Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis (NCT01369498), a randomized phase 2 study. The primary outcome is Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score.

2. Clinical Question

The study addresses a tissue-based measure of myelofibrosis, rather than a single symptom or laboratory value. The fibrosis score ranges from 0 to 3: 0 represents scattered linear reticulin with no fiber intersections and normal marrow, while 3 represents dense reticulin fibrosis with fiber intersections, often with osteosclerosis. A lower score from baseline was defined as improvement for this endpoint.

The clinical question is framed separately for simtuzumab given alone and for simtuzumab added to stable-dose ruxolitinib. These are two stages with different treatment contexts. The posted outcome figures describe response within each arm; the registry comparisons use the Stage 1 200 mg arm as the reference. Because the stages have different treatment contexts, those reference comparisons do not by themselves establish a randomized comparison between all four groups.

3. Trial Design

This was a completed, Phase 2, randomized, open-label, parallel-group study of simtuzumab in adults with primary myelofibrosis or myelofibrosis following polycythemia vera or essential thrombocythemia. The recorded enrollment was 54. The study began on 2011-06-30, and primary completion was 2014-06-05.

The trial had two stages. In Stage 1, participants were randomized to simtuzumab 200 mg or 700 mg. The Stage 1 descriptions specify treatment for up to 24 weeks, with continuation possible when the treating physician judged there was evidence of clinical benefit. In Stage 2, participants already on stable doses of ruxolitinib were randomized to receive simtuzumab 200 mg or 700 mg. Simtuzumab was to be given for at least 24 weeks, with possible continuation based on the treating physician’s judgment of clinical benefit.

The design therefore asks questions in two settings: simtuzumab alone and simtuzumab added to ruxolitinib. It is not a single four-arm comparison in which all participants were drawn from one treatment context. The posted primary outcome group sizes were 11 for Stage 1 simtuzumab 200 mg, 12 for Stage 1 simtuzumab 700 mg, 15 for Stage 2 simtuzumab 200 mg plus ruxolitinib, and 15 for Stage 2 simtuzumab 700 mg plus ruxolitinib. These are the numbers reported for the primary outcome and should not be assumed to be identical to the numbers used for every other outcome.

Masking was listed as none. The registry record does not report further details of the randomization procedure, allocation concealment, or the rationale for the selected doses and treatment durations. A formal sample-size justification and the full statistical analysis plan 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.

Before assignment: 62 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Per Protocol Analysis Set included participants who were randomized, received at least 1 dose of study drug, did not violate any major entry criteria, and had at least 80% adherence with 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: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score, measured over Baseline; Week 24.

The primary endpoint is the percentage of participants with a reduction in bone marrow fibrosis score at Week 24 compared with baseline. The score runs from 0 to 3, with 0 describing normal marrow reticulin and 3 describing dense reticulin fibrosis, often with osteosclerosis. Under the endpoint definition, a reduction from baseline counts as improvement.

This measure focuses on marrow fibrosis, a defining tissue feature of the condition studied. It provides a structured way to record whether the score moved in a favorable direction during the assessment period. The outcome is binary at the participant level: a participant either met the reduction criterion or did not. The reported percentage is the proportion meeting that criterion in each treatment arm.

The primary outcome was assessed in the Per Protocol Analysis Set. This set included randomized participants who received at least one dose of study drug, did not violate any major entry criteria, and had at least 80% adherence with study drug. The registry record does not report the handling of participants who lacked a Week 24 score, the scoring or review procedures, or whether assessment was centrally or locally performed.

The endpoint is a Week 24 response measure, not a description of the duration of response or of change at later time points. It also does not, by itself, summarize symptoms, blood counts, safety, or other aspects of disease status. Those are distinct outcomes, several of which were listed as secondary outcomes.

7. Results Posted in the Registry

• Stage 1: SIM 700 mg: 16.7% (2/12) versus 0.0% (0/11) on control; risk difference 16.7 percentage points (95% CI -4.4 to 37.8); unadjusted two-proportion z-test p = 0.156.
• Stage 2: SIM 200 mg+Ruxolitinib: 6.7% (1/15) versus 0.0% (0/11) on control; risk difference 6.7 percentage points (95% CI -6.0 to 19.3); unadjusted two-proportion z-test p = 0.382.
• Stage 2: SIM 700 mg+Ruxolitinib: 13.3% (2/15) versus 0.0% (0/11) on control; risk difference 13.3 percentage points (95% CI -3.9 to 30.5); unadjusted two-proportion z-test p = 0.207.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary outcome percentage represent?

