Efficacy and Safety of Roxadustat for Treatment of Anemia in Participants With Lower Risk Myelodysplastic Syndrome With Low Red Blood Cell Transfusion Burden: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Roxadustat for Treatment of Anemia in Participants With Lower Risk Myelodysplastic Syndrome With Low Red Blood Cell Transfusion Burden (NCT03263091), a randomized phase 3 study. The primary outcome is OL and OL High-EPO Components: Number of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) ≥8 Weeks (≥56 Consecutive Days) Since First Dose in the First 28 Weeks of Treatment.

2. Clinical Question

The trial concerned participants with anemia and lower-risk myelodysplastic syndrome (MDS), including very low, low, or intermediate IPSS-R risk with <5% blasts. Participants were also described as having low red blood cell (RBC) transfusion burden. The registry record does not report additional eligibility details in the information available for this analysis.

The intervention was roxadustat. Its open-label component used sequential escalating doses to identify a starting dose for the double-blind period; the listed cohorts received 1.5 mg/kg, 2.0 mg/kg, or 2.5 mg/kg, and the high-EPO component also used roxadustat 2.5 mg/kg. The double-blind component compared roxadustat with matching placebo for a stated duration of 52 weeks. Details of the treatment schedule beyond those described in the registry record are not reported in the registry record.

The primary question in the posted outcome was whether participants in the open-label and open-label high-EPO components achieved RBC transfusion independence (TI) for at least 8 weeks, or 56 consecutive days, since first dose in the first 28 weeks of treatment. The registry defined TI as no intravenous RBC transfusion, whether packed cells or whole blood, during any consecutive 56 days in the treatment period.

The record also posts double-blind comparisons of roxadustat and placebo for several secondary outcomes. These include TI during treatment and reduction in transfusion burden. Those comparisons address related but distinct questions; they are not the same endpoint or analysis population as the listed primary outcome.

3. Trial Design

This was a Phase 3, randomized, quadruple-masked, parallel study with roxadustat and placebo interventions. Its stated purpose was to investigate efficacy and safety for anemia in participants with lower-risk MDS and low RBC transfusion burden. The registry lists enrollment of 184 and status as terminated. The start date was 2018-01-29, and the primary completion date was 2023-03-09.

The treatment description includes an open-label component and an open-label high-EPO component, as well as a double-blind component. In the open-label cohorts, participants received sequential escalating roxadustat doses of 1.5 mg/kg, 2.0 mg/kg, and 2.5 mg/kg to identify a starting dose for the double-blind period. The high-EPO component is separately listed at 2.5 mg/kg. For the double-blind component, participants received roxadustat or matching placebo; the placebo description states a duration of 52 weeks.

Although the study is described as randomized and quadruple-masked, the open-label components were not described as masked. The registry record does not report the allocation sequence, concealment procedures, the precise roles covered by quadruple masking, or how participants moved between components. It also does not report whether every enrolled participant entered each component.

The primary outcome results are reported for the open-label cohorts, rather than as a roxadustat-versus-placebo comparison. The separate double-blind results include 80.0 participants in the roxadustat group and 57.0 in the placebo group for one posted secondary outcome; denominators differ for the listed open-label cohorts. These outcome denominators should not be read as the total enrollment count. Further details on participant flow, exclusions, and reasons for discontinuation 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: Participants were enrolled in sequential dose level cohorts in OL lead-in component prior to the start of DB component. Concurrent with enrollment in DB component, participants with high serum EPO levels (\>400 milli-international units \[mIU\]/milliliter \[mL\]), exclusionary for DB component, were enrolled in an OL high-EPO component. Participants with lower-risk myelodysplastic syndrome (MDS) with low transfusion burden (LTB) were randomized 3:2 to roxadustat or matching placebo in DB component.

OL Component

Reasons for not completing this period:

OL High-EPO Component

Reasons for not completing this period:

DB Component

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The full analysis set (FAS) included all enrolled participants who received at least 1 dose of study medication, and at least 1 corresponding on-treatment hemoglobin (Hb) assessment.

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 all participants who received at least 1 dose of study drug.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as OL and OL High-EPO Components: Number of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence (TI) ≥8 Weeks (≥56 Consecutive Days) Since First Dose in the First 28 Weeks of Treatment, measured over 28 weeks.

The primary endpoint counts participants who achieved RBC transfusion independence for at least 8 weeks (at least 56 consecutive days) since first dose during the first 28 weeks of treatment. The registry definition requires no intravenous RBC transfusion, including packed red cells or whole blood, over a consecutive 56-day interval. The reported measure is a count of participants meeting that definition, not the duration of independence for each participant or a change in hemoglobin.

