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
TEMPO-2 was a randomized, parallel-group phase 3 trial evaluating tenecteplase versus antiplatelet treatment in patients with minor acute ischemic stroke with proven occlusion. The registered primary endpoint was a binary responder outcome based on return to baseline neurological functioning measured with the modified Rankin Scale at 90 days.
| Feature | TEMPO-2 |
|---|---|
| Trial name | TEMPO-2 |
| ClinicalTrials.gov identifier | NCT02398656 |
| Phase | Phase 3 |
| Condition | Stroke, Acute |
| Therapeutic area | Cardiovascular; Neurology |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Single |
| Primary purpose | Treatment |
| Enrollment | 1274 |
| Primary endpoint type | Binary |
| Primary hypothesis | Superiority |
| Results posted | Yes |
| Statistical analyses posted | 1 |
| Lead sponsor | University of Calgary |
| Status | Completed |
2. Clinical Question
The central clinical question was whether tenecteplase produced a different probability of return to baseline neurological functioning at 90 days compared with antiplatelet treatment in patients with minor acute ischemic stroke with proven occlusion.
Population
Participants with acute stroke, specifically the trial population described by the brief title as patients with minor ischemic stroke with proven occlusion.
Intervention
Tenecteplase, identified in the registry as a drug intervention and abbreviated tNK in the posted safety data.
Comparator
Antiplatelet treatment, identified in the registry as the control intervention and described in the posted safety data as antiplatelet agents.
Primary question
Does tenecteplase improve the probability of returning to baseline neurological functioning by 90 days compared with antiplatelet treatment?
3. Trial Design
Tenecteplase
- Tenecteplase was the active drug intervention.
- The posted safety data identify this group as Tenecteplase (tNK).
Antiplatelet treatment
- Antiplatelet treatment was the comparator intervention.
- The posted safety data identify this group as Control (Antiplatelet Agents).
Trial timeline
Trial start
The registered study start date was 2015-04-01.
Primary completion
The registered primary completion date was 2024-01-19.
Registry status
The study is listed as completed in the ClinicalTrials.gov record.
4. Primary Endpoint
The primary endpoint was the number of participants with return to baseline neurological functioning measured by the modified Rankin Scale (mRS), assessed at 90 days.
| Endpoint component | Registered definition |
|---|---|
| Endpoint | Number of Participants With Return to Baseline Neurological Functioning Measured by the Modified Rankin Scale (mRS) |
| Time frame | 90 Days |
| Endpoint type | Binary |
| Outcome scale | Modified Rankin Scale, ranging from 0 to 6; higher scores mean a worse outcome. |
| Premorbid mRS 0–1 | mRS 0–1 at 90 days is defined as a good outcome. |
| Premorbid mRS 2 | mRS 0–2 at 90 days is defined as a good outcome. |
| Premorbid assessment | Structured mRS assessed prior to randomization. |
| 90-day assessment | Assessed by an individual blinded to treatment assignment. |
| Assessment method | Structured mRS questionnaire; completed in person where possible and by telephone otherwise. |
The endpoint therefore converts the ordinal mRS scale into a clinically defined binary responder outcome. The definition depends on each participant's premorbid mRS: participants with a premorbid score of 0 or 1 are responders if their 90-day score is 0 or 1, whereas participants with a premorbid score of 2 are responders if their 90-day score is 0, 1, or 2.
5. Statistical Methodology
Binary responder analysis
The registry describes the primary endpoint as a responder analysis. Each participant is classified as either having or not having a return to baseline neurological functioning according to the prespecified mRS definition at 90 days.
A risk ratio compares the probability of the specified binary outcome between the two randomized groups.
Posted effect measure
The posted statistical analysis reports a risk ratio (RR). The estimate was 0.96 with a two-sided 95% confidence interval of 0.88 to 1.04.
Primary endpoint risk ratio
95% CI: 0.88–1.04 · Superiority hypothesis
Endpoint: return to baseline neurological functioning at 90 days.
A risk ratio of 0.96 means that the estimated probability of the defined responder outcome in the tenecteplase group was 0.96 times the corresponding probability in the antiplatelet-treatment group. Because the estimate is below 1, the point estimate corresponds to a lower estimated responder probability with tenecteplase relative to control under this analysis.
6. Primary Result
Return to baseline neurological functioning at 90 days
Risk ratio for the binary responder outcome
95% CI: 0.88–1.04 · Two-sided 95% confidence interval
Superiority hypothesis; tenecteplase versus antiplatelet agents.
The point estimate of 0.96 indicates that the estimated probability of the prespecified 90-day responder outcome was 4% lower in the tenecteplase group relative to the antiplatelet-treatment group, when expressed as a risk ratio. This is a relative comparison of probabilities, not a 4-percentage-point difference in response rates.
