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
PRISMS was a randomized, double-blind, parallel phase 3 trial evaluating alteplase in participants with mild stroke. The registry reports 313 enrolled participants, two arms, a binary primary endpoint at Day 90, and six posted statistical analyses.
| Feature | PRISMS |
|---|---|
| Trial name | PRISMS |
| Brief title | A Study of the Efficacy and Safety of Alteplase in Participants With Mild Stroke |
| Phase | Phase 3 |
| Condition | Stroke |
| Design | Randomized, parallel, double-masked, treatment-focused trial |
| Enrollment | 313 |
| Primary endpoint type | Binary |
| Results posted | Yes |
| Outcome measures posted | 9 |
| Statistical analyses posted | 6 |
| Lead sponsor | Genentech, Inc. |
| Sponsor type | Industry |
| Trial status | Terminated |
| ClinicalTrials.gov | NCT02072226 |
2. Clinical Question
The statistical question is whether the randomized comparison between alteplase plus aspirin placebo and alteplase placebo plus aspirin differs in the percentage of participants achieving a favorable Day 90 functional outcome defined by a modified Rankin Scale (mRS) score of 0 or 1.
Population
Participants with mild stroke enrolled in the PRISMS phase 3 trial.
Intervention
Alteplase with aspirin placebo.
Comparator
Alteplase placebo with aspirin.
Primary question
What is the difference between randomized groups in the percentage of participants with an mRS score of 0 or 1 at Day 90?
3. Trial Design
Alteplase + Aspirin Placebo
- Alteplase
- Aspirin placebo
- Serious adverse events: 40/154
Alteplase Placebo + Aspirin
- Alteplase placebo
- Aspirin
- Serious adverse events: 20/153
4. Trial Timing and Early Termination
Study start
The registry lists May 31, 2014 as the study start date.
Primary completion
The registry lists March 22, 2017 as the primary completion date.
Study status
The trial is listed as terminated. The registry caveat states that the study was terminated early due to low enrollment, leading to a smaller number of participants analyzed.
5. Primary Endpoint
| Endpoint | Registry definition | Time frame | Type |
|---|---|---|---|
| Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 or 1 at Day 90 | mRS score was determined by the investigator. The mRS is a 7 point scale (0-6) with 0: No symptoms at all, 1: No significant disability despite symptoms, able to carry out all usual duties and activities. | Day 90 | Binary |
The primary endpoint converts the seven-level mRS into a binary outcome: whether the participant has a score of 0 or 1 at Day 90. This creates a clinically interpretable responder-type endpoint, but it also discards information contained in mRS scores above 1. The registry's posted primary analysis therefore focuses on the between-group difference in the percentage meeting this binary criterion.
6. Results: Primary Endpoint
The registry reports an intention-to-treat analysis including all randomized participants. The comparison was between alteplase plus aspirin placebo and alteplase placebo plus aspirin.
Adjusted risk difference
95% CI: -9.44 to 7.25 · Two-sided
Analysis population: Intent-to-Treat population
| Primary endpoint | Effect measure | Estimate | 95% CI |
|---|---|---|---|
| mRS score 0 or 1 at Day 90 | Adjusted Risk Difference | -1.10 | -9.44 to 7.25 |
The reported adjusted risk difference of -1.10 means that the estimated percentage of participants achieving an mRS score of 0 or 1 at Day 90 was 1.10 percentage points lower in the alteplase-plus-aspirin-placebo group than in the alteplase-placebo-plus-aspirin group, according to the posted analysis.
The estimate does not mean that treatment reduced every participant's probability by 1.10 percentage points, nor does it describe an individual patient's expected outcome. It is a population-level between-group effect estimate.
The 95% confidence interval of -9.44 to 7.25 is wide enough to include both negative and positive risk differences. Thus, the point estimate alone provides an incomplete description of the evidence. The interval indicates substantial statistical uncertainty around the estimated difference, which is particularly relevant given the registry's statement that the study was terminated early because of low enrollment.