Transfusion independence is used as a clinically interpretable measure of whether a participant went through a sustained interval without RBC transfusion. It differs from an outcome that simply counts transfusion packs or measures a laboratory value: it focuses on whether the specified transfusion-free interval occurred. That general distinction helps explain why TI and transfusion reduction appear as separate outcomes in this record.

The primary outcome population is the full analysis set (FAS), defined in the record as enrolled participants who received at least 1 dose of study medication and had at least 1 corresponding on-treatment hemoglobin assessment. The reported primary components are open-label and open-label high-EPO cohorts. The record gives counts for these cohorts, but does not provide confidence intervals, a formal comparison between cohorts, or a placebo comparison for this endpoint.

The measurement window matters to interpretation: this endpoint concerns a qualifying interval within the first 28 weeks, whereas some posted secondary outcomes assess TI over 52 weeks or at any time during the study. Those measures do not have identical observation windows and should not be treated as interchangeable.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports counts for the primary outcome and risk-difference estimates for three double-blind secondary comparisons. A count states how many participants met the endpoint within an analysis group. It does not, by itself, quantify uncertainty or compare groups. For the primary endpoint, the record gives cohort sizes and counts but no confidence interval, p-value, or reported comparative analysis. The primary results therefore support descriptive reading only.

What does a risk difference describe?

General statistical explanation: for a binary outcome, a risk difference expresses the difference between the proportions meeting the outcome in two groups. A value above zero indicates a higher observed proportion in the group named for the estimate than in its comparator; a value below zero indicates a lower observed proportion. The risk difference is an absolute contrast, rather than a relative measure. The registry’s posted estimates are unadjusted and should be interpreted in that light.

For the double-blind TI outcome over 52 weeks, the risk difference estimate is 0.146. Its confidence interval extends from -0.021 to 0.314. A confidence interval conveys uncertainty around an estimate under the method used to construct it. In general, a wide interval indicates that the data are compatible with a broader range of possible values than a narrow interval. Here, the reported interval includes zero, so the posted estimate does not rule out no difference under that interval-based interpretation. The same applies to the other two posted secondary intervals: -0.025 to 0.308 and -0.069 to 0.245.

How should the p-values be read?

The unadjusted p-values for the three posted comparisons are 0.091, 0.097, and 0.266. General statistical explanation: a p-value measures how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, nor does it measure the probability that a result is due to chance. The record labels these p-values unadjusted, and no multiplicity adjustment is reported. They should be considered alongside the estimates, intervals, design, and analysis limitations rather than interpreted in isolation.

Why does the primary endpoint differ from the secondary comparisons?

The primary outcome is reported for open-label dose cohorts and the open-label high-EPO component. No two-arm placebo comparison or uncertainty estimate is posted for those counts. The three secondary comparisons instead concern roxadustat and placebo in the double-blind component. They use different outcome definitions and time windows: TI since first dose over 52 weeks, TI anytime during the study, and a reduction in transfusions over 8 weeks. Differences in groups and outcome windows mean that the secondary estimates cannot be used as a substitute analysis of the primary endpoint.

What do the planning illustrations mean?

The registry’s planning illustrations are based on observed effects and specified assumptions: a two-sided significance level of 0.05, equal allocation, and a normal approximation. They describe participants per arm for stated power levels under assumed effect sizes expressed as fractions of the observed effect. These figures are hypothetical planning illustrations, not the trial’s actual design justification and not observed power. The trial’s own sample-size justification is not reported in the registry record. A planning exercise based on an observed estimate can also be unstable when that estimate is imprecise; the resulting figures should not be treated as evidence that the completed trial was adequately or inadequately powered.

The record reports no sponsor-reported analyses for the listed secondary comparisons. A recalculated, unadjusted result would not replace a sponsor analysis when the two disagree; no such discrepancy is indicated in this record. More broadly, interpretation depends on assumptions about endpoint ascertainment, analysis populations, missing outcomes, and the validity of the statistical model. Details for these matters are not reported in the registry record.