The estimate does not mean that individual participants had exactly a 4% lower chance of recovery, nor does it describe the magnitude of neurological change among participants who did not meet the responder definition.
The 95% confidence interval of 0.88–1.04 indicates uncertainty around the estimated risk ratio. Because the interval includes 1.00, the posted interval is compatible with a range of relative effects that includes no difference in the probability of the binary outcome.
The confidence interval describes uncertainty around the estimated population-level effect under the statistical framework; it does not mean that 95% of individual participants experienced an effect inside this interval.
No p-value is reported in the posted statistical analysis. A p-value would address evidence against a specified null hypothesis, whereas the risk ratio and its confidence interval describe the estimated magnitude and precision of the treatment comparison.
7. Interpreting the Risk Ratio
The risk ratio is particularly natural for a binary endpoint because it directly compares probabilities of the prespecified outcome. If the response probability in the tenecteplase group is denoted by pT and the response probability in the control group by pC, then:
RR = 1 represents equal response probabilities; RR > 1 represents a higher response probability in the treatment group; RR < 1 represents a lower response probability in the treatment group.
For TEMPO-2, the posted estimate of 0.96 is close to 1. The corresponding confidence interval extends from 0.88 to 1.04, so the estimate is not precise enough to exclude both modestly lower and modestly higher relative probabilities of the defined responder outcome.
The risk ratio should not be confused with a risk difference. A risk ratio of 0.96 does not identify the absolute difference in percentage points unless the underlying response probabilities are also known.
8. Statistical Methods Explained
What is a responder analysis?
A responder analysis classifies each participant according to whether a prespecified clinical criterion has been achieved. In TEMPO-2, the criterion is return to baseline neurological functioning at 90 days according to the participant's premorbid mRS and the corresponding 90-day mRS threshold.
Why use a risk ratio for this endpoint?
Because the primary endpoint is binary, each participant contributes a yes/no outcome. A risk ratio directly compares the probability of being a responder between the randomized groups, making the effect measure straightforward to interpret as a relative probability.
What does an RR of 0.96 mean?
An RR of 0.96 means that the estimated responder probability in the tenecteplase group was 0.96 times the responder probability in the control group. Expressed as a relative comparison, the point estimate is 4% below the control probability.
Why does the confidence interval include 1?
For a risk ratio, 1 is the value representing equal probabilities between groups. The 95% CI of 0.88–1.04 crosses 1, meaning that the interval includes values corresponding to no relative difference as well as values on either side of that reference.
Why can't the RR be converted directly into a percentage-point difference?
Relative and absolute effects contain different information. A risk ratio compares probabilities multiplicatively. A percentage-point difference requires the two absolute response probabilities, which are not included in the posted statistical analysis.
Why does randomization matter for interpreting the RR?
Randomization assigns participants to treatment groups independently of the clinical outcome that will subsequently be observed. This provides the foundation for interpreting a between-group difference as a treatment comparison rather than simply an association with baseline characteristics, assuming the trial is conducted and analyzed appropriately.
What does the posted analysis not tell us about the method?
The ClinicalTrials.gov statistical analysis identifies the endpoint as binary and reports a risk ratio with a two-sided 95% confidence interval, but the specific statistical method used to generate that estimate is not reported in the posted analysis. For a binary randomized endpoint, risk-ratio estimation can be performed using several statistical approaches; the appropriate choice depends on the prespecified analysis plan and implementation details.
9. Why the 90-Day Endpoint Is Statistically Distinct
The primary endpoint has a fixed follow-up time rather than a time-to-event definition. The question is whether each participant meets the responder criterion at 90 days, not how quickly a participant reaches recovery or how long the participant remains free of an event.
Fixed-time outcome
The primary endpoint is evaluated at 90 days. The primary effect measure is therefore a risk ratio rather than a hazard ratio.
Binary classification
The analysis reduces the mRS measurement to a prespecified responder/non-responder outcome based on baseline neurological functioning.
Clinical threshold
The definition differs according to premorbid mRS, preserving the concept of return to the participant's baseline level of neurological functioning.
Blinded assessment
The 90-day outcome was assessed by an individual blinded to treatment assignment, according to the registry description.
10. Assessment of the Modified Rankin Scale
The modified Rankin Scale is the underlying neurological disability measure used to define the primary responder outcome. The registry describes it as a scale from 0 to 6, with higher scores representing worse outcomes.
| Component | Role in the TEMPO-2 endpoint |
|---|---|
| Premorbid mRS 0–1 | 90-day mRS 0–1 qualifies as a good outcome. |
| Premorbid mRS 2 | 90-day mRS 0–2 qualifies as a good outcome. |
| 90-day mRS | Determines whether the participant meets the responder definition. |
| Assessment timing | 90 days. |
| Assessment format | Structured mRS questionnaire. |
| Administration | In person where possible and by telephone otherwise. |
| Assessor | An individual blinded to treatment assignment. |
This endpoint is therefore not simply a conventional fixed mRS threshold applied to everyone. The responder threshold is anchored to each participant's premorbid neurological functioning. That distinction is important when interpreting what the binary result represents.
