-level analyses can describe recurrence or total burden. The posted results give affected-patient counts for serious and other adverse events by stratum, but do not report episode counts, event timing, or duration.
What a time-to-event analysis would describe. The stated aim in Stratum 1 concerns time to progression based on volumetric MRI. In general, time-to-event methods use both the timing of events and follow-up information for participants who have not yet had the event. They can account for participants whose event time is not observed during follow-up through censoring, provided the assumptions and censoring information are adequately described. The registry record does not report a time-to-progression estimate, number of progression events, follow-up distribution, censoring details, or analysis method. It is therefore not possible to assess the intended time-to-event analysis from the posted results.
What a radiographic response analysis would describe. The stated aim in Stratum 2 concerns objective radiographic responses based on volumetric MRI. In general, a response analysis requires a defined response rule, assessment schedule, and an approach to missing or unevaluable scans. The registry summary does not report those details or any response counts. Without them, the intended response endpoint cannot be reconstructed or independently interpreted from the record.
Uncertainty and statistical testing. General explanation: an estimate is more informative when accompanied by a measure of uncertainty, such as a confidence interval, because the observed value alone does not show how much the estimate may vary across comparable samples. A p-value, when used, addresses compatibility of data with a specified null model; it does not measure the size or importance of an effect. The registry record reports no p-values or confidence intervals for the outcomes, and the number of analyses is recorded as 0. That registry field does not establish that no analyses were conducted; detailed analytical results are simply not reported in the registry record.
Over-dispersion and repeated events. General explanation: if event counts vary more than a chosen statistical model expects, over-dispersion can make conventional standard errors too small and confidence intervals too narrow. Methods that account for over-dispersion may be appropriate for event-count outcomes under suitable assumptions. This study’s posted primary outcome is a number of patients with an event, and the reported safety summaries do not provide repeated event counts or a model of event frequency. The record therefore does not support conclusions about whether over-dispersion was evaluated or whether any particular count model was used.
Planning illustrations. General explanation: a sample-size calculation describes the number of participants or events a hypothetical design would plan for under stated assumptions. It is not a description of how many participants were observed and is not evidence that a study had a particular probability of detecting an effect. The planning assumptions associated with the illustration specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect set to a stated fraction of the observed effect. Time-to-event illustrations use a total number of events; other illustrations use participants per arm. Because the registered study is single group and non-randomized, those two-arm planning assumptions should not be mistaken for its actual design. The numerical planning outputs are not reported in the registry record.
Analysis populations. The primary safety population is defined by treatment exposure and post-baseline assessment: participants had to receive at least one dose and have at least one post-baseline safety assessment. General explanation: population definitions matter because excluding participants without follow-up assessments can change the group represented by a safety summary. The record provides that definition but does not report the number included in the safety population, participant-level exclusions, or an analysis population for the intended efficacy outcomes.
10. Multiplicity, Missing Data and Analysis Populations
The study description names more than one efficacy question: time to progression in Stratum 1 and objective radiographic response in Stratum 2. It also identifies adverse-event assessment as the primary outcome. The registry record does not report whether these outcomes were assigned a formal testing hierarchy, whether adjustment for multiple comparisons was planned, or whether any interim analyses were conducted. Those details are not reported in the registry record and should not be inferred from the number of stated aims.
Multiplicity matters in general when several hypotheses or outcomes are tested: the chance of at least one apparently unusual result can rise as more tests are considered, depending on the analysis plan. A prespecified hierarchy or adjustment can address that issue, but neither is described in the registry record. No efficacy analyses or inferential results are posted, so there is no reported set of efficacy tests to evaluate for multiplicity.
The safety population includes participants who received at least one dose and had at least one post-baseline safety assessment. The record does not report the number included in that population, the number excluded, or the amount and pattern of missing safety data. It also does not state how missing observations were handled for the intended MRI outcomes, whether all enrolled participants had evaluable scans, or how participants who discontinued treatment were treated in efficacy analyses. These elements are important because missingness can affect both the population represented and the interpretation of observed outcomes.