Each participant either met the endpoint definition—a reduction in bone marrow fibrosis score from baseline at Week 24—or did not. The arm-level percentage expresses the share of participants meeting that definition. This is a binary outcome, even though the underlying fibrosis score has several ordered levels. The reported percentages should be read together with the participant counts and confidence intervals, particularly because the groups were small.

What is a confidence interval?

General explanation: a confidence interval describes the statistical uncertainty around an estimated quantity under the assumptions of the method used. It is not a range containing a known fraction of individual participant outcomes, and it does not express the probability that the true value lies within a particular calculated interval. In repeated use of a method under its assumptions, intervals at a stated confidence level have a long-run coverage interpretation. The posted primary outcome uses 90% confidence intervals.

The arm-specific intervals are wide relative to their point estimates. That is consistent with limited precision in small groups: the observed percentages are estimates, not exact measurements of the response rate that would be seen in a wider population. For the reference arm, no participant in the primary outcome group met the endpoint, but its interval extends above 0%. An observed zero therefore does not demonstrate that the underlying response probability is exactly zero.

How should the comparisons be read?

The posted comparisons use risk differences, an absolute contrast between the percentage meeting the outcome in an arm and the percentage in the reference arm. A risk difference of zero represents no difference in those proportions. The reported confidence intervals for the comparisons included zero, and the reported p-values are unadjusted. The registry record does not report an adjustment for multiple comparisons or a separate adjusted model. These comparisons are therefore best treated as exploratory descriptions of the posted data, rather than as definitive evidence of a difference or of equivalence.

General explanation: a p-value measures how incompatible the observed data are with a specified null model, assuming that model and the analysis assumptions hold. It is not the probability that the null hypothesis is true, the probability that the findings occurred by chance, or a measure of clinical importance. A p-value above a conventional threshold does not establish that two treatments have the same effect. Here, the point estimates and intervals matter alongside the p-values, and the small event counts limit how sharply the comparisons can distinguish among plausible effects.

Why does the trial structure matter?

Randomization supports comparisons between groups randomized within the same stage and treatment context. Stage 1 randomized participants to simtuzumab 200 mg or 700 mg without ruxolitinib described as part of the treatment. Stage 2 involved participants on stable ruxolitinib and randomized them to one of the two simtuzumab doses. Because those stage populations and treatment settings differ, the Stage 2 versus Stage 1 reference contrasts are not equivalent to a direct randomized comparison across a four-arm trial. Differences between stages could reflect the differing contexts as well as the assigned simtuzumab dose.

Open-label status means masking was listed as none. General explanation: knowledge of assigned treatment can affect behavior, co-interventions, or assessment, especially for outcomes involving judgment. The registry record does not report how fibrosis scoring was conducted, whether assessors were blinded, or what safeguards were used to limit assessment bias. No conclusion about the presence or absence of bias can be drawn from that missing detail alone.

What do the planning illustrations mean?

General explanation: a sample-size calculation estimates how many participants would be needed under stated assumptions to detect a specified effect with a chosen statistical procedure. The planning illustrations associated with the posted results are based on the observed effect, assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. They are planning illustrations, not the original trial’s design justification and not observed power. The trial’s own sample-size justification is not reported in the registry record.

General explanation: observed power calculated after a study from its observed effect does not add a separate interpretation to the confidence interval and p-value. The more informative description is the estimate, its uncertainty, the number of participants, and the analysis context. The registry record does not report the assumptions or calculations used to choose the original enrollment target.

What does over-dispersion mean in general?

General explanation: over-dispersion occurs when the variability in data is greater than a statistical model assumes. It can make standard errors too small and confidence intervals too narrow if the model does not accommodate that extra variability. The primary outcome is binary and is reported as arm-level percentages with confidence intervals; the registry record does not describe an over-dispersion model or report a model-based adjustment for it. It would not be appropriate to assume that such an adjustment was performed.

The posted primary analysis set also matters. It is restricted to randomized participants who received at least one dose, met major entry criteria, and had at least 80% adherence. This is not the same as an analysis of every randomized participant regardless of treatment received or adherence. The registry record does not report a separate intention-to-treat estimate for the primary endpoint or a sensitivity analysis comparing analysis populations.

