Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS) (NCT01842646), a na phase 2 study. The primary outcome is Overall International Working Group (IWG) 2006 Response Rate.

2. Clinical Question

The study was intended to assess safety and test how well the investigational drug might work in refractory or relapsed MDS or CMML. Its primary endpoint combines several response categories into one overall measure. Responses were to be recorded from treatment start until disease progression or recurrence, and each response had to last at least 8 weeks.

The response definition includes bone marrow and blood criteria. Complete remission requires a specified marrow finding alongside blood-count criteria. Partial remission allows some marrow blasts to remain when the other complete-remission criteria are met. Marrow complete remission and hematological improvement capture additional response patterns. These categories make the endpoint broader than complete remission alone.

Because the registry record does not report the number who met the response criteria, it does not establish the observed response rate. The stated decision thresholds were an overall response rate of 10% or less, at which further investigation would not be warranted, and 30% or more, at which it would be warranted. The record does not report whether either threshold was met.

3. Trial Design

This was a phase II, single-group study of PF-04449913. The registry lists enrollment as 35 and describes treatment with oral PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. Treatment was to be given on an outpatient basis. The record identifies MDS and CMML as the conditions under study and describes the intended population as people with refractory or relapsed disease.

There was no randomized allocation and no masking. With a single treatment group, the study can describe outcomes among participants receiving PF-04449913, but it does not provide a like-for-like control group for estimating a treatment contrast. Differences between this group and an external population would not, by themselves, isolate an effect of treatment.

The primary outcome was overall IWG 2006 response rate. The registry also lists median overall survival, median event-free survival, median time to transformation to acute myeloid leukemia, and the number of participants with treatment-emergent adverse events as secondary outcomes. Although these outcomes are listed, their numerical results are not reported in the registry record.

The registry status is completed. The recorded study start was 2013-08-29, and primary completion was recorded as 2016-01-31. The sponsor was H. Lee Moffitt Cancer Center and Research Institute. These administrative details establish the study context but do not supply missing endpoint results or explain the statistical analysis plan.

The treatment description says participants with no evidence of progressive disease may continue treatment, but the duration following the initial treatment cycles is not fully reported in the registry record. The record also does not report a comparator, allocation ratio, masking procedure, or a detailed account of how participants entered the analysis population.

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

Analysis population for the primary outcome, as defined in the registry: All participants

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: All participants

6. Primary Endpoint

The registry lists the primary outcome as Overall International Working Group (IWG) 2006 Response Rate, measured over Up to 2 years, 4 months.

The primary endpoint is the overall IWG 2006 response rate: the proportion of participants whose response falls into one of the defined response categories. It combines complete remission (CR), partial remission (PR), marrow complete remission, and hematological improvement (HI). Each response must last at least 8 weeks, and responses are recorded from treatment start until disease progression or recurrence.

The criteria use findings from bone marrow and peripheral blood. In broad terms, complete remission requires low marrow blasts with normal maturation of blood cell lines, together with specified blood-count findings. Partial remission allows marrow blasts to remain above the complete-remission threshold when they have decreased from pretreatment levels and the other complete-remission criteria are met. Marrow complete remission and hematological improvement capture further response patterns; the description says hematological improvement is noted in addition to marrow complete remission where applicable.

A combined response endpoint can capture clinically relevant patterns that would be missed by counting only complete remissions. It also requires careful interpretation: the categories are not identical, and a combined rate does not reveal how many participants fell into each category. The registry record describes the endpoint and its decision thresholds but does not report the observed count or rate, category-specific results, or an uncertainty interval. Therefore, the primary response finding cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level classification: a participant either meets the combined response definition or does not. General statistical explanation: for a binary endpoint, the central descriptive quantity is the proportion of participants meeting the definition among those included in the analysis. That proportion alone does not convey its precision. A confidence interval is a range of values compatible with the observed data under a specified statistical method; it communicates uncertainty around an estimate rather than guaranteeing that the true value lies within the range.

What does a single-group response estimate describe?

In a single-group study, an observed response proportion describes the participants assessed under the study conditions. It is not a randomized contrast. A comparison against a historical benchmark, if made, depends on assumptions that the benchmark and study population are sufficiently comparable. The registry record states decision thresholds of 10% or less and 30% or more, but does not report a formal statistical comparison against either threshold or the result of such a comparison.

The response definition combines CR, PR, marrow CR, and HI. A combined endpoint can increase the range of response patterns counted, but it can also conceal variation among its component categories. Separate category counts would help describe the composition of the combined response. Such counts are not reported in the registry record.

Why does response duration matter?

