This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
THALES was a completed, randomized, parallel-group, quadruple-masked phase 3 trial in acute ischaemic stroke and transient ischaemic attack. The registry reports 11,016 enrolled participants, two intervention arms, seven posted statistical analyses, and a primary analysis comparing ticagrelor with placebo for subsequent stroke or death from randomisation through visit 3.
| Feature | THALES |
|---|---|
| Trial name | THALES |
| NCT identifier | NCT03354429 |
| Therapeutic area | Neurology |
| Conditions | Acute Ischaemic Stroke; Transient Ischaemic Attack |
| Phase | Phase 3 |
| Status | Completed |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Primary purpose | Treatment |
| Enrollment | 11,016 |
| Lead sponsor | AstraZeneca |
| Sponsor type | Industry |
| Start | January 22, 2018 |
| Primary completion | December 13, 2019 |
2. Clinical Question
The central statistical question was whether ticagrelor differed from placebo with respect to the registered composite endpoint of subsequent stroke or death among participants with acute ischaemic stroke or transient ischaemic attack, measured from randomisation through visit 3.
Population
Participants with acute ischaemic stroke or transient ischaemic attack enrolled in the phase 3 THALES trial.
Intervention
Ticagrelor.
Comparator
Placebo.
Primary question
How does ticagrelor compare with placebo for the composite of subsequent stroke or death from randomisation through visit 3?
3. Trial Design
Ticagrelor
- Intervention type: drug
- Randomized treatment arm
- Compared with placebo in the posted analyses
Placebo
- Intervention type: drug
- Randomized comparator arm
- Reference group in the posted effect measures
4. Endpoints
The registry lists one primary endpoint and seven posted outcome measures/statistical analyses. The primary endpoint is registered as binary, while its posted statistical analysis uses a time-to-event formulation and a Cox proportional-hazards model.
| Endpoint | Registry definition / time frame | Analysis |
|---|---|---|
| Composite of Subsequent Stroke or Death | Participants with subsequent stroke or death; from randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
| Ischaemic Stroke | From randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
| Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3 | Visit 3 (day 30-34) | Logistic regression; odds ratio |
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe | From randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
| ICH or Fatal Bleeding Event | From randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe | From randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
| Premature Permanent Discontinuation of IP Due to Bleeding | From randomisation (day 1) to visit 3 (day 30-34) | Cox proportional-hazards model; hazard ratio |
5. Statistical Methodology
Primary analysis population
The primary endpoint analysis used the full analysis set including all randomised patients. The analysis text also identifies the intention-to-treat principle. This is important because the treatment comparison remains anchored to the randomized assignment rather than being redefined according to subsequent treatment exposure.
Cox proportional-hazards model
The registry reports a Cox regression analysis for the primary composite and for the other time-to-event endpoints. The effect measure is the hazard ratio, with placebo as the reference group.
The hazard ratio compares the modeled instantaneous event rates between treatment groups. In the THALES analyses, an HR below 1 indicates a lower estimated hazard for ticagrelor relative to placebo under the fitted model.
Logistic regression
The mRS >1 endpoint at visit 3 was analysed with logistic regression. The posted analysis specifies covariate adjustment for NIHSS score and history of stroke (yes/no). Patients with missing mRS score or missing covariates, NIHSS score, and history of stroke were addressed in the analysis-population wording in the registry record.
The exponentiated treatment coefficient can be interpreted as an odds ratio comparing ticagrelor with placebo after adjustment for the listed covariates.
Effect measures
Two principal effect measures appear in the posted analyses: hazard ratios for time-to-event endpoints and an odds ratio for the binary mRS endpoint. These measures should not be treated as interchangeable.
| Measure | Used in THALES for | What it compares |
|---|---|---|
| Hazard ratio | Primary composite, ischaemic stroke, bleeding endpoints, discontinuation due to bleeding | Relative modeled event hazard over time |
| Odds ratio | mRS score >1 at visit 3 | Relative odds of the binary outcome |
6. Results: Primary Endpoint
Composite of Subsequent Stroke or Death
The primary analysis compared ticagrelor with placebo in the full analysis set including all randomised patients. The registered time frame was from randomisation (day 1) to visit 3 (day 30-34), and the posted analysis used a Cox proportional-hazards model.
Hazard ratio for subsequent stroke or death
95% CI: 0.71–0.96 · P = 0.015 · Two-sided
Reference group: placebo
An HR of 0.83 means that, under the fitted Cox model, the estimated instantaneous hazard of the composite event was 0.83 times that in the placebo group. Expressed as a simple relative interpretation, this corresponds to a 17% lower estimated hazard for ticagrelor relative to placebo.