The registry does not report a p-value for this primary analysis. A p-value, when available, would address evidence against a specified null hypothesis; it would not measure the magnitude or clinical importance of the treatment effect. The risk difference and its confidence interval provide the more direct description of the estimated effect and its precision.
Reading the confidence interval
On this scale, 0 represents no estimated difference between groups. Negative values favor a higher percentage in the control group for this particular subtraction; positive values favor a higher percentage in the alteplase group.
The reported interval extends across zero. That matters because zero corresponds to no between-group difference on the risk-difference scale. The interval therefore does not restrict the plausible treatment-effect range to only one direction under the stated confidence framework.
7. Secondary Endpoint Results
The registry posts five secondary statistical analyses in addition to the primary analysis. These results use the intention-to-treat population for efficacy outcomes and the safety population for the intracranial hemorrhage outcomes.
Distribution of Participants Across the Ordinal mRS
Odds ratio
95% CI: 0.527 to 1.244 · Two-sided
Analysis population: ITT
The odds ratio compares the odds associated with the reported mRS distribution between the randomized groups under the posted analysis. The registry does not report the statistical method used to obtain this odds ratio.
Global Favorable Recovery on mRS, NIHSS, BI, and GOS
Odds ratio
95% CI: 0.529 to 1.393 · Two-sided
Analysis population: ITT
This endpoint combines favorable recovery across the mRS, NIHSS, BI, and GOS measures. The posted estimate is an odds ratio of 0.858 with a 95% confidence interval from 0.529 to 1.393. The registry does not report the formal statistical method used to generate the estimate.
Symptomatic Intracranial Hemorrhage
Difference in percentages
95% CI: 0.75 to 7.38 · Two-sided
Analysis population: Safety population
The reported difference in percentages was 3.25 percentage points for symptomatic intracranial hemorrhage within 36 hours after study drug administration on Day 1. The safety population included all participants who received any amount of study drug.
Any ICH — Site Report
Difference in percentages
95% CI: -0.34 to 10.07 · Two-sided
Within 36 hours after study drug administration on Day 1
For any intracranial hemorrhage reported by site, the estimated difference in percentages was 4.53 percentage points, with a 95% confidence interval from -0.34 to 10.07.
Any ICH — Central Reader
Difference in percentages
95% CI: -1.23 to 9.49 · Two-sided
Within 36 hours after study drug administration on Day 1
The corresponding analysis using any ICH reported by a central reader produced a difference in percentages of 3.87 percentage points, with a 95% confidence interval from -1.23 to 9.49.
| Secondary endpoint | Effect measure | Estimate | 95% CI | Population |
|---|---|---|---|---|
| Distribution of participants across the ordinal mRS | Odds Ratio | 0.810 | 0.527 to 1.244 | ITT |
| Global favorable recovery on mRS, NIHSS, BI, and GOS | Odds Ratio | 0.858 | 0.529 to 1.393 | ITT |
| Symptomatic ICH | Difference in percentages | 3.25 | 0.75 to 7.38 | Safety |
| Any ICH, site reported | Difference in percentages | 4.53 | -0.34 to 10.07 | Safety |
| Any ICH, central reader | Difference in percentages | 3.87 | -1.23 to 9.49 | Safety |
8. Safety Results
The registry provides serious adverse event counts by randomized arm in terms of affected participants over the corresponding number at risk.
| Safety measure | Alteplase + Aspirin Placebo | Alteplase Placebo + Aspirin |
|---|---|---|
| Serious adverse events | 40/154 | 20/153 |
The serious-adverse-event figures should be kept separate from the efficacy analysis. Safety describes events observed among participants who received study drug, while the primary efficacy comparison is based on randomized assignment in the ITT population. The registry does not provide a formal statistical comparison for these serious adverse event counts in the ClinicalTrials.gov record.
9. Statistical Methodology
What the registry reports
The posted primary analysis uses an adjusted risk difference for the binary Day 90 mRS 0-or-1 endpoint and identifies the ITT population as the analysis population. The registry does not name the statistical method used to produce the adjusted estimate.
