A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis (NCT00931762), a na phase 2 study. The primary outcome is Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria.

2. Clinical Question

3. Trial Design

This was a phase II, single-group study evaluating panobinostat in participants with primary myelofibrosis and myelofibrosis following polycythemia vera or essential thrombocythemia. The registry lists enrollment as 35 and identifies Novartis Pharmaceuticals as the sponsor. The listed start date is 2009-08-31, the primary completion date is 2011-08-29, and the study status is terminated.

The intervention was oral panobinostat given as a single agent. The regimen was 40 mg three times a week on Monday, Wednesday, and Friday, with or without food, for up to 6 treatment cycles of 28-days each. Dose adjustments were possible. The brief summary separates participants into cohorts according to whether they had a JAK2 mutation. It does not describe those cohorts as randomized comparisons.

There was no comparator arm, and masking was listed as none. This matters when interpreting the endpoint: an observed response percentage in a single group can describe outcomes among treated participants, but it cannot by itself estimate a treatment contrast against a concurrent control group. The record does not report a protocol-level statistical plan, the reason for termination, or a sample-size justification.

The primary endpoint was overall response under IWG-MRT criteria, with a timeframe of up to approximately 2 years. The registry defines the primary analysis population as participants who received at least one dose of study drug. Secondary outcomes include changes in Myelofibrosis Symptom Assessment Form scores and counts of participants with adverse events and serious adverse events. The registry lists 6 outcome measures, but no analysis-level results are reported.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS population included all participants who received at least one dose of study drug.

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.

Population: Full Analysis set (FAS) population included all participants who received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response (OR) Rate Per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Criteria, measured over Up to approximately 2 years.

The primary endpoint is the percentage of participants with an overall response under International Working Group for Myelofibrosis Research and Treatment criteria. Overall response is defined as the combination of complete remission, partial remission, and clinical improvement. These categories use disease-related symptoms and signs, blood-count criteria, bone marrow findings, transfusion status, spleen size, and other measures described in the registry record.

Complete remission requires resolution of disease-related symptoms and signs, specified blood-count levels below the upper normal limit, a normal leukocyte differential, and bone marrow histologic remission. Partial remission uses the complete-remission criteria except that bone marrow histologic remission is not required. Clinical improvement can be met through specified changes in hemoglobin or transfusion status, splenomegaly, platelet count, or absolute neutrophil count. The record’s detailed criteria include a hemoglobin level of 110 grams per deciliter (g/L), platelet count of 100 x 10^9/liter (L), and absolute neutrophil count of 1.0 x 10^9/L for complete remission, with each of those blood counts below the upper normal limit.

A composite endpoint can capture more than one kind of clinically assessed change, rather than requiring every participant to meet the same remission category. Its interpretation therefore depends on the definitions and on how many participants meet each component. The registry record does not report component-specific counts or the observed overall response percentage. It also does not report the endpoint’s 95% confidence interval, so neither the estimated response nor its precision can be evaluated from the posted primary result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The central statistical issue is the distinction between defining an endpoint and reporting its estimate. The registry defines overall response as a percentage and specifies a 95% confidence interval, but it does not report either the observed percentage or the interval. A definition tells readers what would count as an event; it does not reveal how often that event occurred. Without the estimate and its denominator, the primary outcome’s magnitude and precision cannot be assessed.

What does a percentage endpoint represent?

In general, a percentage endpoint represents the proportion of an analysis population meeting a defined outcome. The numerator is the number meeting the endpoint, and the denominator is the number assessed in the relevant analysis population. Here, the registry describes the FAS population as participants who received at least one dose, but does not report the analyzed count or the number meeting overall response. It is therefore not possible to reconstruct the endpoint percentage from the registry record, and enrollment cannot be substituted for the analysis denominator.

The endpoint combines complete remission, partial remission, and clinical improvement. Such a composite can classify participants as responders through different routes. In general, a combined response percentage is most interpretable when the component definitions are clear and component results are also available. The registry supplies definitions for the response categories, but component-level results are not reported. Readers therefore cannot tell which category contributed to any observed overall response, or whether the categories had different frequencies.

What does a confidence interval add?

In general, a confidence interval describes the statistical uncertainty around an estimated quantity under the assumptions of the analysis. It is not a guarantee that the true value lies within the interval, nor does it replace the estimate itself. A narrower interval generally indicates greater precision than a wider interval, while an interval’s position can help describe which values remain compatible with the data and method. The registry names a 95% confidence interval for the primary endpoint but does not report its limits or the point estimate. No claim about precision or compatibility of particular response values can be made from the posted primary result.

