A Study to Assess the Effect of Ticagrelor in Reducing the Number of Days With Pain in Patients With Sickle Cell Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Effect of Ticagrelor in Reducing the Number of Days With Pain in Patients With Sickle Cell Disease (NCT02482298), a randomized phase 2 study. The primary outcome is Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary.

2. Clinical Question

The main question is about pain-day frequency, not simply whether pain occurred at any point during the study. The endpoint expresses pain days as a proportion of days and compares change over the specified period. The registry also lists pain intensity and analgesic use among the study’s concerns, but the primary question is the change in the proportion of days with pain.

3. Trial Design

The registry describes a randomized, double-blind, double-dummy, parallel-group, multicenter Phase IIb study. Its official title identifies a comparison of ticagrelor with placebo in young adults with sickle cell disease. The sponsor is AstraZeneca, and the study status is completed. The recorded start date is 2015-07-09 and the primary completion date is 2016-11-16.

Enrollment was 87. Participants were assigned to placebo or one of two ticagrelor regimens. The registry’s primary efficacy analysis included randomized patients with at least 1 eDiary record after dosing, and says participants were analyzed according to their randomized investigational product. The arm counts reported for the primary outcome are 30 for placebo, 27 for the 10 mg ticagrelor regimen, and 30 for the 45 mg ticagrelor regimen. These are the outcome analysis counts, not a separate statement about all randomized participants.

Randomization means allocation was intended to be determined by chance rather than by clinical selection. Blinding is intended to reduce the influence of treatment knowledge on participant reporting and study conduct. The double-dummy description indicates that placebo was used in conjunction with the active regimen structure; details of how the masking was implemented are not reported in the registry record. The record identifies the study as multicenter but does not report the number or locations of centers.

The registry lists five outcome measures and four analyses. It reports two mixed-model comparisons for the primary endpoint, each against placebo, with 90% confidence intervals. A detailed statistical analysis plan, the randomization method, allocation concealment details, and the rationale for the enrollment target are not reported in the registry record. The posted record therefore supports a description of the design and reported estimates, but not a reconstruction of all trial procedures.

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: The study duration was approximately 18 weeks, consisting of a screening period including a 4-week single-blind placebo treatment for baseline assessments, a 12-week double-blind randomised treatment period, and a 2-week follow-up period. A total of 87 patients were randomized

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.

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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary, measured over Baseline through Week 12.

The primary endpoint is the change in the proportion of days with pain due to sickle cell disease, measured by eDiary from baseline through Week 12. It represents how frequently participants reported pain across the observation period, expressed as a proportion of days rather than as a single pain rating. The registry’s stated objective was to investigate whether two ticagrelor doses reduced the number of days with pain relative to placebo.

A proportion-based endpoint can summarize recurring symptoms over time. It makes the frequency of reported pain the target of the comparison and differs from an endpoint that measures the intensity of the worst pain on a particular day. The eDiary is the recorded source for this endpoint, so completeness and timing of entries matter to the information available for analysis. The registry’s efficacy population required at least 1 post-dose eDiary record, but the amount and pattern of missing diary data are not reported in the registry record.

The endpoint is reported as a least-squares mean change for each group, with a 90% confidence interval. The sponsor’s reported contrasts are mixed-model mean differences in final values. These summaries address related but distinct aspects of the analysis: group-level change estimates and model-based comparisons. A confidence interval communicates uncertainty around an estimate; it is not a guarantee that the true value lies within the interval. The endpoint describes recorded pain-day frequency, not every aspect of sickle cell disease or pain burden.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is summarized using least-squares means. In general, a least-squares mean is a model-based estimate of a group mean, rather than necessarily a simple arithmetic average of all recorded values. Such estimates can depend on the statistical model and the data included. The registry reports the endpoint as a change in the proportion of days with pain, and separately reports mixed-model comparisons of final values. The detailed model specification, including its covariates and assumptions, is not reported in the registry record.

