Study to Assess the Effect of Long-term Treatment With Voxelotor in Participants Who Have Completed Treatment in Study GBT440-031: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Assess the Effect of Long-term Treatment With Voxelotor in Participants Who Have Completed Treatment in Study GBT440-031 (NCT03573882), a na phase 3 study. The primary outcome is Number of Participants With Sickle Cell Disease (SCD)-Related Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

The study was designed as an extension of earlier voxelotor trials, rather than as a new randomized comparison. Its primary outcome concerns the number of participants with sickle cell disease-related treatment-emergent adverse events (TEAEs). The registry defines the relevant events through a set of preferred terms, including sickle cell anaemia with crisis, acute chest syndrome, pneumonia, priapism, and osteonecrosis.

The question is a safety-focused description of events during exposure to study drug. It does not, by itself, estimate what would have happened to the same participants without voxelotor. Because treatment assignment was not randomized in this extension and there was no concurrent control group, observed event counts cannot be interpreted as a controlled estimate of a treatment effect. The registry record does not report the primary endpoint result or an analysis comparing outcomes across groups.

3. Trial Design

This was a Phase 3, open-label extension study of voxelotor in people with sickle cell disease who had participated in voxelotor clinical trials. The study used a single-group model, with no masking and no allocation to a concurrent comparison group. The registry lists an enrollment of 179 participants. The sponsor was Pfizer.

Participants were to receive oral voxelotor at the highest dose, either 900 mg or 1500 mg, deemed safe by the Data Safety Monitoring Board. The record does not explain how a participant’s dose was selected or describe a dose-comparison plan. The prior-treatment categories in the adverse-event information identify participants by their treatment in GBT440-031; they do not establish randomized comparison arms in this extension.

The study start date was 2018-06-06, and the primary completion date was 2024-11-12. The study status is terminated. These dates and status describe the registry record; they do not establish why the study was terminated or whether all planned follow-up was completed.

The primary safety outcome counts participants with sickle cell disease-related TEAEs. Listed secondary outcomes include changes in hemoglobin level and percentage changes in reticulocytes, absolute reticulocytes, and indirect bilirubin at Week 48. The registry lists 10 outcome measures, but lists no outcome analyses. The registry record does not report a detailed statistical analysis plan, a sample-size justification, interim-analysis procedures, or the reasons for termination.

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: A total of 179 participants were enrolled in the study. The study was terminated as emerging clinical data observed in studies other than the current study (GBT440-034) indicated that risk profile of voxelotor in people with sickle cell disease (SCD) exceeded benefits observed in previously generated global research and required further assessment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety population included all enrolled participants who received treatment with study drug voxelotor in the current study.

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: Safety population included all enrolled participants who received treatment with study drug voxelotor in current study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Sickle Cell Disease (SCD)-Related Treatment Emergent Adverse Events (TEAEs), measured over From date of informed consent up to 28 days after last dose of study drug (maximum up to 300.7 weeks).

The primary endpoint is the number of participants with sickle cell disease-related treatment-emergent adverse events. A treatment-emergent adverse event was defined as an adverse event with onset on or after informed consent through 28 days after the last dose of study drug. The stated timeframe extends from informed consent until 28 days after the final dose, with a maximum of 300.7 weeks.

The registry defines an adverse event as an untoward medical occurrence associated with drug use, whether or not it is considered drug-related. For this endpoint, sickle cell disease-related events include the preferred terms sickle cell anaemia with crisis, acute chest syndrome, pneumonia, priapism, and osteonecrosis. The endpoint counts participants who experienced any qualifying event; it is not a count of all event episodes.

Participant counts are a direct way to describe how many people in the defined safety population experienced an event during observation. In an extension study, such a safety measure can describe events recorded while participants are exposed to study drug over follow-up. It does not establish that the drug caused an event, and, without a concurrent comparison group, it does not quantify how the frequency differs from what would occur under another treatment or no treatment.