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("OL Component (Cohort 1): Roxadustat 1.5 mg/kg", "OL Component (Cohort 2): Roxadustat 2.0 mg/kg", "OL Component (Cohort 3): Roxadustat 2.5 mg/kg", "OL High-EPO Component: Roxadustat 2.5 mg/kg")
n      <- c(8, 8, 8, 20)
events <- c(3, 1, 5, 3)
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  OL Component (Cohort 1): Roxadustat 1.5 mg/kg  8  3  37.5  8.5  75.5  13.7  69.4  13.7  70.1
ARM  OL Component (Cohort 2): Roxadustat 2.0 mg/kg  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2
ARM  OL Component (Cohort 3): Roxadustat 2.5 mg/kg  8  5  62.5  24.5  91.5  30.6  86.3  29.9  86.3
ARM  OL High-EPO Component: Roxadustat 2.5 mg/kg  20  3  15.0  3.2  37.9  5.2  36.0  5.4  36.3

11. Multiplicity, Missing Data and Analysis Populations

The record lists 12 outcome measures and 1 analysis, and it posts 10 secondary outcomes. Three double-blind secondary outcomes have comparative estimates in the results; the record lists no reported analyses for those comparisons. It does not describe a hierarchy of endpoints, a testing sequence, or an adjustment for examining multiple outcomes. The protocol’s statistical analysis plan and any multiplicity procedure are not reported in the registry record.

Multiplicity matters because each additional statistical test creates another opportunity to observe an apparently unusual result under a null model. General statistical explanation: a prespecified strategy can help control how conclusions are drawn across several tests, for example by prioritizing an endpoint or adjusting inference. Without the strategy, unadjusted p-values should not be treated as though they represent a single isolated test. The posted confidence intervals are likewise presented without a reported multiplicity adjustment.

Missing-data handling is also not reported in the registry record. The primary FAS definition requires at least 1 dose and at least 1 corresponding on-treatment hemoglobin assessment. The record does not explain how participants with missing outcome assessments, discontinuation, or incomplete follow-up were handled. It does not state whether missing outcomes were imputed, treated as failures, or excluded under another rule. Those details can affect both the number analyzed and the interpretation of a binary endpoint.

The record does not provide a complete account of analysis populations for every secondary outcome, nor does it explain the difference between enrollment and the denominators reported for individual outcomes. It also does not describe interim analyses, stopping rules, or the sample-size justification. These omissions do not establish that particular methods were or were not used; they mean the methods cannot be evaluated from the registry record.

For the primary endpoint, the available numbers are descriptive counts by open-label cohort. For the secondary comparisons, the estimates are explicitly unadjusted. These distinctions should remain central when interpreting the evidence, especially because the trial status is terminated and the reason is not reported.

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 (12.5%), acute myocardial infarction (12.5%), cardiac failure (12.5%), inguinal hernia (12.5%), general physical health deterioration (12.5%).

The registry records serious adverse event counts and deaths separately for each component and group. In the double-blind component, 22 of 82 participants in the roxadustat group and 10 of 58 in the placebo group were recorded with serious adverse events. Deaths were recorded for 7 participants in the roxadustat group and 4 in the placebo group. These are descriptive counts; they do not establish that an event or death was caused by study treatment.

The open-label cohorts also have serious adverse event counts: 4 of 8, 3 of 8, and 1 of 8 participants in the three dose cohorts, and 6 of 20 in the open-label high-EPO component. Recorded deaths were 1, 0, 0, and 3, respectively. These open-label observations are from different components and should not be combined with the double-blind comparison as if they formed a single randomized contrast.

The registry lists serious-event terms including febrile neutropenia, acute myocardial infarction, cardiac failure, inguinal hernia, general physical health deterioration, and portal hypertension, each with a listed value of 12.5%. The available information does not establish the relationship of these events to treatment or provide enough detail to interpret the percentages as comparative risks. Definitions, exposure-adjusted rates, event timing, and follow-up completeness are not reported in the registry record. The counts therefore describe what was recorded, not a causal safety conclusion.

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

The registry results describe outcomes observed in a terminated study of roxadustat in participants with lower-risk MDS and low RBC transfusion burden. The primary results are counts of participants who met the transfusion-independence definition in open-label cohorts. They do not include a placebo comparison, statistical uncertainty estimates, or a reported comparative analysis. Those counts alone cannot establish whether roxadustat changed the likelihood of meeting the endpoint relative to placebo.

The double-blind secondary comparisons provide risk-difference estimates and confidence intervals. Each interval includes zero, and each comparison is reported as unadjusted. The estimates are therefore uncertain and should not be interpreted as proof of a treatment effect or proof that no effect exists. Their different endpoint definitions and timeframes also prevent treating them as interchangeable replications of one primary question.