10. Confidence Intervals and Precision

The primary outcome estimates have substantial uncertainty. The 90% confidence intervals were 0% to 23.8% for Stage 1 simtuzumab 200 mg, 3.0% to 43.8% for Stage 1 simtuzumab 700 mg, 0.3% to 27.9% for Stage 2 simtuzumab 200 mg plus ruxolitinib, and 2.4% to 36.3% for Stage 2 simtuzumab 700 mg plus ruxolitinib. The groups contained 11, 12, 15, and 15 participants, respectively. The interval widths reflect that the arm-level percentages are not estimated precisely.

For the comparisons against the Stage 1 simtuzumab 200 mg reference, every reported confidence interval included zero. This means the posted data are compatible with no difference under those contrasts, but also with differences in either direction within the intervals. It does not prove equal response rates. The reported unadjusted p-values were 0.156, 0.382, and 0.207 for the three comparisons.

General explanation: precision describes how narrowly an estimate is pinned down by the data and the statistical method. A point estimate alone can appear more definite than the evidence warrants. Confidence intervals help show how much uncertainty remains, but they do not correct for limitations in design, outcome measurement, missing data, or multiplicity. These intervals are also conditional on the method’s assumptions.

For a binary outcome with few participants meeting the response criterion, a small number of outcomes can have a notable effect on the estimated percentage. The zero responses in the reference group and the small response counts in the other groups are therefore important context when interpreting the apparent differences. The estimates should not be generalized with high precision to a broader population on the basis of these groups alone.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five secondary outcomes in addition to the primary endpoint. They include clinical response defined by blood count improvement, adverse events, myelofibrosis symptom score, cytokine levels, and anti-simtuzumab antibody formation. The registry record does not report a multiplicity-control procedure, such as an adjustment to account for evaluating multiple outcomes or comparisons. The primary comparisons are reported with unadjusted p-values. Without a stated multiplicity approach, the p-values should not be interpreted as if they were adjusted to control the chance of false-positive findings across all outcomes and comparisons.

The registry record does not report the method used to handle missing Week 24 fibrosis scores, participants who discontinued treatment, or other missing outcome data. It also does not report a sensitivity analysis for missingness. Consequently, the extent to which missing observations could affect the primary estimates cannot be assessed from the posted information.

The primary endpoint used a Per Protocol Analysis Set defined by randomization, receipt of at least one dose, no major entry-criteria violation, and at least 80% adherence. The registry record does not report a separate intention-to-treat analysis for this endpoint or results under alternative analysis populations. The primary endpoint group sizes are listed, but the approach for reconciling those groups with the full randomized population is not described.

Interim analyses, stopping rules, and a detailed prespecified statistical analysis plan are not reported in the registry record. The original sample-size justification is also not reported. These gaps limit assessment of whether the analyses followed prespecified procedures and how the planned enrollment related to the primary question. They do not establish that such procedures were absent; they mean the registry record does not describe them.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (16.7%), diarrhoea (8.3%), disease progression (8.3%), pyrexia (8.3%), abdominal infection (8.3%).

The serious adverse event figures report the number of participants affected and the number at risk in each treatment group. In Stage 1 simtuzumab 200 mg, 8 of 12 participants were affected; in Stage 1 simtuzumab 700 mg, 1 of 12 was affected. In Stage 2 simtuzumab 200 mg plus ruxolitinib, 5 of 15 were affected; in Stage 2 simtuzumab 700 mg plus ruxolitinib, 4 of 15 were affected. These are group-level counts, not rates adjusted for time on treatment.

The registry also lists serious adverse event terms, including febrile neutropenia at 16.7%, and diarrhoea, disease progression, pyrexia, abdominal infection, and cellulitis at 8.3% each. The record does not provide enough detail to infer whether participants experienced more than one listed event or how events were distributed across treatment groups.

Deaths were recorded as 0, 1, 1, and 0 in the four groups in the same order. These counts do not establish that a death was caused by study treatment; the registry record does not report that attribution in these figures. Comparisons of safety counts should be cautious because the groups are small and the record does not provide adjustment for duration of exposure or other differences between stages.

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

The posted results describe the proportion of participants in the primary analysis set who had a reduction in marrow fibrosis score at Week 24. Response percentages ranged from 0% in Stage 1 simtuzumab 200 mg to 16.7% in Stage 1 simtuzumab 700 mg. In the ruxolitinib groups, the reported percentages were 6.7% with simtuzumab 200 mg and 13.3% with simtuzumab 700 mg. The confidence intervals were broad, and the posted comparisons against the Stage 1 200 mg reference had intervals that included zero.

These findings do not establish that one dose is better than another, that treatment groups are equivalent, or that any observed difference is caused by simtuzumab. The Stage 2 arms involved participants on stable ruxolitinib, while the Stage 1 arms evaluated simtuzumab alone; comparisons spanning those stages require particular caution. The registry comparisons are unadjusted, and the primary groups are small.