The secondary analyses likewise identify their effect measures—odds ratios for two functional outcomes and differences in percentages for ICH outcomes—but the ClinicalTrials.gov record does not report the formal methods used to calculate those estimates.
The posted estimate is -1.10, with a two-sided 95% confidence interval from -9.44 to 7.25.
Why risk difference is useful
Risk difference is an absolute effect measure. Unlike an odds ratio, it remains directly expressed in percentage points of the outcome probability. For a binary endpoint such as mRS 0 or 1 at Day 90, this makes the measure straightforward to connect to the proportion of participants achieving the specified outcome.
The word adjusted is important. An adjusted risk difference is not necessarily the same as a simple subtraction of two raw observed percentages. Because the registry does not report the adjustment model or covariates in the ClinicalTrials.gov record, the precise calculation of the -1.10 estimate cannot be reconstructed from the posted information alone.
Odds ratios
Two secondary analyses use odds ratios. An odds ratio compares odds rather than probabilities. The distinction becomes important when an outcome is not rare: an odds ratio should not automatically be read as though it were a risk ratio or a percentage-point difference.
An OR of 1 represents equal odds. Values below 1 and above 1 indicate different directions depending on how the outcome and treatment contrast are coded.
Confidence intervals
Each posted statistical estimate is accompanied by a two-sided 95% confidence interval. The interval provides information about precision and sampling uncertainty under the analysis framework. It should not be interpreted as the range of outcomes that individual participants will experience.
Intention-to-treat analysis
The primary analysis population is explicitly the Intent-to-Treat population, defined in the ClinicalTrials.gov record as including all randomized participants. ITT analysis preserves treatment assignment as the basis of comparison and therefore maintains the principal randomized structure of the trial.
Safety population
The ICH analyses use a safety population consisting of participants who received any amount of study drug. This population definition is exposure-based rather than purely assignment-based. That distinction is methodologically important because the population used to assess treatment exposure and safety can differ from the population used for randomized efficacy comparisons.
10. Statistical Methods Explained
Why use an intention-to-treat population?
ITT analysis evaluates randomized participants according to their randomized assignment. This maintains the treatment comparison created by randomization. In PRISMS, the registry explicitly states that all randomized participants were included in the ITT population. The approach is particularly relevant when interpreting an estimate as a randomized treatment comparison rather than as a comparison of people who actually completed or adhered to treatment.
What does a risk difference of -1.10 mean?
A risk difference of -1.10 means the estimated probability of the specified favorable binary outcome was 1.10 percentage points lower in the alteplase group under the posted treatment contrast. The value is an absolute difference, not a relative percentage change. It also does not mean that an individual participant's outcome probability changes by exactly 1.10 percentage points.
Why does the confidence interval matter more than the point estimate alone?
The point estimate is only one summary of the data. The 95% confidence interval from -9.44 to 7.25 demonstrates that the estimate is imprecise enough that the interval includes both negative and positive values. A reader who considered only -1.10 would miss much of the uncertainty conveyed by the analysis.
What does an odds ratio of 0.810 mean?
An odds ratio of 0.810 indicates that the estimated odds under the treatment contrast were 0.810 times the comparison odds, according to the posted analysis. It does not mean that the probability was 19.0% lower, because odds and probabilities are different quantities. The accompanying 95% confidence interval, 0.527 to 1.244, is essential for assessing the precision of the estimate.
Why are the ICH analyses in the safety population?
Safety outcomes are naturally linked to exposure to study treatment. The registry defines the safety population for the ICH analyses as participants who received any amount of study drug. This differs from the ITT population used for the primary efficacy analysis because safety analysis asks a somewhat different question: what adverse events were observed among participants exposed to study treatment?
Why is the early termination statistically important?
The registry states that low enrollment caused early termination and resulted in a smaller number of participants analyzed. Smaller information sets generally produce less precise estimates. In PRISMS, the primary confidence interval extends from -9.44 to 7.25, so the uncertainty around the estimated risk difference is an important part of the result rather than a secondary footnote.