Counts of serious adverse events and deaths describe events recorded in the treatment groups. They do not show whether events were caused by treatment, and comparisons based on the reported counts alone do not account for differences in follow-up or exposure. The registry does not provide the additional information needed for a fuller causal safety assessment.

General statistical interpretation: a registry result is evidence to be considered with its design, analysis methods, completeness, and uncertainty. Here, the absence of a reported primary comparison, the unadjusted nature of secondary estimates, missing detail on missing-data methods and multiplicity, and the terminated status all limit conclusions. The reason for termination is not reported in the registry record, so no explanation for that status should be inferred.

These results do not establish that roxadustat works or does not work, and they do not support individual treatment decisions. They describe the outcomes and analyses recorded for this trial. Further protocol and analysis details would be needed to assess how the posted results relate to the trial’s planned statistical questions.

14. Why This Trial Matters Statistically

This trial illustrates why an endpoint’s label, population, and comparison group matter as much as its numerical result. The primary endpoint is clinically interpretable as a transfusion-free interval, but the posted primary counts come from open-label cohorts. Without a comparator and uncertainty estimates, the counts cannot answer a comparative treatment question on their own.

The registry also separates those primary results from secondary results in the double-blind component. The secondary risk differences are accompanied by confidence intervals, which make the uncertainty visible; each interval includes zero. Yet those estimates concern distinct outcome definitions and windows, and they are unadjusted. Their apparent consistency in point-estimate direction should not be taken as an independent confirmation of the primary endpoint.

The record highlights other statistical issues common to clinical trials: multiple endpoints, the need to distinguish planned analyses from post hoc or descriptive summaries, and the importance of understanding missing outcomes and analysis populations. The registry lists 12 outcome measures, but its multiplicity approach, sample-size justification, missing-data procedures, and interim analysis plan are not reported. Without these details, readers cannot fully assess the intended inferential framework.

Finally, enrollment, endpoint-specific denominators, and termination status answer different questions. Enrollment does not mean every participant contributed to every outcome, while termination alone does not reveal why the study stopped. Careful interpretation keeps these distinctions intact and avoids treating isolated counts or p-values as complete evidence.

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.

Several limitations specific to this record constrain interpretation. First, the primary outcome is reported for the open-label components and is presented as counts by cohort. There is no posted primary comparison with placebo, and no confidence intervals or p-value are reported for those counts. Second, the primary measure is a qualifying 56-day interval within the first 28 weeks, whereas the available double-blind secondary measures use other observation periods or endpoint definitions.

Third, the double-blind secondary comparisons are unadjusted and have confidence intervals that include zero. The record does not report how multiplicity was handled or whether these outcomes were intended to be confirmatory. No reported analyses are listed for the secondary comparisons. The estimates should not be promoted to a definitive conclusion beyond what their uncertainty permits.

Fourth, the registry reports enrollment of 184, but the analysis denominators vary by component and endpoint. Participant flow, reasons for exclusions, outcome completeness, and missing-data methods are not reported in the registry record. The FAS definition is stated for the primary endpoint, but further details about how it was applied are not given.

Fifth, the study is terminated, but the reason for termination, any impact on follow-up, and the relationship between termination and the posted analyses are not reported. The record also lacks the trial’s sample-size justification, statistical analysis plan, interim analysis information, and detailed allocation and masking procedures. These gaps prevent a full assessment of whether the analyses match the planned design.

Safety counts are also limited: the registry does not provide exposure-adjusted rates, event timing, or causal attribution in the information. The serious-event percentages listed by term cannot replace group-level risk estimates. These limitations describe gaps in the record and do not establish what methods were used outside the reported information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety of Roxadustat for Treatment of Anemia in Participants With Lower Risk Myelodysplastic Syndrome With Low Red Blood Cell Transfusion Burden — NCT03263091.
• Registry record last updated 2024-08-01; status last verified 2024-07.
• Results first posted 2024-08-01.
• 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

NCT03263091 is a Phase 3, randomized, quadruple-masked, parallel study of roxadustat and placebo for anemia in participants with lower-risk MDS and low RBC transfusion burden. The registry lists enrollment of 184 and status as terminated. The primary outcome counts participants achieving at least 56 consecutive days of RBC transfusion independence since first dose in the first 28 weeks. Results are posted for open-label cohorts, without a reported placebo comparison or uncertainty estimates.

Three double-blind secondary comparisons report unadjusted risk differences and confidence intervals; each interval includes zero. The registry lists serious adverse event and death counts by component and group. The reason for termination, multiplicity strategy, missing-data methods, sample-size justification, and detailed statistical plan are not reported in the registry record.