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
ENCHANTED was a randomized, single-masked, phase 3 factorial trial enrolling 4587 participants with ischemic stroke and high blood pressure. The design evaluated two treatment dimensions: rtPA dose and blood-pressure management.
| Feature | ENCHANTED |
|---|---|
| Trial acronym | ENCHANTED |
| Full title | Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) |
| Phase | Phase 3 |
| Status | Completed |
| Conditions | Ischemic Stroke; High Blood Pressure |
| Allocation | Randomized |
| Design model | Factorial |
| Masking | Single |
| Primary purpose | Treatment |
| Enrollment | 4587 |
| Number of arms | 4 |
| Lead sponsor | The George Institute |
| Sponsor type | OTHER |
| Start date | 2012-03 |
| Primary completion date | 2018-08 |
| ClinicalTrials.gov | NCT01422616 |
2. Clinical Question
The registry identifies two treatment dimensions within the ENCHANTED factorial design: the dose of recombinant tissue plasminogen activator (rtPA) and the strategy used for blood-pressure management. The primary outcome is combined death and disability at 90 days, defined using the modified Rankin Scale.
Population
Participants with ischemic stroke and high blood pressure enrolled in the phase 3 ENCHANTED study.
Intervention dimensions
Low-dose rtPA versus standard-dose rtPA, together with intensive blood-pressure lowering versus BP management policies.
Comparator dimensions
The factorial structure creates four treatment combinations from the two treatment dimensions identified in the registry.
Primary question
How do the randomized treatment dimensions relate to the 90-day combined outcome of death and disability?
3. Trial Design
The factorial structure
A factorial trial studies more than one intervention dimension within the same randomized experiment. Here, one dimension concerns rtPA dose and the other concerns blood-pressure management. With two choices on each dimension, the design produces four combinations, matching the registry's report of four arms.
rtPA dose
- Low-dose rtPA
- Standard-dose rtPA
Blood-pressure management
- Intensive blood-pressure lowering
- BP management policies
The registry does not report arm-level enrollment counts. Consequently, the overall enrollment of 4587 should not be divided into four equal groups without additional evidence.
4. Endpoints
| Endpoint | Time frame | Registry definition |
|---|---|---|
| Combined death and disability | 90 days | Unadjusted modified Rankin Scale [mRS] score 2-6 |
Understanding the primary endpoint
The primary endpoint combines death and disability into a binary outcome based on the modified Rankin Scale. A score from 2 through 6 constitutes the event according to the registry definition. The analysis therefore asks whether the proportion of participants meeting that definition differs between randomized treatment groups at 90 days.
5. Statistical Methodology
The registry identifies ENCHANTED as a randomized factorial phase 3 trial but does not post statistical analyses for the primary endpoint. The appropriate statistical framework for an endpoint defined as mRS 2-6 is therefore a comparison of binary outcome proportions between randomized groups, with the factorial design determining how the two treatment dimensions are represented in the analysis.
Binary outcome analysis
Because the primary endpoint classifies each participant as either meeting the combined death-and-disability definition or not meeting it, common analyses include a comparison of proportions using a risk difference, risk ratio, or odds ratio, together with a confidence interval and hypothesis test.
For each randomized comparison, the event proportion describes the fraction of participants with a 90-day modified Rankin Scale score of 2-6 under the registry definition.
Factorial analysis
The factorial structure permits the two treatment dimensions to be evaluated within a common randomized experiment. A factorial analysis can estimate the effect associated with rtPA dose while accounting for the BP-management dimension, and can similarly estimate the effect associated with BP management while accounting for rtPA dose.
The interaction term represents whether the effect of one treatment dimension depends on the level of the other treatment dimension. Whether an interaction was formally tested, and how it was handled, is not reported in the registry information available here.
Unadjusted endpoint
The registry explicitly describes the primary endpoint as unadjusted. In statistical reporting, that wording distinguishes a direct outcome comparison from an analysis that adjusts the endpoint for baseline covariates through a regression model or another covariate-adjusted procedure.