A confidence interval gives a range of values that are reasonably compatible with the observed data under the model and its assumptions. In repeated use, intervals at a stated confidence level would cover the underlying quantity at that rate if the method’s assumptions held. An interval is not a probability statement about a fixed true value after the data have been observed. For the posted primary contrasts, the 90% intervals include zero, so the data do not precisely distinguish the reported comparisons from no difference at that confidence level. The interval’s endpoints also show that effects in either direction remain compatible with the estimates.

The registry’s group estimates and its contrasts answer different questions. An arm-level change describes the estimated change from baseline in that arm. A between-arm contrast asks whether the outcome differs between an active regimen and placebo. Improvement within an arm cannot establish that the intervention caused the improvement, because the placebo arm may also change over the same period. Randomized comparisons are the relevant basis for assessing differences between assigned groups.

The sponsor reports mixed-model analyses for the primary comparisons. In general, mixed models can accommodate structured observations and model relationships among measurements, depending on their specification. The registry does not report enough model details to assess which repeated-measure structure or covariate adjustments were used. The sponsor’s own analysis is therefore the primary source for those model-based contrasts. The posted record gives no p-values for these analyses, so none should be inferred from the estimates or intervals.

The secondary endpoint of average daily worst pain is a continuous summary, with means and standard deviations reported for each group. The posted unadjusted recalculations compare the group means using simple summary-statistic methods. In general, an unadjusted comparison does not account for other variables or multiple testing, and it need not reproduce a model-based analysis. Its role is descriptive and exploratory, not a replacement for the sponsor’s analysis. No sponsor-reported analysis for this secondary endpoint is listed in the record.

The posted planning illustrations use the observed secondary mean differences as a starting point, then consider stated fractions of those observed effects. In general, power is the chance that a specified statistical procedure will detect an effect of a given size under stated assumptions. A planning calculation asks how many participants per arm might be needed for a target power under those assumptions. It is not observed power and does not establish that the original study was designed around that effect. The registry explicitly says the illustration uses a two-sided significance level of 0.05, equal allocation, and a normal approximation; its effect sizes are fractions of the observed effect. The trial’s own design assumptions and sample-size justification are not reported in the registry record.

Over-dispersion is a general concern when observed variability is greater than a model assumes. If a method assumes less variability than the data contain, its uncertainty estimates may be too small, making confidence intervals too narrow and tests too optimistic. For outcomes with variable participant responses or repeated diary records, the appropriateness of the variability model matters. The registry record does not report a specific over-dispersion assessment for these outcomes, so no conclusion about it can be drawn from the posted summary statistics alone.

Multiplicity is the general problem that arises when multiple outcomes, groups, or comparisons are tested. With many opportunities to find a nominally notable result, unadjusted tests can overstate the strength of evidence. The record lists multiple outcomes and more than one primary comparison but does not report whether a hierarchy, correction, or other multiplicity procedure was used. Accordingly, unadjusted secondary p-values and exploratory comparisons should not be treated as confirmatory evidence.

Missing outcome data can affect interpretation when diary records are absent, especially if missingness is related to pain or treatment assignment. The primary efficacy population required at least 1 post-dose diary record, but the registry does not describe the extent, timing, or reasons for missing records, nor its method for handling them. General statistical methods may address missing data under assumptions, but the assumptions and methods used are not reported in the registry record. This uncertainty limits assessment of how fully the analyses represent all randomized participants.

10. Analyses Reported by the Sponsor

The sponsor’s primary comparisons are mixed-model estimates of mean differences in final values. For placebo compared with the 10 mg ticagrelor regimen, the reported difference is 0.045, with a 90% confidence interval from -0.061 to 0.151. For placebo compared with the 45 mg regimen, it is 0.080, with a 90% confidence interval from -0.023 to 0.183. The record gives no p-values for either comparison.