11. Understanding the Primary Result
The adjusted risk difference of -1.10 is an absolute, population-level comparison for the percentage of participants with an mRS score of 0 or 1 at Day 90. Its interpretation depends on the direction of the treatment contrast specified by the registry: alteplase plus aspirin placebo versus alteplase placebo plus aspirin.
The 95% CI of -9.44 to 7.25 spans 16.69 percentage points from its lower to upper endpoint. This is a wide interval relative to the point estimate, indicating that the observed estimate should not be treated as a highly precise measurement of the underlying treatment difference.
The posted estimate does not by itself establish a treatment recommendation, does not quantify an individual patient's probability of recovery, and does not provide a measure of benefit or harm for every participant. It summarizes the randomized comparison for one prespecified binary functional endpoint.
The ClinicalTrials.gov record contains an estimate and two-sided 95% confidence interval but no p-value. Therefore, a p-value should not be reconstructed from the confidence interval or introduced from another source. The confidence interval is the appropriate reported measure of uncertainty for this page.
12. Interpreting the Secondary Odds Ratios
| Endpoint | OR | 95% CI | Interpretive point |
|---|---|---|---|
| Distribution of participants across the ordinal mRS | 0.810 | 0.527 to 1.244 | The interval spans 1, the null value for an odds ratio. |
| Global favorable recovery on mRS, NIHSS, BI, and GOS | 0.858 | 0.529 to 1.393 | The interval spans 1, so the point estimate should not be interpreted without its uncertainty interval. |
For odds ratios, 1 is the null value. Both posted intervals include 1. That does not mean the true effect is exactly 1; rather, the confidence intervals encompass the no-difference value under the stated statistical framework.
There is also a conceptual distinction between these secondary endpoints. The first describes the distribution of participants across the ordinal mRS, whereas the second defines global favorable recovery using mRS, NIHSS, BI, and GOS. They should not be collapsed into a single efficacy measure merely because both are reported as odds ratios.
13. Interpreting the ICH Results
| ICH endpoint | Difference in percentages | 95% CI |
|---|---|---|
| Symptomatic ICH | 3.25 | 0.75 to 7.38 |
| Any ICH, site reported | 4.53 | -0.34 to 10.07 |
| Any ICH, central reader | 3.87 | -1.23 to 9.49 |
These three results illustrate why endpoint definition and ascertainment method matter. The symptomatic ICH analysis is a more specific safety endpoint, while the two any-ICH analyses differ according to whether the hemorrhage was reported by the site or by a central reader.
The two any-ICH confidence intervals cross zero, whereas the reported confidence interval for symptomatic ICH is entirely above zero. The registry supplies these estimates and intervals but does not supply p-values or a formal multiplicity framework for these secondary analyses. Accordingly, the results should be described as the posted statistical estimates rather than converted into an unsupported hierarchy of findings.
14. Analysis Populations
| Population | Definition / role |
|---|---|
| Intent-to-Treat | Included all randomized participants. Used for the primary efficacy analysis and the two posted functional secondary analyses. |
| Safety Population | Included all participants who received any amount of study drug. Used for the posted symptomatic ICH and any-ICH analyses. |
This distinction is more than a technical labeling issue. The ITT analysis estimates the effect associated with assignment to the randomized strategy, whereas the safety population is defined by actual exposure to study drug. Mixing these populations could create confusion about what a reported treatment difference represents.
15. Limitations and Interpretation Issues
- Early termination: the registry states that the trial was terminated early because of low enrollment, resulting in a smaller number of participants analyzed.
- Precision: the primary 95% confidence interval ranges from -9.44 to 7.25, indicating substantial uncertainty around the adjusted risk difference.
- Method reporting: the ClinicalTrials.gov record does not identify the formal statistical method or model used to calculate the adjusted primary risk difference.
- No primary p-value posted in the ClinicalTrials.gov record: the primary analysis contains an estimate and confidence interval but no p-value. A p-value should not be inferred from another source.