The registry requires each response to last at least 8 weeks and defines the observation period as treatment start until disease progression or recurrence. This duration rule helps distinguish a qualifying response from a change that does not persist for the specified period. It also means response classification depends on follow-up and assessment timing. The record does not report how often assessments occurred, how response adjudication was conducted, or how participants without adequate follow-up were classified.

How should uncertainty be assessed?

General statistical explanation: the amount of uncertainty in a proportion depends on the observed data and the analysis method. A confidence interval would show the range of estimates consistent with those data under its assumptions. A point estimate without an interval gives less information about precision. Neither the primary estimate nor a confidence interval is reported in the registry record, so precision cannot be evaluated. No recalculated estimate can be made from the posted registry entries.

For count outcomes, the denominator is important: it identifies the population in which the event count was assessed. For response, the record says the population is all participants but does not report the analyzed denominator or missing response status. Enrollment is a recruitment figure, not necessarily the denominator used for each analysis. The record does not specify whether participants who discontinued treatment, lacked follow-up, or had unevaluable assessments were included in the response analysis.

What do the planning assumptions mean?

The sample-size planning assumptions described for illustrative calculations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is described as a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses a total event count; for other outcomes, it expresses participants per arm. These are planning conventions, not observed study outcomes or evidence that the trial had a particular power.

The actual study is a single-group trial, whereas the generic planning description refers to two-arm allocation. That planning description should therefore not be read as the design of this trial. The registry record does not report numerical planning estimates, a sample-size justification for this study, or the basis for choosing the enrollment target. It also does not report that the planning assumptions were used to determine the trial's enrollment.

Why can over-dispersion matter?

General statistical explanation: over-dispersion occurs when observed variation in count data exceeds what a chosen model expects. If a model assumes less variability than is present, standard errors may be too small and uncertainty may appear understated. This concept is relevant to some count-data analyses, but the primary endpoint is described as a participant count for a binary response classification. The registry record does not report a count model, an over-dispersion assessment, or any model-based primary analysis.

What is not available for checking the analysis?

The registry record does not report a primary response estimate, confidence interval, analysis method, analysis population details, missing-data approach, or sensitivity analysis. It also does not report an interim analysis plan or a detailed statistical analysis plan. Without those items, readers cannot verify how the stated response criteria were translated into the final analysis or how uncertainty was quantified.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and four secondary outcomes: median overall survival, median event-free survival, median time to transformation to acute myeloid leukemia, and the number of participants with treatment-emergent adverse events. Listing several outcomes raises a general multiplicity issue: when many outcomes are examined, the chance of at least one apparently notable result can increase. Adjustment methods or a hierarchy of testing can address this in some settings, but the registry record does not report a multiplicity plan.

The record lists zero analyses and does not report numerical results for the primary or secondary outcomes. It therefore provides no analysis-specific details about hypothesis tests, confidence intervals, or any adjustment for multiple comparisons. The absence of reported analyses does not establish what analyses may have been conducted outside the registry record.

Missing-data handling is not reported in the registry record. For the primary response endpoint, the record identifies all participants as the population but does not state how participants without an evaluable response, who discontinued treatment, or who lacked sufficient follow-up were treated. The analysis population for the secondary outcomes is also not reported. Enrollment alone cannot resolve those questions because it does not state which participants contributed data to each analysis.

The record does not report whether any outcome assessments were adjudicated, whether sensitivity analyses were conducted, or whether analytic decisions were prespecified. These omissions limit assessment of how outcome availability, multiple endpoints, and analysis choices may affect interpretation.

11. Safety Results

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

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: death nos (5.7%), lung infection (5.7%), intracranial hemorrhage (5.7%), febrile neutropenia (2.9%), cardiac arrest (2.9%).

The registry lists 35 participants at risk and 11 affected for serious adverse events. For other adverse events, it lists 35 at risk and 35 affected. These are participant counts in the treatment group, not a comparison with a control group. The record also lists serious adverse event terms with percentages: Death NOS, lung infection, and intracranial hemorrhage at 5.7% each; febrile neutropenia, cardiac arrest, and ileus at 2.9% each.

These figures should be read as reported safety information, not as proof that PF-04449913 caused the events. A serious adverse event is not necessarily an event judged to be related to treatment. The registry record does not report causal attribution in the listed figures, event timing, duration, severity details beyond the serious-event classification, or participant-level overlap among event terms. A participant may have experienced more than one event, so the listed terms should not be added together.

The percentages describe the selected terms as recorded; they do not replace a full review of adverse-event definitions and follow-up. Without a comparator group, the counts cannot show whether event frequency was higher or lower than under another treatment or no treatment. The record does not report a complete comparative safety analysis.