The unadjusted recalculations, where available, are simple calculations from posted summary statistics. They are not equivalent to the sponsor’s mixed-model analysis: the sponsor’s model may account for features of the data that a summary-statistic calculation does not. The sponsor’s own analysis takes precedence when interpreting the registry’s reported primary comparisons. No discrepancy is flagged in the record, but that does not make the unadjusted and model-based methods interchangeable.

The secondary endpoint of average daily worst pain has posted summary statistics and unadjusted comparisons, but no sponsor-reported analysis is listed for it. Those recalculations should be understood as exploratory summaries, not as sponsor-confirmed results. The registry does not report a sponsor analysis for the listed analgesic-use endpoint either.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome measures and analyses, including two primary comparisons against placebo. It does not report whether the comparisons were arranged in a testing hierarchy, whether any adjustment for multiplicity was used, or how the secondary outcomes were intended to contribute to the overall conclusions. Without that information, nominally favorable findings among several outcomes would warrant caution. The posted primary estimates should be interpreted through their confidence intervals, and unadjusted secondary results should be treated as exploratory rather than as a set of independent confirmations.

Missing diary information is particularly relevant because the primary endpoint depends on repeated eDiary reporting. The registry defines the efficacy analysis set as randomized patients with at least 1 eDiary record after dosing. It does not report how many randomized participants lacked a post-dose record, how many diary entries were missing, when records were missing, or why they were absent. It also does not describe imputation, likelihood-based handling, or sensitivity analyses for missing data. These details are not reported in the registry record.

In general, missing-data methods rely on assumptions about why observations are absent. If missingness is related to pain experience, ability to complete the diary, or assigned treatment, the observed records may not fully represent the intended outcome. The registry does not provide enough information to determine whether missingness was balanced between groups or whether the analysis addressed informative missingness.

The primary population is not described as all randomized participants; it requires at least 1 post-dose eDiary record and uses assignment to randomized investigational product. This definition should be kept in mind when reading the arm counts and estimates. The detailed analysis population rules beyond that definition, the treatment of protocol deviations, and the use of sensitivity analyses are not reported in the registry record. The sample-size justification and any interim analyses are also not reported in the registry record.

12. 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 5% 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 (19.2%), gastroenteritis (6.7%), lower respiratory tract infection (3.8%), arthralgia (3.8%), headache (3.8%).

The registry reports serious adverse events for groups of 30, 26, and 30 participants at risk. The numbers affected were 6 in the placebo group, 6 in the 10 mg ticagrelor group, and 5 in the 45 mg ticagrelor group. These are counts of participants with a serious adverse event, not counts of all individual events. The record also lists serious-event terms and percentages, including sickle cell anaemia with crisis at 19.2%, gastroenteritis at 6.7%, and lower respiratory tract infection, arthralgia, headache, and acute chest syndrome each at 3.8%.

These summaries should be read descriptively. The groups are small, and the registry record does not provide comparative safety analyses or enough detail to establish whether differences between groups are meaningful. Serious adverse events can reflect the underlying disease as well as other circumstances; a listed event does not by itself establish that the assigned treatment caused it. Deaths are recorded as null, which means death counts are not reported in the registry record; it should not be interpreted as a reported count of zero. The safety figures do not establish overall safety or risk beyond the recorded study information.

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

The posted results describe changes in eDiary-reported pain-day proportions during the study and model-based comparisons of each ticagrelor regimen with placebo. The arm estimates are negative, while the sponsor’s comparative confidence intervals include zero. The data therefore leave uncertainty about the direction and size of any difference between the assigned groups. The registry provides no p-values for the primary comparisons, and none are needed to understand that the posted intervals do not precisely rule out no difference.

These results do not show that an observed within-group change was caused by the assigned regimen. A randomized comparison is the relevant contrast, and the placebo group also had a negative change estimate. The estimates concern the specified pain-day endpoint over baseline through Week 12; they do not summarize every dimension of sickle cell disease, pain intensity, analgesic use, or longer-term outcomes.