The HR does not mean that 17% of participants avoided stroke or death, that every participant experienced a 17% reduction in risk, or that the absolute probability of the event was reduced by 17 percentage points. Hazard is a time-dependent rate concept, not an individual probability.
The 95% CI of 0.71–0.96 describes the statistical uncertainty around the estimated hazard ratio under the analysis framework. It is narrower than an interval extending substantially above 1, but it does not describe the range of individual treatment effects across participants.
The P = 0.015 value addresses evidence against the null hypothesis within the prespecified superiority framework; it does not measure the size or clinical importance of the treatment effect. Effect size and uncertainty are better conveyed jointly by the HR and its confidence interval.
Because this is a Cox analysis, interpretation also depends on the model's proportional-hazards assumption. A single HR summarizes the relative hazard over the analysis period and can be incomplete if the relative hazards change materially over time. The analysis population is also important: this result comes from the full analysis set including all randomised patients.
7. Secondary Endpoint Results
Ischaemic Stroke
The secondary endpoint of ischaemic stroke was analysed from randomisation (day 1) to visit 3 (day 30-34) using a Cox proportional-hazards model in the full analysis set including all randomised patients.
Hazard ratio for ischaemic stroke
95% CI: 0.68–0.93 · P = 0.004 · Two-sided
Reference group: placebo
The HR of 0.79 corresponds to a 21% lower estimated hazard of ischaemic stroke for ticagrelor relative to placebo under the Cox model. This is a relative hazard interpretation, not a statement that 21% of participants were protected from stroke or that absolute stroke risk fell by 21 percentage points.
The 95% CI of 0.68–0.93 quantifies uncertainty around the estimated relative hazard. The P-value of 0.004 is evidence evaluated against the relevant null hypothesis; it is not a measure of effect magnitude. As with the primary analysis, the interpretation assumes that the Cox model provides an appropriate representation of the time-to-event relationship.
Number of Participants With Modified Rankin Scale (mRS) Score >1 at Visit 3
This binary endpoint was measured at visit 3 (day 30-34). The posted analysis used logistic regression with NIHSS score and history of stroke (yes/no) included as covariates. The analysis population was the full analysis set including all randomised patients, with the registry specifying exclusions related to missing mRS score or missing covariate information.
Adjusted odds ratio for mRS score >1
95% CI: 0.89–1.07 · P = 0.613 · Two-sided
Reference group: placebo
An adjusted OR of 0.98 indicates that the modeled odds of having an mRS score >1 at visit 3 were estimated to be 0.98 times the corresponding odds in the placebo group after adjustment for NIHSS score and history of stroke.
The OR is close to 1, and the 95% CI of 0.89–1.07 spans 1. The P-value of 0.613 does not provide evidence of a statistically detectable difference under the reported superiority analysis. This should not be translated into proof that the treatment groups are identical; the confidence interval expresses the uncertainty around the estimated comparison.
An odds ratio is also not a risk ratio. If the outcome probability is not small, the numerical value of an OR can differ materially from the corresponding risk ratio. The covariate adjustment is another important part of the result: this is an adjusted estimate rather than an unadjusted comparison of proportions.
8. Bleeding and Treatment Discontinuation Results
The registry contains four additional prespecified analyses involving bleeding or premature permanent discontinuation of investigational product due to bleeding. Each used the full analysis set including all randomised patients and a Cox proportional-hazards model, with placebo as the reference group.
| Endpoint | Hazard ratio | 95% CI | P-value |
|---|---|---|---|
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Severe | 3.99 | 1.74–9.14 | 0.001 |
| ICH or Fatal Bleeding Event | 3.66 | 1.48–9.02 | 0.005 |
| Bleeding Event That Fulfils Serious Adverse Event Criteria and is Categorised as GUSTO Moderate/Severe | 3.27 | 1.67–6.43 | <0.001 |
| Premature Permanent Discontinuation of IP Due to Bleeding | 4.80 | 3.28–7.02 | <0.001 |
How to interpret these hazard ratios
Each estimate is above 1, meaning the estimated hazard was higher in the ticagrelor group than in the placebo group under the corresponding Cox model. For example, an HR of 3.99 means an estimated instantaneous hazard approximately 3.99 times that of placebo; it does not mean that 399% of participants experienced the event or that the absolute probability was 3.99 times higher.