Effect measures
For a binary endpoint, several effect measures can communicate the same treatment comparison from different perspectives. The risk difference describes the absolute change in event probability; the risk ratio describes the relative event probability; and the odds ratio compares the odds of the event between groups.
| Measure | Interpretation |
|---|---|
| Risk difference | Absolute difference in the probability of mRS 2-6 between groups. |
| Risk ratio | Ratio of the probability of mRS 2-6 between groups. |
| Odds ratio | Ratio of the odds of mRS 2-6 between groups. |
6. Planned Analysis
The primary endpoint is planned to be assessed at 90 days using the registry-defined binary outcome of an unadjusted modified Rankin Scale [mRS] score 2-6.
For this type of endpoint, a typical analysis would compare the proportion of participants with mRS 2-6 between randomized treatment groups and report an effect estimate with a confidence interval and a corresponding hypothesis test. Because ENCHANTED uses a factorial design, the analysis would ordinarily distinguish the main effects of the two treatment dimensions and consider whether there is evidence that their effects interact.
Why the factorial design changes the analysis question
A simple two-group comparison is not the only statistical question in a factorial trial. The design makes it possible to examine each intervention dimension while using information from the full randomized population. This can be statistically efficient, provided the assumptions underlying the factorial analysis are appropriate.
The key additional question is interaction: does the effect associated with one factor differ according to the level of the other factor? If the treatment effects are compatible across the levels of the other factor, main-effect summaries can provide a compact description of the factorial experiment. If an interaction is important, interpretation should instead focus on the treatment combinations.
7. Statistical Methods Explained
Why use a factorial design?
A factorial design allows two treatment dimensions to be studied in the same randomized experiment. In ENCHANTED, the dimensions are rtPA dose and blood-pressure management. Rather than conducting two completely separate trials, the factorial structure creates four treatment combinations within one study.
What does "unadjusted mRS 2-6" mean?
The endpoint classifies participants according to whether their 90-day modified Rankin Scale score falls from 2 through 6. "Unadjusted" indicates that the endpoint itself is defined without incorporating additional baseline covariates into the outcome definition.
Why is mRS 2-6 a binary endpoint?
The modified Rankin Scale is an ordered disability scale, but the registry's primary endpoint converts it into a binary outcome: scores 2, 3, 4, 5, and 6 count as the event, while scores below 2 do not. This changes the statistical question from comparing the full ordinal distribution to comparing the probability of crossing a prespecified threshold.
What is a main effect in a factorial trial?
A main effect summarizes the association between one randomized factor and the outcome while accounting for the other factor in the factorial structure. For ENCHANTED, one main-effect question concerns rtPA dose and another concerns blood-pressure management.
What is an interaction?
An interaction occurs when the effect of one treatment dimension differs depending on the level of the other dimension. For example, an interaction would mean that the comparison between low-dose and standard-dose rtPA is different under intensive BP lowering than under BP management policies. An interaction is therefore about whether treatment effects vary across combinations, not simply whether one overall comparison is statistically significant.
Why report a confidence interval?
A confidence interval communicates the precision of an estimated treatment effect. A narrow interval indicates greater statistical precision than a wide interval, while the location of the interval indicates which effect sizes remain compatible with the data and the chosen statistical model.
Why is a p-value not an effect size?
A p-value addresses evidence against a specified null hypothesis under a statistical model. It does not describe the magnitude of the treatment effect. For a clinical outcome such as death and disability, an effect estimate and its confidence interval are needed to understand the size and precision of the observed difference.
8. Interpreting the 90-Day Endpoint
The primary endpoint represents the probability that a participant has a 90-day modified Rankin Scale score of 2-6. An analysis of this endpoint therefore compares the frequency of the defined death-and-disability outcome across randomized treatment groups.