The record is a Phase IIb study with an enrollment of 87 and reported primary outcome counts of 30, 27, and 30 across the three groups. The size and uncertainty of the estimates should be considered alongside the limited detail about missing diary data, analysis assumptions, and multiplicity. The registry’s results cannot establish whether other patient groups, regimens, follow-up periods, or settings would have similar outcomes.

No medical conclusion should be drawn from these statistics alone. The registry’s posted estimates document what was observed and modeled in this study, not a definitive answer about treatment effectiveness. The incomplete reporting of some secondary results and analysis details further limits the conclusions that can be supported from the record.

14. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the distinction between change within a group and a randomized comparison between groups. Each arm’s pain-day proportion declined from baseline according to the posted estimates, but that pattern alone does not identify an intervention effect. The sponsor’s contrasts, with 90% confidence intervals that include zero, are the relevant estimates for comparing each ticagrelor regimen with placebo.

It also shows why uncertainty matters. A point estimate provides a single central summary, while a confidence interval displays a range of values compatible with the data and model. Here, the comparative intervals allow for effects in either direction. A reader should not treat the sign of a point estimate as a conclusive answer when its uncertainty is substantial.

The endpoint relies on eDiary reporting, which creates a direct connection between measurement completeness and analysis. The registry defines an efficacy population using post-dose diary records, but does not describe the extent or handling of missing records. That gap limits assessment of how the available observations represent the randomized population.

Finally, the record separates sponsor-reported primary analyses from unadjusted secondary calculations and planning illustrations. Those have different roles. A model-based primary contrast, an exploratory secondary comparison, and a sample-size planning exercise are not interchangeable forms of evidence. Keeping them distinct helps prevent overinterpretation of results from a small Phase IIb study.

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 registry record leaves several trial-specific uncertainties. Although it describes the study as randomized, double-blind, double-dummy, parallel-group, and multicenter, it does not report the randomization procedure, allocation concealment details, or how masking was maintained. The number and locations of study centers are not reported in the registry record.

The primary efficacy population required at least 1 post-dose eDiary record, but the record does not report the number or pattern of missing diary entries, reasons for missingness, or methods used to address missing data. Since the primary outcome depends on diary reports, those omissions make it difficult to assess whether the observed records could differ systematically from unrecorded experiences.

The sponsor reports mixed-model comparisons, but the model specification, covariate adjustments, assumptions, and sensitivity analyses are not reported in the registry record. The record also does not report a multiplicity strategy despite listing multiple outcomes and comparisons. These gaps constrain evaluation of the model-based estimates and the weight to place on secondary findings.

Numerical results for the listed analgesic-use outcome are not reported in the registry record. The posted secondary pain-rating comparisons are unadjusted and have no sponsor-reported analysis listed. The reason for the enrollment target, original sample-size assumptions, interim analyses, and detailed statistical analysis plan are not reported in the registry record. These limitations mean that the posted results can be described, but the analysis cannot be fully reconstructed from the registry record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Assess the Effect of Ticagrelor in Reducing the Number of Days With Pain in Patients With Sickle Cell Disease — NCT02482298.
• Registry record last updated 2018-12-19; status last verified 2018-11.
• Results first posted 2017-12-14.
• 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.

19. Record Summary

NCT02482298 is a completed randomized, double-blind, double-dummy, parallel-group, multicenter Phase IIb study sponsored by AstraZeneca. It enrolled 87 participants and compared placebo with two ticagrelor regimens in young adults with sickle cell disease. The primary endpoint was change in the proportion of days with pain, measured by eDiary from baseline through Week 12.

The posted arm estimates were negative in all groups. Sponsor-reported mixed-model comparisons against placebo had 90% confidence intervals that included zero. The registry also lists secondary pain-rating and analgesic-use outcomes, but numerical results for the analgesic-use measure are not reported in the registry record. Missing-data procedures, multiplicity handling, detailed model specifications, and the sample-size justification are not reported in the registry record.