The confidence intervals are important because the bleeding endpoints are event-specific estimates rather than measurements of all adverse outcomes. The intervals for all four posted bleeding-related analyses lie above 1, while their P-values are reported as 0.001, 0.005, <0.001, and <0.001, respectively.
These results also illustrate why a clinical trial cannot be reduced to one efficacy statistic. The primary composite and ischaemic-stroke analyses have HRs below 1, while the reported bleeding analyses have HRs above 1. Statistical interpretation therefore requires examining the endpoint definitions, effect measures, confidence intervals, and time frame separately.
9. Safety Results
The registry data provide serious adverse event counts by randomized treatment arm in terms of affected participants and participants at risk.
| Safety measure | Ticagrelor | Placebo |
|---|---|---|
| Serious adverse events | 571 / 5,523 affected / at risk | 609 / 5,493 affected / at risk |
The serious-adverse-event figures should be kept distinct from the specific bleeding endpoints above. The bleeding analyses concern narrowly defined outcomes and use time-to-event models, whereas the safety summary here reports affected participants and participants at risk for serious adverse events.
10. Statistical Methods Explained
Why was a Cox proportional-hazards model used?
The primary composite and several secondary or prespecified safety endpoints are time-to-event outcomes. A Cox model uses both whether an event occurred and when it occurred, while accommodating censoring. That makes it suitable for comparing event hazards over a defined follow-up period rather than reducing the analysis to a single binary count.
What does the primary hazard ratio of 0.83 mean?
Because placebo is the reference group, an HR of 0.83 indicates that the modeled instantaneous hazard of subsequent stroke or death was estimated at 83% of the placebo hazard. Equivalently, 1 − 0.83 = 0.17, or a 17% lower estimated hazard. This is not the same as a 17-percentage-point reduction in event probability.
Why is the confidence interval important?
The estimate 0.83 is a single point estimate. Its 95% CI of 0.71–0.96 shows the uncertainty around that estimate under the statistical model. A confidence interval is therefore more informative than the point estimate alone: it communicates both the estimated effect and the range of values compatible with the sampling uncertainty represented by the analysis.
Why doesn't the P-value measure effect size?
The P-value evaluates the evidence against a null hypothesis within the specified statistical framework. It is affected by both the observed data and the amount of information available. Two studies can have similar effect estimates but different P-values, or different effect estimates with similar P-values. The HR or OR and its confidence interval are therefore necessary to describe the magnitude and precision of the estimated treatment effect.
Why was logistic regression used for the mRS endpoint?
The registry describes the mRS >1 endpoint as binary at visit 3, making logistic regression a natural model for the probability of belonging to one of the two outcome categories. The posted analysis additionally adjusted for NIHSS score and history of stroke, so the resulting OR of 0.98 is an adjusted comparison rather than a simple unadjusted treatment-group ratio.
Why are the bleeding hazard ratios interpreted differently from the primary hazard ratio?
The mathematical interpretation of the HR is the same, but the endpoint differs. An HR below 1 for the primary composite indicates a lower modeled hazard for ticagrelor relative to placebo, whereas an HR above 1 for a bleeding endpoint indicates a higher modeled hazard. Statistical interpretation must therefore begin with the precise endpoint definition before assigning clinical meaning to the direction of the estimate.
11. Intention-to-Treat Analysis
The primary endpoint analysis used the full analysis set including all randomised patients, and the registry explicitly identifies intention-to-treat analysis as a concept in the analysis text. This is a central feature of randomized trial inference.
Preserves randomization
Analysing participants according to randomized assignment maintains the original treatment comparison created by randomization.
Handles post-randomization events conceptually
Participants do not cease to belong to their randomized group simply because subsequent events or treatment changes occur.
Primary analysis population
The posted primary analysis specifies the full analysis set including all randomised patients.
Not the same as every possible analysis
Safety and other endpoint-specific analyses can have different data-handling requirements, so the analysis population must always be checked for the endpoint being interpreted.
12. Covariate Adjustment for the mRS Endpoint
The logistic regression analysis for the number of participants with mRS score >1 at visit 3 included NIHSS score and history of stroke (yes/no) as covariates.
The purpose of covariate adjustment is to estimate the treatment association while accounting for prespecified or analysis-specified prognostic variables included in the model. The resulting OR should therefore not be interpreted as an unadjusted odds ratio.
For educational purposes, this distinction is important because adjustment changes the question being answered. An unadjusted comparison asks how the outcome differs between randomized groups without incorporating additional predictors into the model. The posted THALES mRS analysis instead reports a model-based treatment comparison after incorporating NIHSS and history of stroke.