11. Safety Results
The registry reports serious adverse events by treatment arm. The available safety measure is presented as affected participants divided by participants at risk.
| Safety measure | Tenecteplase (tNK) | Control (Antiplatelet Agents) |
|---|---|---|
| Serious adverse events | 16/432 | 2/452 |
The reported serious-adverse-event counts are descriptive safety data and should be interpreted separately from the primary efficacy analysis. The denominators for this safety measure are 432 for tenecteplase and 452 for control, rather than the overall enrollment of 1274.
12. Trial Stopping and Futility
The registry states that the trial was ended based on a recommendation from the Data and Safety Monitoring Board that continuing was futile.
The futility decision is an important design consideration when interpreting the final posted primary analysis. A trial that stops for futility can have different statistical characteristics from a trial that proceeds to its originally anticipated information target, particularly when the stopping decision is based on accumulating data.
13. Superiority Hypothesis
The registered hypothesis type for the primary analysis was superiority. Under a superiority framework for a binary endpoint, the treatment comparison asks whether the probability of the prespecified outcome differs between the randomized groups in the hypothesized direction or, depending on the exact testing convention, whether the null of no treatment difference can be rejected.
The posted 95% confidence interval of 0.88–1.04 includes this reference value.
Because the posted analysis does not provide a p-value or the exact testing procedure, the confidence interval is the clearest quantitative description of uncertainty available from the posted analysis. It shows that the estimated relative effect is close to the no-difference reference and that the interval includes values on both sides of 1.
14. Randomization and Causal Interpretation
Randomization is the central design feature that makes the primary comparison a treatment comparison rather than a simple observational association. Participants were allocated to the two interventions under a randomized parallel-group design, and the primary endpoint was subsequently assessed at a common 90-day time point.
What randomization contributes
Randomization is intended to balance prognostic factors across treatment groups in expectation, supporting a causal interpretation of the treatment comparison.
What randomization does not guarantee
Randomization does not make the groups numerically identical at baseline, eliminate missing outcomes, or guarantee that every analysis is unbiased regardless of implementation.
The single-masked design and blinded assessment of the 90-day mRS are additional features relevant to outcome measurement. The registry specifically states that the 90-day outcome was assessed by an individual blinded to treatment assignment.
15. Confidence Interval Interpretation
The 95% confidence interval for the primary RR is 0.88–1.04. Relative to the null value of 1, this interval spans both lower and higher responder probabilities for tenecteplase compared with control.
The interval is also useful for understanding precision. A narrower interval would indicate greater precision around the estimated relative effect, while a wider interval would indicate greater uncertainty. Here, the interval extends on both sides of the null value.
The confidence interval should not be interpreted as saying that there is a 95% probability that the true treatment effect lies between 0.88 and 1.04. In the conventional frequentist interpretation, the interval is generated by a procedure designed to contain the true parameter in 95% of repeated samples under the relevant assumptions.
16. Risk Ratio Versus Risk Difference
The posted analysis uses a risk ratio rather than a risk difference. These measures answer related but distinct questions.
| Measure | Question answered | TEMPO-2 status |
|---|---|---|
| Risk ratio | How does the probability of the outcome compare proportionally between groups? | Reported: 0.96 |
| Risk difference | How many percentage points higher or lower is the probability in one group? | Not reported in the posted analysis |
| Odds ratio | How do the odds of the outcome compare between groups? | Not reported in the posted analysis |
| Hazard ratio | How do instantaneous event rates compare over follow-up? | Not the reported primary effect measure |
For readers interpreting clinical-trial results, this distinction is important. A relative measure such as RR can be highly informative, but it does not by itself reveal the absolute number of additional or fewer responders associated with treatment.
17. What the Primary Result Does Not Establish
- It does not describe the entire mRS distribution: the primary endpoint is a binary responder classification derived from the mRS.
- It does not provide an absolute response-rate difference: the posted statistical analysis provides the RR but not the corresponding two absolute probabilities.
- It does not establish a treatment effect for every neurological outcome: the reported analysis addresses the prespecified responder endpoint at 90 days.
- It does not identify the exact analysis algorithm: the statistical method used to produce the posted RR is listed as not reported.
- It does not provide a p-value: no p-value appears in the posted statistical analysis.
- It does not convert the result into an individual prognosis: the RR is a group-level comparative effect measure.