The registry record does not report the primary endpoint result. The adverse-event information separately lists serious adverse events by prior-treatment category, but those figures are not identified as the primary endpoint result. They should not be substituted for the count of participants with any SCD-related TEAE.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of endpoint is this? The primary outcome is a participant count: the number of people with at least one SCD-related treatment-emergent adverse event in the defined period. This is a binary status for each participant—an event was recorded or was not recorded—summarized as a count across the safety population. It is not the total number of separate event episodes, nor does the count alone describe how many events each affected participant experienced.

The endpoint definition sets a time window and a list of qualifying SCD-related preferred terms. The registry defines TEAEs by onset from informed consent through 28 days after the last dose, and gives a maximum observation period of 300.7 weeks. Applying an endpoint definition consistently matters because event counts depend on which events qualify, the time window, and which participants are included. The record states these definitions, but does not give the primary count or explain whether any further adjudication procedures were used.

What does a count tell the reader? A count is easy to understand as a description of the observed safety population. A count without a denominator does not show the proportion of participants affected. A count paired with the number at risk gives context about the population under observation, but interpretation still depends on follow-up time, event definitions, and complete ascertainment. General statistical explanation: when follow-up durations vary, a simple participant count may not capture differences in time exposed to risk; time-to-event methods can address event timing and censoring when suitable data and analyses are reported. The registry record does not report a time-to-event analysis for the primary endpoint.

Why does study design matter? This extension is open label and uses a single-group model. There is no concurrent randomized control group in the listed design. The adverse-event categories use participants’ prior treatment in GBT440-031, but prior treatment labels do not make those groups randomized comparisons within this study. A difference between category counts can be described, but cannot by itself be attributed to the current study drug or interpreted as a causal effect. Participants may differ in their prior experience, follow-up, or other characteristics; the record does not provide adjusted comparisons that address such differences.

How should uncertainty be assessed? General statistical explanation: an estimate is more informative when accompanied by an uncertainty measure, such as a confidence interval. A confidence interval expresses the range of estimates compatible with the data and the assumptions of the method; it does not remove design limitations or establish causality. The registry record lists no analyses and reports no confidence intervals or p-values for the primary outcome. Therefore, a statistically supported comparison or a precision assessment cannot be reconstructed from the posted record.

What is and is not described about the analysis? The record identifies the safety population as enrolled participants who received voxelotor in the current study. That definition tells the reader which population is intended for safety reporting. It does not give the number included in the endpoint analysis, the number with complete follow-up, or the handling of participants whose event status or follow-up information was unavailable. Those analysis details are not reported in the registry record.

The record lists 10 outcome measures, including Week 48 laboratory outcomes, but no outcome analyses. It does not report the statistical methods used for those outcomes, the treatment of repeated measurements, or any covariate adjustment. General statistical explanation: repeated measurements on the same participant are related, so analyses of change over time generally need to account for that dependence. The record does not say whether or how such methods were used.

There is also no reported multiplicity strategy for considering several outcome measures. General statistical explanation: when many outcomes or tests are examined, the chance of at least one apparently unusual result can increase if no adjustment or prespecified hierarchy is used. The presence of multiple listed outcomes does not establish that multiple hypothesis tests were conducted; the record lists no analyses. No inference about multiplicity-adjusted findings is possible from the registry information.

The registry identifies the study as terminated, but does not report the reason, whether termination affected planned follow-up, or whether the analysis plan changed. General statistical explanation: stopping a study early or having incomplete follow-up can affect the amount and pattern of information available, but the consequences depend on the circumstances and analysis. Since the record does not describe these details, no specific impact on the endpoint can be determined.