13. Time-to-Event Analysis and Censoring
The primary composite and the other Cox-model endpoints were measured from randomisation (day 1) to visit 3 (day 30-34). Time-to-event analysis uses the timing of the event rather than simply classifying each participant as an event or non-event without regard to when the event occurred.
The survival function represents the probability of remaining free of the specified event beyond time t. Cox regression models the relative hazard rather than directly modeling the survival probability itself.
Censoring is important because not every participant necessarily contributes an observed event during the complete analysis period. A censored observation contributes information up to the censoring time under the assumptions required by the survival-analysis framework. The ClinicalTrials.gov record does not provide detailed censoring counts or censoring patterns, so no additional quantitative characterization is made here.
14. Hazard Ratios Versus Odds Ratios
| Feature | Hazard ratio | Odds ratio |
|---|---|---|
| THALES endpoint example | Composite of subsequent stroke or death | mRS score >1 at visit 3 |
| Outcome structure | Time-to-event | Binary at a defined visit |
| Model | Cox proportional-hazards model | Logistic regression |
| Reference group | Placebo | Placebo |
| Interpretation | Relative modeled instantaneous hazard | Relative odds of the binary outcome |
Keeping these effect measures separate prevents a common statistical mistake: treating every ratio below 1 as if it represented the same type of relative risk. The primary HR of 0.83 and the mRS OR of 0.98 answer different statistical questions because they arise from different outcome structures and models.
15. Multiple Endpoints and Interpretation
The registry reports seven statistical analyses: one primary analysis, one secondary ischaemic-stroke analysis, one secondary mRS analysis, and four additional prespecified bleeding or discontinuation analyses.
| Endpoint role | Number represented in posted analyses | Principal method |
|---|---|---|
| Primary | 1 | Cox proportional-hazards model |
| Secondary | 2 | Cox proportional-hazards model; logistic regression |
| Other prespecified | 4 | Cox proportional-hazards model |
| Total statistical analyses posted | 7 | Cox proportional-hazards model and logistic regression |
The primary endpoint has a reported superiority analysis with a two-sided confidence interval and P-value. The other posted analyses should be interpreted according to their own endpoint roles and statistical context. The ClinicalTrials.gov record does not specify a multiplicity-adjustment procedure, alpha allocation, or hierarchical testing strategy for these seven posted analyses.
16. What the Primary Result Does — and Does Not — Mean
The primary HR of 0.83 represents a modeled relative hazard comparison of ticagrelor versus placebo for subsequent stroke or death. A value below 1 indicates a lower estimated hazard in the ticagrelor group under the Cox model.
The HR does not tell us the absolute number or percentage of participants who avoided the composite endpoint. An absolute treatment effect requires event probabilities, cumulative incidence estimates, or another absolute-risk measure.
The 95% CI of 0.71–0.96 quantifies uncertainty around the estimated HR. It does not describe the range of responses that individual participants would experience.
The P-value of 0.015 is evidence against the relevant null hypothesis in the reported superiority analysis. It should not be interpreted as the probability that the null hypothesis is true, nor as a measure of how large the treatment effect is.
17. Comparing Efficacy and Bleeding Signals
One of the most instructive statistical features of THALES is that the direction of the estimated effect depends on the endpoint being studied.
| Endpoint | Effect | Direction relative to placebo |
|---|---|---|
| Composite of Subsequent Stroke or Death | HR 0.83 (95% CI 0.71–0.96) | Lower estimated hazard |
| Ischaemic Stroke | HR 0.79 (95% CI 0.68–0.93) | Lower estimated hazard |
| mRS Score >1 at Visit 3 | OR 0.98 (95% CI 0.89–1.07) | Odds estimate close to 1 |
| GUSTO Severe bleeding | HR 3.99 (95% CI 1.74–9.14) | Higher estimated hazard |
| ICH or Fatal Bleeding | HR 3.66 (95% CI 1.48–9.02) | Higher estimated hazard |
| GUSTO Moderate/Severe bleeding | HR 3.27 (95% CI 1.67–6.43) | Higher estimated hazard |
| Permanent discontinuation due to bleeding | HR 4.80 (95% CI 3.28–7.02) | Higher estimated hazard |
This is a useful reminder that treatment effects are always endpoint-specific. A drug can have estimates in opposite directions for different outcomes without any statistical contradiction. The appropriate interpretation is to examine the complete set of prespecified outcomes, their definitions, analysis populations, effect measures, uncertainty, and statistical context.