- Multiple secondary analyses: six statistical analyses are posted, but the ClinicalTrials.gov record does not describe a multiplicity-adjustment strategy.
- Different analysis populations: efficacy analyses use ITT, while ICH analyses use the safety population.
- Binary endpoint: converting mRS into 0-or-1 versus other scores provides a simple binary endpoint but does not preserve all information contained in the seven-point mRS scale.
- Ordinal mRS analysis: the registry reports an odds ratio for the distribution across the ordinal mRS but does not identify the formal statistical model used.
- Safety interpretation: serious adverse event counts are reported by arm, but the ClinicalTrials.gov record does not provide a formal statistical comparison for those counts.
16. Why This Trial Matters Statistically
PRISMS is a useful teaching case because it shows how the statistical interpretation of a randomized trial depends not only on a point estimate but also on endpoint construction, analysis population, confidence intervals, safety definitions, and the amount of information actually accumulated.
| Concept | How it appears in PRISMS |
|---|---|
| Randomization | Participants were assigned in a randomized parallel phase 3 design. |
| Blinding | The trial used a double-masked design. |
| Intention-to-treat analysis | The primary efficacy analysis included all randomized participants. |
| Binary endpoint | The primary endpoint was the percentage with an mRS score of 0 or 1 at Day 90. |
| Risk difference | The primary effect measure was an adjusted risk difference of -1.10. |
| Confidence interval | The primary estimate was accompanied by a two-sided 95% CI of -9.44 to 7.25. |
| Odds ratio | Two secondary functional analyses reported odds ratios. |
| Safety population | ICH analyses included participants who received any amount of study drug. |
| Early termination | Low enrollment led to early termination and a smaller number of participants analyzed. |
| Multiple analyses | Six statistical analyses were posted across the primary and secondary outcomes. |
17. A Practical Framework for Reading PRISMS
Start with the endpoint
The primary question is binary: whether the participant had an mRS score of 0 or 1 at Day 90. This determines the natural effect measures and the null value for the risk difference.
Then read the estimate
The adjusted risk difference is -1.10 percentage points. This is the estimated absolute contrast between the randomized groups under the posted analysis.
Then read the interval
The 95% CI extends from -9.44 to 7.25. The width and crossing of zero are central to understanding the uncertainty.
Then inspect the population
The primary analysis is ITT, whereas the ICH analyses use the safety population. The population definition changes the interpretation of the estimate.
This sequence is broadly useful in clinical-trial statistics: endpoint → analysis population → effect measure → point estimate → confidence interval → design limitations. It reduces the risk of treating a single number as if it were the entire statistical result.
18. Statistical Concepts in This Trial
Learn more about the methods and concepts used in this trial:
19. Related Statistical Calculators
20. Sources
- ClinicalTrials.gov: PRISMS, NCT02072226.
- Linked publication: PubMed PMID 29998337.
- Linked publication: PubMed PMID 25638754.
- Linked publication: PubMed PMID 25628404.
Continue through Clinical Biostats
Use the related tutorials and statistical calculators to explore the methods behind randomized clinical-trial results, binary endpoints, confidence intervals, odds ratios, and absolute treatment effects.
21. Record Summary
PRISMS provides a compact example of how to interpret a randomized clinical trial when the central result is a binary functional endpoint and the available sample is limited by early termination. The primary Day 90 outcome was analyzed in the ITT population using an adjusted risk difference of -1.10, with a two-sided 95% confidence interval of -9.44 to 7.25. The registry also reports odds-ratio analyses for functional outcomes and percentage differences for intracranial hemorrhage outcomes, with the latter based on the safety population.
The most important statistical lesson is that the point estimate cannot be separated from its uncertainty and design context. The primary confidence interval spans zero, while the study was terminated early because of low enrollment. Secondary analyses use different endpoints and, for safety outcomes, a different analysis population. The ClinicalTrials.gov record does not report the formal statistical methods behind the adjusted estimate, nor does it provide a p-value for the primary analysis or a multiplicity-adjustment strategy for the posted secondary analyses.