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("Prior Treatment of Placebo in GBT440-031 (NCT03036", "Prior Treatment of Voxelotor 900mg in GBT440-031(N", "Prior Treatment of Voxelotor 1500 mg in GBT440-031")
n      <- c(62, 58, 58)
events <- c(47, 42, 42)
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  Prior Treatment of Placebo in GBT440-031 (NCT03036  62  47  75.8  63.3  85.8  63.8  84.8  63.8  84.7
ARM  Prior Treatment of Voxelotor 900mg in GBT440-031(N  58  42  72.4  59.1  83.3  59.8  82.2  59.7  82.2
ARM  Prior Treatment of Voxelotor 1500 mg in GBT440-031  58  42  72.4  59.1  83.3  59.8  82.2  59.7  82.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures, including the primary safety count and secondary laboratory outcomes at Week 48. It lists no outcome analyses. The registry record does not report whether a testing hierarchy, multiplicity adjustment, or other strategy was planned for interpreting multiple outcomes. Listing several outcomes does not show that each was statistically tested, and no conclusion about multiplicity-adjusted results can be drawn.

The safety population is described as all enrolled participants who received voxelotor in the current study. The record does not report the number of participants included in the primary endpoint analysis or how missing event information, incomplete follow-up, or withdrawal was handled. It also does not describe imputation or sensitivity analyses. These details are important because the available observations may not represent every participant’s full observation period, but the registry does not permit assessment of whether that occurred.

The status is terminated, while a primary completion date is listed. The registry record does not explain the reason for termination, its timing relative to follow-up, or whether it affected the planned analysis. It does not describe interim analyses or stopping rules. These omissions prevent a fuller assessment of how study conduct may have influenced the amount of available information.

General statistical explanation: missing-data methods rely on assumptions about why information is unavailable and how missing observations relate to outcomes. Different assumptions can lead to different estimates. Without the missing-data approach and analysis population details, the primary outcome’s completeness and robustness cannot be assessed from 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: sickle cell anaemia with crisis (58.1%), acute chest syndrome (12.9%), priapism (9.5%), anaemia (8.6%), pneumonia (6.5%).

The serious adverse-event information is organized by prior treatment in GBT440-031, not by randomized assignment in the extension. The prior-placebo category lists 62 at risk and 42 affected; the prior-voxelotor 900mg category lists 58 at risk and 35 affected; and the prior-voxelotor 1500mg category lists 58 at risk and 26 affected. The record lists deaths of 3, 2, and 5 in the same respective categories. These are reported counts, not evidence that one category had a higher or lower causal risk.

The registry also lists serious-event terms with percentages: sickle cell anaemia with crisis (58.1%), acute chest syndrome (12.9%), priapism (9.5%), anaemia (8.6%), pneumonia (6.5%), and osteomyelitis (4.8%). The denominator for these percentages is not reported in the registry record’s adverse-event information, so they should be read as listed term percentages rather than as percentages of all enrolled participants.

Serious adverse events and the primary endpoint are not interchangeable. The primary endpoint counts participants with specified SCD-related TEAEs, while the adverse-event information concerns serious events and separately lists terms and deaths. The record does not establish that these categories have identical definitions or populations. The counts are descriptive and do not show event causation or a treatment comparison.

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

The record establishes that an open-label, single-group extension study of voxelotor was registered for participants with sickle cell disease who had participated in earlier voxelotor trials. It describes the intended dose range, the safety population definition, the primary safety endpoint, and a set of secondary laboratory outcomes. It also provides adverse-event counts organized by prior treatment category.

It does not report the result for the primary endpoint: the number of participants with SCD-related TEAEs. It lists no outcome analyses, and does not provide an endpoint estimate with a confidence interval or p-value. As a result, the primary outcome’s observed magnitude and statistical precision cannot be assessed from the registry record.

The serious-event counts and listed event-term percentages are descriptive. Because there is no concurrent control group and the prior-treatment categories are not like-for-like randomized extension arms, these figures cannot establish that voxelotor caused or prevented events, or that event risk differed because of treatment. The death counts are also not accompanied by cause information in the listed adverse-event details.

General statistical explanation: a study can describe what was observed among participants while still being unable to identify what would have happened to those same participants under a different treatment. A controlled design and an appropriate analysis are generally needed to support causal comparisons. This extension’s listed design does not provide that concurrent contrast.