The endpoint does not by itself distinguish among the individual mRS scores from 2 through 6. A participant with an mRS score of 2 and a participant with an mRS score of 6 are both classified as events under this definition.
An absolute risk difference and a relative risk ratio answer different questions. The risk difference describes how many additional or fewer events occur per unit of the analyzed population, whereas a risk ratio describes the proportional relationship between the event probabilities.
The four-arm structure should not automatically be treated as an ordinary four-group comparison. The factorial design has two identifiable treatment dimensions, so the statistical interpretation should preserve those dimensions and distinguish main effects from any interaction between them.
9. Analysis Populations and Randomization
The registry identifies ENCHANTED as randomized, but the available registry information does not provide detailed definitions for intention-to-treat, per-protocol, or safety analysis populations.
| Feature | Registry information |
|---|---|
| Randomization | Randomized |
| Enrollment | 4587 |
| Arms | 4 |
| Masking | Single |
| Analysis population definitions | Not reported in the available registry information |
| Arm-level enrollment | Not reported in the available registry information |
Randomization is important statistically because it creates the basis for comparing treatment groups without relying on observational adjustment alone. The factorial structure then extends that randomized comparison across two treatment dimensions.
10. Safety and Secondary Outcomes
The available registry information identifies the primary endpoint but does not provide posted statistical analyses or arm-specific serious-adverse-event results. Accordingly, there are no safety effect estimates to interpret here.
11. Trial Timeline
Trial start
The ENCHANTED study began in March 2012 according to the registry.
Randomized factorial study
The trial used randomized allocation, a factorial design, single masking, and four arms, with a total enrollment of 4587 participants.
Primary completion
The registry lists August 2018 as the primary completion date.
Registry status
The current registry record identifies the study status as completed.
12. Understanding the Factorial Trial Statistically
The most important statistical feature of ENCHANTED is its factorial structure. A factorial design is not simply a four-arm trial with four unrelated treatment groups. The four groups arise from combinations of two treatment dimensions.
| Statistical concept | Application to ENCHANTED |
|---|---|
| Factor | A randomized treatment dimension, such as rtPA dose or BP management. |
| Level | A specific option within a factor, such as low-dose or standard-dose rtPA. |
| Factorial combination | A particular combination of levels from the two treatment dimensions. |
| Main effect | The overall treatment effect associated with one factor within the factorial structure. |
| Interaction | Evidence that the effect of one factor depends on the level of the other factor. |
| Binary endpoint | The 90-day mRS 2-6 definition creates an event/non-event outcome. |
| Unadjusted analysis | The registry defines the primary endpoint as an unadjusted mRS 2-6 measure. |
Why interaction deserves special attention
Suppose the effect of rtPA dose were essentially the same regardless of the BP-management strategy. In that situation, a main-effect summary can describe the rtPA comparison efficiently. If the effect of rtPA differed substantially between the BP strategies, however, a single overall rtPA effect could conceal an important feature of the trial.
The same reasoning applies in the opposite direction. The BP-management comparison may be summarized across rtPA levels only when that summary is scientifically and statistically appropriate. Interaction assessment is therefore a central component of interpreting a factorial experiment.
13. Primary Endpoint: Statistical Interpretation
What is measured?
Whether the participant has an unadjusted modified Rankin Scale score of 2-6 at 90 days.
What is compared?
The frequency of the defined outcome across randomized treatment comparisons within the factorial design.
What is the time point?
The registry specifies 90 days.
What remains unknown?
The available registry information does not provide a posted effect estimate, confidence interval, or p-value.
The absence of a posted statistical estimate means the endpoint should be understood primarily through its definition and design context rather than through an effect-size summary. The correct statistical analysis would depend on the prespecified statistical analysis plan, including the exact treatment contrasts, handling of the factorial structure, hypothesis-testing framework, and analysis population.
14. Limitations
- No posted statistical analysis: the registry does not provide a formal statistical analysis for the primary endpoint in the available record.