18. Statistical Considerations for Binary Clinical Endpoints
Binary clinical endpoints are attractive because they produce an easily communicated responder classification. Their statistical interpretation, however, depends strongly on the definition of the response threshold.
Definition drives meaning
The clinical interpretation of the RR depends on exactly what counts as a responder. TEMPO-2 defines response using premorbid mRS and the 90-day mRS.
Relative versus absolute effects
RR describes a proportional difference in probabilities. Absolute benefit or harm requires the underlying response rates.
Precision matters
The 95% CI communicates uncertainty around the point estimate and should be interpreted together with the estimate itself.
Analysis population matters
The meaning of the treatment comparison depends on how randomized participants and missing endpoint assessments were handled in the prespecified analysis.
19. Limitations
- Limited statistical-method detail: the posted statistical analysis reports the risk ratio and confidence interval but does not report the method used to generate the estimate.
- No posted p-value: the statistical analysis does not provide a p-value for the primary comparison.
- Binary endpoint reduction: converting the mRS into a responder outcome simplifies interpretation but does not preserve all information contained in the underlying ordinal scale.
- Absolute response rates are not reported in the posted analysis: the RR alone does not provide the absolute probability of response in either group.
- Futility stopping: the registry states that the trial was ended after a DSMB recommendation that continuation was futile. The registry does not provide the detailed DSMB futility rule in the available trial information.
- Safety denominator differs from enrollment: serious adverse events are reported using affected/at-risk counts of 16/432 and 2/452, respectively.
- Outcome measurement: although the registry specifies blinded assessment and structured mRS administration, 90-day assessments could be performed in person or by telephone.
20. Why This Trial Matters Statistically
TEMPO-2 is a useful teaching case because it demonstrates how a randomized clinical trial can combine a clinically defined binary endpoint with a relative effect measure while also illustrating the importance of endpoint construction, confidence intervals, outcome assessment, and trial stopping.
| Concept | How it appears in TEMPO-2 |
|---|---|
| Randomization | Participants were randomly allocated to tenecteplase or antiplatelet treatment. |
| Parallel-group design | The registry identifies a parallel design with two arms. |
| Binary endpoint | The primary endpoint classifies participants according to return to baseline neurological functioning at 90 days. |
| Modified Rankin Scale | The mRS is used to define the responder outcome. |
| Risk ratio | The posted primary effect measure is RR 0.96. |
| Confidence interval | The 95% CI is 0.88–1.04. |
| Superiority hypothesis | The registered primary hypothesis type is superiority. |
| Blinded assessment | The 90-day outcome was assessed by an individual blinded to treatment assignment. |
| Futility | The trial was ended following a DSMB recommendation that continuing was futile. |
| Safety analysis | Serious adverse events are reported by arm using affected/at-risk counts. |
21. Overall Statistical Interpretation
The posted primary analysis for TEMPO-2 reports a risk ratio of 0.96 for return to baseline neurological functioning at 90 days, comparing tenecteplase with antiplatelet treatment. The corresponding two-sided 95% CI is 0.88–1.04.
The point estimate is close to the null value of 1 and is below 1, corresponding to a lower estimated probability of the defined responder outcome with tenecteplase relative to control. However, the confidence interval crosses 1, so the interval includes both a relative decrease and a relative increase in the probability of the prespecified outcome.
The result should be understood specifically as a comparison of the probability of meeting the registry-defined responder criterion. It is not an analysis of the full mRS distribution, not a hazard ratio, and not an absolute risk difference.
The registry also reports that the trial was stopped after a DSMB recommendation that continuing was futile. That stopping history is part of the statistical context for interpreting the final trial evidence.
22. Related Tutorials
Learn more about the methods used in this trial:
23. Related Calculators
24. Sources
- ClinicalTrials.gov: NCT02398656.
- PubMed: PMID 38768626.
- PubMed: PMID 42734928.
- PubMed: PMID 42318629.
- PubMed: PMID 41980227.
- PubMed: PMID 41143808.
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25. Record Summary
TEMPO-2 provides a focused example of statistical analysis for a randomized phase 3 trial with a clinically defined binary neurological endpoint. The primary outcome was return to baseline neurological functioning at 90 days, defined from the participant's premorbid mRS and the 90-day mRS. The posted analysis reports a risk ratio of 0.96 with a two-sided 95% CI of 0.88–1.04 for tenecteplase versus antiplatelet treatment.
The statistical interpretation depends on understanding several linked concepts: randomization establishes the treatment comparison, the responder definition determines what the RR represents, the risk ratio expresses a relative probability rather than an absolute difference, and the confidence interval describes uncertainty around the estimate. The registry additionally reports serious adverse events of 16/432 with tenecteplase and 2/452 with antiplatelet agents, and states that the trial was ended following a DSMB recommendation that continuing was futile.