18. Trial Timeline
Trial start
The THALES trial began according to the ClinicalTrials.gov record.
Primary completion
The ClinicalTrials.gov record identifies December 13, 2019 as the primary completion date.
Results posted
The registry record is marked completed and contains seven posted outcome measures and seven statistical analyses.
19. Limitations
- Registry-level information: this analysis is limited to the ClinicalTrials.gov record. It does not introduce additional numerical results from publications or other sources.
- Limited absolute-risk information: the registry-reported primary analysis reports a hazard ratio and confidence interval but does not provide event probabilities or absolute risk differences for the primary endpoint.
- No detailed Kaplan-Meier data: the ClinicalTrials.gov record does not contain event-time tables, censoring counts, or Kaplan-Meier estimates, so a numerical survival curve cannot be reconstructed from the registry summary alone.
- Cox model assumptions: interpretation of each HR depends on the appropriateness of the proportional-hazards model. The ClinicalTrials.gov record does not report a formal proportional-hazards diagnostic.
- Multiplicity information: seven statistical analyses are posted, but the ClinicalTrials.gov record does not specify an overall multiplicity-adjustment strategy across these analyses.
- Covariate and missing-data detail: the mRS analysis identifies NIHSS score and history of stroke as covariates, but the ClinicalTrials.gov record does not provide a complete statistical-analysis-plan description of missing-data handling or sensitivity analyses.
- Safety scope: the registry-reported safety summary provides serious adverse events by arm but does not provide a complete adverse-event table.
- Endpoint-specific interpretation: the primary composite, ischaemic stroke, mRS, bleeding, and discontinuation outcomes are different endpoints and should not be collapsed into one effect measure.
20. Why This Trial Matters Statistically
THALES is a useful teaching case because it combines randomized treatment comparison, quadruple masking, time-to-event analysis, binary-outcome modeling, covariate adjustment, and endpoint-specific safety analysis in a single phase 3 trial.
| Concept | How it appears in THALES |
|---|---|
| Randomization | The trial uses randomized allocation with two parallel treatment arms. |
| Blinding | The registry describes the trial as quadruple masked. |
| Intention-to-treat analysis | The primary analysis uses the full analysis set including all randomised patients. |
| Time-to-event endpoints | The primary composite, ischaemic stroke, bleeding endpoints, and discontinuation endpoint are analysed with Cox regression. |
| Cox proportional-hazards model | Used for the primary and multiple prespecified time-to-event analyses. |
| Hazard ratio | The principal effect measure for the time-to-event outcomes. |
| Logistic regression | Used for mRS score >1 at visit 3. |
| Odds ratio | Used for the adjusted binary mRS endpoint. |
| Covariate adjustment | NIHSS score and history of stroke were included in the mRS logistic regression. |
| Confidence intervals | All posted estimates with confidence intervals use two-sided 95% intervals. |
| Endpoint-specific safety | Four additional posted analyses address bleeding or permanent discontinuation due to bleeding. |
21. Related Tutorials
Learn more about the methods used in this trial:
22. Related Calculators
23. Sources
- ClinicalTrials.gov: THALES — NCT03354429.
- PubMed: PMID 37637218.
- PubMed: PMID 34477459.
- PubMed: PMID 34244703.
- PubMed: PMID 33940954.
- PubMed: PMID 33198608.
Continue through the Clinical Biostats statistical pathway
Use the trial's endpoints and methods as a practical starting point for deeper study of survival analysis, regression, confidence intervals, and randomized clinical-trial methodology.
24. Record Summary
THALES provides a compact example of how several statistical methods operate together in a randomized phase 3 trial. The primary endpoint, a composite of subsequent stroke or death from randomisation (day 1) to visit 3 (day 30-34), was analysed with a Cox proportional-hazards model in the full analysis set including all randomised patients. The reported HR was 0.83 with a 95% CI of 0.71–0.96 and P = 0.015. A secondary ischaemic-stroke analysis produced an HR of 0.79, while the adjusted mRS analysis used logistic regression and produced an OR of 0.98.
The additional prespecified analyses demonstrate why endpoint-specific interpretation matters. The reported bleeding hazard ratios were above 1, including HRs of 3.99, 3.66, 3.27, and 4.80 for the specified bleeding and discontinuation outcomes. The serious-adverse-event summary also reports 571/5,523 affected/at risk for ticagrelor and 609/5,493 for placebo.