The study’s single-group design also limits the role of an interval. In general, an interval around one group’s percentage quantifies uncertainty in that group’s outcome estimate; it does not create a randomized treatment contrast. A treatment comparison requires a comparator and an appropriate estimate of the difference between groups. The registry lists no control arm and no randomized allocation, so a causal treatment contrast is not reported.

How should the study structure guide interpretation?

Allocation is listed as NA, masking as none, and the model as single-group. These design features are not substitutes for a comparator. The two cohorts in the brief summary are based on JAK2 mutation status, but the registry does not characterize them as randomly assigned. Any difference between those cohorts, if reported elsewhere, would require careful interpretation because the record does not specify a randomized comparison or an adjusted analysis for cohort differences.

The outcome timeframe is up to approximately 2 years. That description indicates the endpoint’s stated observation period; it does not tell readers how long each participant was followed, how many completed follow-up, or how assessments made at different times were combined. Those details are not reported in the registry record. The primary completion date is 2011-08-29, but that date alone does not establish complete endpoint ascertainment.

What can the planning illustration tell readers?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, variability or event rates, significance level, power, allocation, and analysis method. It is not an observed result and does not establish what the completed study was capable of detecting. The registry’s sample-size assumptions describe a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. The assumptions are not a description of this trial’s single-group design, and the record says the illustration is not the trial’s own design.

Any sample-size values associated with that illustration should therefore be read as planning illustrations, never as observed power. The record does not report a trial-specific sample-size justification or statistical plan. The planning assumptions cannot fill in the absent primary endpoint estimate, establish the analysis population, or demonstrate that the study was powered for the endpoint as conducted.

For a binary percentage endpoint, statistical methods generally need to account for the number assessed and the number meeting the defined outcome. The specific method used to calculate the stated confidence interval is not reported in the registry record. Without that method, its assumptions, and the missing result itself, the interval cannot be independently checked or interpreted more specifically.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Panobinostat")
n      <- c(35)
events <- c(1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Panobinostat  35  1  2.9  0.1  14.9  0.5  14.5  0.7  14.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures. The named secondary outcomes include changes from baseline in Myelofibrosis Symptom Assessment Form scores, including at Cycle 6, and the number of participants with adverse events and serious adverse events. The overall response rate is identified as the primary endpoint. The registry record does not report whether statistical testing across multiple outcomes was planned, whether any adjustment for multiplicity was used, or how outcomes were prioritized beyond the primary designation.

Multiplicity matters in general when several outcomes or comparisons are tested: the chance of at least one apparently notable result can increase as the number of tests grows. Whether and how to address that issue depends on the prespecified analysis plan and the purpose of each outcome. Since the statistical plan and analysis-level results are not reported in the registry record, no conclusion can be drawn about the multiplicity strategy used.

The primary analysis population is described as the FAS population, including participants who received at least one dose of study drug. However, the number analyzed, the number with missing endpoint assessments, and the handling of missing data are not reported in the registry record. It is also not reported whether participants were included according to a different analysis population for any outcome. Those omissions prevent assessment of the extent to which missingness or population definitions may affect the reported findings.

The registry lists 0 analyses. That means the record does not contain analysis-level results to evaluate; it does not, by itself, establish why results are absent or how the underlying study data were analyzed. The reason for termination and the implications for outcome collection are not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: thrombocytopenia (20.0%), pyrexia (5.7%), pneumonia (5.7%), dyspnoea (5.7%), anaemia (2.9%).

The safety record lists 19 participants affected by serious adverse events among 35 at risk, and 35 participants affected by other adverse events among 35 at risk. It separately lists 1 death. These are descriptive entries for the panobinostat group; the registry does not provide a comparator group for estimating relative safety differences.

The listed serious adverse event terms include thrombocytopenia at 20.0%, pyrexia at 5.7%, pneumonia at 5.7%, dyspnoea at 5.7%, anaemia at 2.9%, and leukopenia at 2.9%. These percentages should be read as the registry’s reported term-level figures, not as proof that a particular event was caused by panobinostat. The record does not report event-level timing, duration, severity grading, or attribution. It also does not state whether individuals experienced more than one serious adverse event term, so the term percentages should not be treated as mutually exclusive categories or added together.

The count of participants with other adverse events is distinct from the count with serious adverse events. The record does not provide enough detail to infer overlap between those participant counts or to connect the listed death to a specific adverse event. These figures support a descriptive account of the safety entries, not a causal comparison or a complete characterization of individual outcomes.

13. What the Result Does, and Does Not, Mean

The registry record identifies a phase II study of panobinostat and defines a primary measure of overall response under IWG-MRT criteria. It also describes the treatment schedule, the population definition for the primary endpoint, a timeframe of up to approximately 2 years, and selected safety counts. Those details clarify what the study set out to assess and how the primary outcome was defined.