The registry record also does not explain why the study was terminated, report the handling of missing data, or describe a statistical analysis plan. Those gaps constrain interpretation, but they do not show that any particular problem occurred. The sound conclusion is limited to the study design and descriptive information recorded: the primary endpoint result and its uncertainty are not reported, and the posted safety figures do not provide a controlled estimate of treatment effect.

14. Why This Trial Matters Statistically

This study illustrates an important distinction in clinical-trial interpretation: a safety endpoint can be clearly defined without a posted result being available for evaluation. The primary endpoint specifies which participants count, which events qualify, and the period during which an event is considered treatment-emergent. Those definitions are essential for consistent reporting, but they do not substitute for the endpoint count, an analysis population, or an estimate of uncertainty.

The extension design also makes the role of a comparator especially clear. Participants were followed in a single-group, open-label study. The adverse-event information divides participants according to prior treatment in GBT440-031, but those labels do not create randomized comparison groups in the extension. This matters because raw counts can be useful for describing observed safety experience while remaining unsuitable for estimating a causal difference between treatments.

The record further illustrates why denominators and analysis details matter. Counts are reported for serious events by category, and percentages are listed for serious-event terms. However, the listed information does not identify the denominator for those term percentages or provide the primary endpoint count. The reader therefore needs to keep each measure’s definition and reporting context distinct rather than treating all event figures as interchangeable.

Finally, the registry lists multiple outcomes and a terminated status but no outcome analyses or detailed statistical plan. The absence of those details limits assessment of multiplicity, missing-data handling, and precision. This is a useful example of how registry entries can document a study’s design and outcome definitions while leaving key information needed for inferential interpretation unreported.

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 central limitation for interpreting results is that the registry record does not report the primary endpoint result or any outcome analyses. It therefore does not provide the primary count, an uncertainty estimate, or a statistical comparison. The posted serious-event counts are not a substitute for that endpoint result.

The study is open label and single group, with no concurrent randomized comparator. Prior-treatment categories are descriptive histories, not like-for-like control groups. Consequently, the adverse-event information cannot support a controlled treatment-effect estimate. The record does not describe adjustment for differences among those categories.

The safety population is defined as enrolled participants who received study drug, but the record does not give the primary endpoint analysis population size or explain how incomplete observation, missing event information, or withdrawal was handled. The listed maximum observation period does not describe each participant’s actual follow-up duration. The registry does not report event-specific exposure time or a time-to-event analysis.

The listed serious-event term percentages have no denominator described in the adverse-event information. The death counts are not accompanied there by cause details. The record also does not explain the reason for termination, whether termination affected planned follow-up, or whether analyses were changed. It does not report a sample-size justification, interim-analysis procedures, or a detailed statistical plan. These are limits of what can be interpreted from the registry record, not evidence that any particular procedure or event was absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Assess the Effect of Long-term Treatment With Voxelotor in Participants Who Have Completed Treatment in Study GBT440-031 — NCT03573882.
• Registry record last updated 2025-11-18; status last verified 2025-11.
• Results first posted 2025-11-18.
• 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

NCT03573882 is a Phase 3, open-label, single-group extension study of oral voxelotor in participants with sickle cell disease who had taken part in voxelotor clinical trials. The listed enrollment is 179, and participants were to receive the highest dose—900 mg or 1500 mg—deemed safe by the Data Safety Monitoring Board. The sponsor is Pfizer; the status is terminated.

The primary outcome is the number of participants with SCD-related TEAEs, assessed from informed consent through 28 days after the last dose, up to a maximum of 300.7 weeks. Listed secondary outcomes include Week 48 changes in hemoglobin, reticulocytes, absolute reticulocytes, and indirect bilirubin. The registry lists 10 outcome measures and no outcome analyses.

Serious adverse-event counts are reported by prior-treatment category, but there is no concurrent randomized comparison. The primary endpoint result, analysis details, and reason for termination are not reported in the registry record.