General explanation: missing data are not automatically equivalent to no event or no response. Their consequences depend on why observations are missing and on the analysis approach. Since the registry record does not describe those reasons or methods, the impact of missing data on the outcomes cannot be assessed.
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 |
|---|---|---|---|
| Stratum 1 | 1 | 4 | 25.0% |
| Stratum 2 | 0 | 5 | 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 |
|---|---|
| Stratum 1 | 4 of 4 |
| Stratum 2 | 5 of 5 |
Most frequent serious adverse event terms
| Event term | Organ system | Stratum 1 | Stratum 2 |
|---|---|---|---|
| Hypersensitivity | Immune system disorders | 1 of 4 | 0 of 5 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Stratum 1 | Stratum 2 |
|---|---|---|---|
| Headache | Nervous system disorders | 3 of 4 | 4 of 5 |
| Fatigue | General disorders | 2 of 4 | 2 of 5 |
| Influenza like illness | General disorders | 3 of 4 | 1 of 5 |
| Mucosal inflammation | General disorders | 2 of 4 | 2 of 5 |
| Abdominal pain | Gastrointestinal disorders | 1 of 4 | 2 of 5 |
| Blood cholesterol increased | Investigations | 1 of 4 | 2 of 5 |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | 1 of 4 | 2 of 5 |
| Ear pain | Ear and labyrinth disorders | 2 of 4 | 0 of 5 |
| Diarrhoea | Gastrointestinal disorders | 2 of 4 | 0 of 5 |
| Dysphagia | Gastrointestinal disorders | 2 of 4 | 0 of 5 |
Serious events with the highest arm-level rate: hypersensitivity (25.0%).
Serious adverse events are reported separately by stratum. In Stratum 1, 1 participant was affected among 4 at risk; in Stratum 2, 0 participants were affected among 5 at risk. The record reports other adverse events in 4 participants among 4 at risk in Stratum 1 and 5 among 5 at risk in Stratum 2. These counts describe the participants included in the registry’s safety summary, not necessarily every enrolled participant, because the number in the defined safety population is not reported in the registry record.
The record lists hypersensitivity at 25.0% among the top serious terms. The percentage’s denominator and the number of hypersensitivity events are not reported in the registry record. It should therefore be read as a posted term-level percentage, not as a basis for deriving a participant count.
General explanation: serious adverse events are a subset defined by seriousness criteria, while “other” adverse events are a separate category in this summary. A participant-level count does not show event frequency, duration, severity distribution, or whether an event led to treatment interruption. The registry description says adverse events were assessed using CTCAE version 4.0 and that grade 5, death, was not used in this study. These descriptive safety counts do not provide a randomized comparison, and the small stratum counts limit how precisely they characterize event occurrence.
12. What the Result Does, and Does Not, Mean
The posted results describe safety events among participants reported at risk in each stratum: serious events affected 1 of 4 in Stratum 1 and 0 of 5 in Stratum 2, while other events affected 4 of 4 and 5 of 5, respectively. These are observed counts, not estimates of a treatment contrast. The registry also records hypersensitivity at 25.0% among the top serious terms, but does not report the denominator for that percentage in the registry record.
The results do not answer the efficacy questions stated in the study summary. No time-to-progression estimate or objective radiographic response result is reported in the registry record. Nor does the record provide enough information to assess MRI assessment rules, missing scans, or the analysis methods intended for those outcomes. The study’s status is terminated, but the reason for termination is not reported in the registry record.
General statistical interpretation: observed outcomes in a small, uncontrolled study are descriptive. They can document what was recorded in the participants followed, but without a randomized comparator they cannot by themselves separate treatment effects from disease course, participant characteristics, or other influences. The reported stratum counts should not be compared as though the strata were randomized groups, because the strata represent different disease status and address different planned questions.