- No posted effect estimates: no primary-endpoint risk difference, risk ratio, odds ratio, confidence interval, or p-value is reported in the available statistical-analysis information.
- No arm-level sample sizes: the registry reports total enrollment of 4587 and four arms but does not provide arm-level enrollment in the information available here.
- Binary endpoint compression: converting mRS into scores 2-6 versus lower scores discards some information about the ordering and severity of disability across individual mRS categories.
- Factorial interaction: interpretation of the main effects depends on whether the two treatment dimensions can appropriately be summarized without a clinically important interaction.
- Analysis-population detail: detailed definitions for efficacy and safety analysis populations are not reported in the available registry information.
- Statistical-plan detail: the available registry information does not specify the complete hypothesis-testing, multiplicity, missing-data, or covariate-adjustment framework.
15. What Can and Cannot Be Learned From the Endpoint Definition
The primary endpoint definition tells us exactly what clinical state is being counted at 90 days, but it does not by itself tell us the magnitude of any treatment effect. This distinction is fundamental in trial interpretation.
| Information | What the endpoint definition tells us | What requires an observed analysis |
|---|---|---|
| Outcome | mRS score 2-6 constitutes the combined death-and-disability endpoint. | How frequently the outcome occurred. |
| Timing | The assessment is at 90 days. | The observed difference between groups. |
| Scale | The modified Rankin Scale is used. | The distribution of individual mRS scores. |
| Analysis type | The endpoint is naturally binary when coded as 2-6 versus below 2. | The prespecified effect measure and hypothesis test. |
| Factorial interpretation | Two treatment dimensions are present. | The estimated main effects and any interaction. |
16. Why This Trial Matters Statistically
ENCHANTED is a useful statistical teaching case because it combines a randomized phase 3 experiment with a factorial design and a clinically interpretable binary functional outcome. The design illustrates how one trial can address more than one treatment question while requiring careful attention to interaction and treatment contrasts.
| Concept | How it appears in ENCHANTED |
|---|---|
| Randomization | Participants were randomly allocated. |
| Factorial design | The trial is identified as factorial with four arms. |
| Multiple treatment dimensions | rtPA dose and blood-pressure management are both studied. |
| Binary endpoint | 90-day mRS 2-6 defines the combined death-and-disability outcome. |
| Unadjusted endpoint | The registry explicitly describes the primary endpoint as unadjusted. |
| Interaction | The factorial design raises the question of whether one treatment effect depends on the other factor. |
| Effect measures | Risk difference, risk ratio, and odds ratio are natural measures for a binary endpoint. |
| Confidence intervals | Precision should accompany any reported treatment-effect estimate. |
| Clinical interpretation | The mRS threshold combines death and disability into one prespecified outcome. |
17. Related Tutorials
Learn more about the methods used in this trial:
18. Related Calculators
19. Sources
- ClinicalTrials.gov: ENCHANTED — NCT01422616.
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20. Record Summary
ENCHANTED is a completed phase 3 randomized factorial trial involving 4587 participants with ischemic stroke and high blood pressure. The study has four arms and evaluates two treatment dimensions: low-dose versus standard-dose rtPA and intensive blood-pressure lowering versus BP management policies. Its registered primary endpoint is combined death and disability at 90 days, defined as an unadjusted modified Rankin Scale score of 2-6.
From a statistical perspective, the factorial structure is central. The trial can be understood as a framework for estimating the effects of two randomized treatment dimensions while also considering whether those dimensions interact. The primary endpoint is binary after applying the registry's mRS threshold, making measures such as risk difference, risk ratio, and odds ratio natural ways to quantify treatment effects once outcome data are available.
The registry does not post formal statistical analyses for the primary endpoint. The most important methodological questions therefore concern the factorial contrasts, the treatment-by-treatment interaction, the binary endpoint definition, and the distinction between an unadjusted outcome definition and the statistical model ultimately used to compare randomized groups.