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

The record establishes that a completed phase II, single-group study evaluated oral PF-04449913 in participants with MDS or CMML and specified an IWG 2006 overall response endpoint. It also records selected safety counts and serious adverse event terms. These registry entries describe the study and the kinds of outcomes it intended to assess.

The main efficacy result cannot be interpreted because the primary response count and rate are not reported in the registry record. There is no reported confidence interval or analysis to indicate the precision of a response estimate. The stated thresholds of 10% or less and 30% or more provide a decision framework in the outcome description, but the record does not say whether the observed outcome met either threshold.

Even if a response proportion were available, the single-group design would support a description of outcomes in the treated group, not a randomized causal comparison. It would not by itself establish what would have happened to comparable participants under another treatment. The registry record also does not report the analysis population or missing-data handling needed to understand the denominator behind a result.

The safety counts and terms likewise have limits. They document reported events in the treatment group, but do not show comparative risk or establish treatment causation. The absence of a control group and the limited event details make causal interpretation particularly constrained.

Accordingly, the registry record can be used to understand the study's question, design, endpoint definitions, and selected safety reporting. It cannot support a conclusion about the magnitude or precision of the primary response result, whether the decision thresholds were reached, or how outcomes compare with another approach. The survival and other secondary outcome results are also not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates an important distinction between a trial's stated endpoint and its reported finding. A detailed response definition can clarify what investigators intended to count, but it cannot substitute for the observed count, denominator, and uncertainty estimate. In this record, the primary endpoint is described in detail while the actual response result is not reported.

The endpoint also shows why definitions matter in clinical research. Combining complete remission, partial remission, marrow complete remission, and hematological improvement creates an overall response measure that captures several response patterns. Readers still need the component results to understand what drove a combined endpoint. The registry record does not report those component counts.

The design is statistically informative in another way: a single-group phase II study answers a different question from a randomized comparison. It can describe outcomes in a treatment group and may be used to assess whether further investigation is warranted under stated criteria. It cannot, on its own, provide a randomized estimate of a treatment contrast. Making that distinction prevents a descriptive result from being mistaken for comparative evidence.

Finally, the record demonstrates why registry completeness is part of statistical interpretation. The absence of a response estimate, analysis method, missing-data approach, and multiplicity plan leaves major questions about results and their precision unanswered. Safety counts add useful descriptive information, but without a comparator or fuller event context they do not establish treatment-related risk. Clear reporting of estimates, denominators, uncertainty, and analysis populations would be needed for a fuller statistical assessment.

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 primary limitation for interpreting efficacy is that the registry record does not report the primary response count or rate. It also does not report a confidence interval, the number assessed, or results by response category. Although the endpoint description specifies the response criteria and the stated decision thresholds, the record does not indicate whether either threshold was reached.

The single-group design has no concurrent control arm, so the study does not provide a randomized comparison. This limits causal interpretation of both response and safety outcomes. The record identifies enrollment as 35, but does not report the analysis denominator for the primary outcome or clarify the handling of participants without an evaluable response.

Details needed to assess endpoint conduct are also not reported in the registry record. These include assessment frequency, response adjudication, missing-data handling, analysis populations, and sensitivity analyses. The record does not report a multiplicity plan for the primary and secondary outcomes or a detailed statistical analysis plan. Numerical findings for the listed survival outcomes are not reported.

The safety information is selective: counts are given for serious and other adverse events, along with selected serious event terms and percentages. The record does not provide comparative safety data, causal attribution for the listed events, or details about overlap among event terms. The listed figures therefore cannot be interpreted as treatment-attributable risks.

Finally, the registry describes possible continuation beyond the initial treatment cycles but does not fully report the duration or conditions for that continuation. The limitations do not establish that analyses or additional information are unavailable elsewhere; they describe what is not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS) — NCT01842646.
• Registry record last updated 2021-06-14; status last verified 2021-06.
• Results first posted 2017-03-14.
• 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.

18. Record Summary

This completed phase II study evaluated PF-04449913 in participants with refractory or relapsed MDS or CMML. The design was single-group, with no masking and no randomized comparator. Enrollment was 35. Treatment was described as oral PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles.

The primary outcome was overall IWG 2006 response rate, combining CR, PR, marrow CR, and HI. The registry record does not report the primary response result or an analysis of it. It lists four secondary outcomes, including survival measures and treatment-emergent adverse events, but does not report their numerical results in the record described.

Safety reporting lists 11 participants affected by serious adverse events among 35 at risk and 35 affected by other adverse events among 35 at risk. Selected serious event terms and percentages are recorded. The sponsor was H. Lee Moffitt Cancer Center and Research Institute; the recorded study start was 2013-08-29 and primary completion was 2016-01-31.