The most important limitation for interpreting efficacy is that the primary response result is not reported in the registry record. Neither the response percentage nor its 95% confidence interval is available. The endpoint’s definition cannot be used as a substitute for the result, and enrollment cannot be treated as the denominator for an unreported analysis. The posted record therefore does not establish the frequency of overall response or how precisely it was estimated.

The single-group design means there is no concurrent control arm in the registry record. Even if a response percentage were available, it would describe outcomes in the study group rather than provide a randomized comparison. The record does not support a causal claim about the effect of panobinostat relative to another treatment or to no treatment. The JAK2 mutation cohorts are not described as randomized comparison groups.

The safety figures provide counts and term-level percentages, but they do not identify whether events were attributed to treatment or supply the detail needed to assess timing and severity. The listed death cannot be linked to a particular event based on the registry entries. These limits should be kept separate from the primary endpoint’s missing result: descriptive safety entries do not resolve the absent efficacy estimate.

The study is marked terminated, but the reason for termination is not reported in the registry record. No analysis-level results, missing-data methods, or multiplicity strategy are reported. Taken together, the record supports a description of the intended endpoint and study structure, but not a quantitative conclusion about the primary response outcome or a comparative treatment effect.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of why a registered endpoint and a reported result are different kinds of information. The record gives a detailed definition of overall response and identifies a 95% confidence interval, but does not provide the estimate or interval. Readers can understand what the endpoint was intended to measure without being able to assess the observed outcome or its precision.

The design also illustrates the distinction between outcome description and treatment comparison. The study is single-group, with no control arm, and masking is listed as none. A single-group endpoint can describe the experience of participants in the study, but it does not by itself separate treatment effects from other explanations for observed outcomes. The cohorts based on JAK2 mutation status do not constitute a randomized comparator as described in the registry.

The safety entries show another interpretive issue: participant counts, event terms, and term-level percentages answer different questions. Serious adverse event counts do not identify causation, and term percentages cannot be summed or assumed to represent disjoint sets of participants. The record does not include the event-level information needed to resolve those issues.

Finally, the registry’s planning assumptions use a two-arm, equal-allocation framework even though the recorded study model is single-group. The record explicitly characterizes the calculation as a planning illustration, not the trial’s own design. Keeping that distinction clear prevents planning values from being mistaken for observed power or for a description of the actual analysis. The missing statistical plan and outcome results make careful separation of design details, planning assumptions, and observed findings especially important.

15. 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 primary endpoint is defined, but its observed value and 95% confidence interval are not reported in the registry record. The number of participants included in the endpoint analysis and the number meeting the endpoint are also not reported. This prevents assessment of the primary result’s magnitude, precision, and denominator.

The study has a single-group design, no control arm, and no masking. The registry does not describe random assignment or an adjusted comparison. The JAK2 mutation cohorts are mentioned in the brief summary, but the record does not provide subgroup outcome estimates or identify those cohorts as a randomized contrast. Any comparative interpretation is therefore unsupported by the registered design information.

The study is marked terminated, but the reason is not reported. It is also not reported whether termination affected follow-up, outcome ascertainment, or the planned analysis. The listed enrollment of 35 should not be interpreted as the number assessed for the primary endpoint because the analysis denominator is not reported.

The record does not describe missing-data methods, a statistical analysis plan, a multiplicity strategy, or the method used to calculate the primary confidence interval. It lists 6 outcome measures and 0 analyses, leaving no analysis-level results for checking. The secondary outcome titles do not include reported estimates in the registry record.

Safety information is limited to participant counts and selected serious adverse event terms and percentages. Event attribution, timing, duration, and severity grading are not reported. The record does not establish whether serious adverse event terms overlap within participants, or whether the listed death was related to a particular event. These gaps constrain interpretation of both the efficacy and safety information in this registry entry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate Safety and Efficacy of Panobinostat in Participants With Primary Myelofibrosis — NCT00931762.
• Registry record last updated 2021-07-30; status last verified 2021-07.
• Results first posted 2021-07-30.
• 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.

19. Record Summary

The registry describes a phase II, single-group study of oral panobinostat for primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. The listed enrollment is 35; the study status is terminated. Treatment was 40 mg three times a week for up to 6 cycles, with dose adjustments possible.

The primary endpoint was overall response under IWG-MRT criteria, measured as a percentage with a stated 95% confidence interval over up to approximately 2 years. The primary analysis population included participants who received at least one dose. The observed response percentage, confidence interval, analysis denominator, and analysis-level results are not reported in the registry record.

The record lists 6 outcome measures, including symptom-score changes and adverse event outcomes. It also lists serious and other adverse event counts and selected serious adverse event terms. The reason for termination, statistical plan, and missing-data methods are not reported.