The findings also do not establish how common an event would be in a broader population, how risks might differ across patient groups, or whether an observed event was caused by study treatment. The registry record provides no confidence intervals or other uncertainty estimates for these safety counts. Accordingly, the most defensible reading is limited to the stated counts, their denominators, the assessment framework, and the absence of posted efficacy results.
13. Why This Trial Matters Statistically
Statistically, this record illustrates why design and outcome details determine what can be concluded. The study is classified as a non-randomized, single-group Phase II study, while the intended efficacy questions concern two different clinical strata. The strata are based on progression status, not randomized allocation. Their results therefore cannot be treated as a controlled comparison, and the study description does not report an alternative comparator.
The registered primary outcome is safety-focused, whereas the summary also describes efficacy aims based on volumetric MRI. Keeping these questions distinct is important: adverse-event counts, time to progression, and objective radiographic response represent different outcomes and require different interpretations. The record gives safety counts by stratum but no numerical results for the stated efficacy aims.
The record also shows why the analysis population and missing-data approach matter. A safety summary is defined for participants who received at least one dose and had at least one post-baseline assessment, but the number meeting that definition is not reported. The MRI analysis populations and handling of missing scans are also not reported in the registry record. Without those details, readers cannot determine how the posted summaries relate to all enrolled participants or how complete outcome assessment was.
Finally, planning illustrations based on an assumed two-arm design should be distinguished from the actual single-group trial. General statistical principle: planning calculations depend on their assumptions and do not turn a small study into a randomized comparison or provide observed evidence about efficacy. The record’s combination of explicit design constraints and missing efficacy analyses makes careful separation of observed safety counts, intended questions, and unreported results especially important.
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.
The enrolled population was small: the record lists 9 participants, with 4 at risk in Stratum 1 and 5 in Stratum 2 for the posted adverse-event summaries. These group sizes leave limited information for characterizing uncommon events or estimating rates precisely. The registry record does not provide confidence intervals for the safety counts.
The study was non-randomized, single group, and open label. There is no randomized comparator described, so the adverse-event observations cannot be interpreted as a controlled estimate of treatment-related risk. The disease-status distinction between strata also means that differences between their counts should not be read as treatment contrasts.
The primary outcome concerns adverse events, while the stated efficacy aims concern MRI-based time to progression and objective radiographic response. Numerical efficacy results are not reported in the registry record. Definitions of progression and response, scan schedules, and MRI assessment procedures are also not reported. The registry status is terminated, but the reason is not reported in the registry record.
Further limitations arise from incomplete reporting of analysis details. The number in the defined safety population, participant disposition, missing-data handling, analysis methods, and any multiplicity strategy are not reported in the registry record. The serious-term percentage for hypersensitivity is posted without a denominator in the summary. These omissions restrict assessment of precision, completeness, and the relationship between the listed outcomes and all enrolled participants.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Efficacy and Safety of RAD001 in Treating Plexiform Neurofibromas (PN) Associated With Neurofibromatosis (NF1) — NCT01365468.
- Registry record last updated 2016-05-12; status last verified 2016-05.
- Results first posted 2016-05-12.
- 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
This is a Phase II, non-randomized, open-label, single-group study of everolimus (RAD001) in participants with plexiform neurofibromas associated with NF1. The registry lists enrollment of 9 and status as terminated. The treatment description gives a body-surface-area-based recommended starting dose ranging from 2.5 mg once daily to 7.5 mg once daily.
The primary outcome counts patients with adverse events assessed by CTCAE version 4.0. Serious adverse events affected 1 of 4 participants at risk in Stratum 1 and 0 of 5 in Stratum 2; other events affected 4 of 4 and 5 of 5, respectively. Hypersensitivity is listed at 25.0% among top serious terms.
The study summary states intended MRI-based efficacy questions for two disease strata, but numerical efficacy results are not reported in the registry record. The reason for termination, detailed analysis methods, and missing-data handling are also not reported in the registry record.