The endpoint is a specific Week 24 change in fibrosis score. It is not a complete account of symptoms, blood counts, quality of life, longer-term disease course, or safety. The registry lists several secondary outcomes, but their detailed results are not included in the information summarized by the primary outcome figures. Conclusions about those outcomes cannot be drawn from the fibrosis endpoint.

General explanation: clinical interpretation depends on both the size of an estimated effect and its uncertainty, the outcome’s relevance, the study design, and the analysis population. Statistical evidence alone does not establish clinical importance. The registry record does not report a threshold defining a clinically important change in the primary endpoint. The data therefore support a description of the observed response counts and their uncertainty, not a broad claim about treatment benefit or lack of benefit.

14. Why This Trial Matters Statistically

This trial illustrates why design context is central to statistical interpretation. Although four treatment groups are reported, they arose from two stages with different treatment settings. Stage 1 randomized between simtuzumab doses alone, while Stage 2 randomized between doses among participants on stable ruxolitinib. The Stage 1 reference comparisons with Stage 2 groups are therefore not simple contrasts among four arms in one common randomized population.

The outcome also shows how sparse binary data affect precision. Only a few participants met the Week 24 reduction criterion, and the reference group had no responses in the primary analysis set. Such counts produce uncertain arm-level percentages and make it important to read intervals alongside point estimates and p-values. A difference in observed percentages is not automatically persuasive evidence of a treatment difference.

The registry record further highlights the distinction between planned sample-size illustrations and the study’s original design rationale. The illustrations based on the observed effect describe hypothetical planning under stated assumptions; they do not show that the study was designed with those assumptions, nor do they represent observed power. The original sample-size justification is not reported.

Finally, the restricted Per Protocol Analysis Set affects the question answered by the primary estimates. The results describe participants meeting the specified adherence and eligibility conditions, rather than necessarily representing every randomized participant. Missing-data handling, multiplicity procedures, and a full statistical plan are not reported. These details are important for judging how robustly the posted estimates answer the trial’s clinical question.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several limitations are specific to interpreting these results. The primary outcome analysis groups were small, with 11 to 15 participants in each arm, and only a few participants met the response definition. The resulting confidence intervals are broad, so the response percentages remain imprecise.

The study’s two-stage structure complicates comparisons across all four groups. Stage 1 evaluated simtuzumab alone, whereas Stage 2 enrolled participants on stable ruxolitinib. The registry’s comparisons use the Stage 1 simtuzumab 200 mg arm as the reference, but the Stage 2 groups differ in treatment context. The record does not report a randomized comparison across all four groups as one population.

The primary outcome was reported in a Per Protocol Analysis Set that required at least one dose, adherence of at least 80%, and no major entry-criteria violation. The registry record does not report an intention-to-treat primary analysis, missing-data methods, or sensitivity analyses. Open-label status was recorded, and the record does not state whether outcome assessors were masked or how fibrosis scoring was standardized.

The registry record does not report a formal sample-size justification, interim-analysis procedures, multiplicity adjustment, or a full statistical analysis plan. The listed safety counts are not adjusted for exposure duration in the information reported, and the death counts do not specify treatment attribution. These limitations constrain the conclusions that can be drawn from the posted estimates; they do not establish that unreported procedures were not conducted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis — NCT01369498.
• Registry record last updated 2020-07-01; status last verified 2020-06.
• Results first posted 2020-07-01.
• 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

NCT01369498 was a completed, Phase 2, randomized, open-label, parallel-group study sponsored by Gilead Sciences. It enrolled 54 adults with primary myelofibrosis or myelofibrosis following polycythemia vera or essential thrombocythemia. The study began on 2011-06-30 and reached primary completion on 2014-06-05.

Participants were randomized in Stage 1 to simtuzumab 200 mg or 700 mg. In Stage 2, participants on stable ruxolitinib were randomized to simtuzumab 200 mg or 700 mg. The primary endpoint was the percentage with a reduction in bone marrow fibrosis score at Week 24, assessed in a defined Per Protocol Analysis Set.

Reported response percentages were 0%, 16.7%, 6.7%, and 13.3% across the four arms, with broad 90% confidence intervals. The posted unadjusted comparisons against the Stage 1 simtuzumab 200 mg group had confidence intervals that included zero. The registry record does not report the original sample-size justification, missing-data methods, multiplicity procedures, or a full statistical analysis plan.