This page separates reported trial results from statistical interpretation. Numerical results presented here are restricted to the ClinicalTrials.gov record for NCT03399370 and its posted statistical analyses.
1. Trial at a Glance
ORION-10 was a randomized, parallel-group, double-masked phase 3 trial of inclisiran versus placebo in participants with atherosclerotic cardiovascular disease and elevated cholesterol. The registry reports an enrollment of 1561 participants and two primary endpoints focused on change in low-density lipoprotein cholesterol (LDL-C).
| Feature | ORION-10 |
|---|---|
| Trial | ORION-10 |
| Phase | Phase 3 |
| Status | Completed |
| Population | Participants with atherosclerotic cardiovascular disease and elevated low-density lipoprotein cholesterol |
| Design | Randomized, parallel-group, double-masked |
| Allocation | Randomized |
| Arms | 2 |
| Interventions | Inclisiran Sodium and Placebo |
| Enrollment | 1561 |
| Primary purpose | Treatment |
| Lead sponsor | The Medicines Company |
| Sponsor type | Industry |
| ClinicalTrials.gov | NCT03399370 |
2. Clinical Question
The statistical question is whether treatment with inclisiran produces a different LDL-C response from placebo in participants with atherosclerotic cardiovascular disease and elevated low-density lipoprotein cholesterol. The registry reports two primary endpoints: percentage change in LDL-C from baseline to Day 510 and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540.
Population
Participants with atherosclerotic cardiovascular disease and elevated low-density lipoprotein cholesterol.
Intervention
Inclisiran Sodium.
Comparator
Placebo, identified in the registry's safety data as Saline Solution.
Primary question
Does inclisiran produce a different LDL-C change from placebo under the prespecified superiority analyses?
3. Trial Design
Inclisiran
- Inclisiran Sodium
- Evaluated against placebo
- Primary efficacy analyses conducted in the ITT population
Placebo
- Placebo
- Identified as Saline Solution in the reported safety data
- Comparator for all reported efficacy analyses
The registry does not provide additional design features in the ClinicalTrials.gov record such as a factorial structure, crossover procedure, non-inferiority margin, Bayesian model, or interim-analysis framework. Those topics therefore are not used to characterize the statistical design of this page.
4. Trial Timing and Enrollment
Trial start
The registry lists December 21, 2017 as the study start date.
Primary completion
The registry lists September 10, 2019 as the primary completion date.
The trial is listed as completed. The registry reports 1561 enrolled participants and two treatment arms.
5. Endpoints
| Endpoint | Registry definition / time frame | Analysis |
|---|---|---|
| Percentage Change in LDL-C From Baseline to Day 510 | Baseline, Day 510 | ANCOVA; ITT population; inclisiran vs placebo |
| Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 | Baseline, Day 90 to Day 540 | ANCOVA; ITT population; inclisiran vs placebo |
The registry identifies both primary endpoints as binary in its inferred endpoint-type field, while the reported outcome unit is percent change and the posted analysis uses ANCOVA with a mean-difference effect measure. This page preserves those registry classifications rather than replacing them with an inferred endpoint type.
6. Statistical Methodology
Analysis population: intention-to-treat
All eight posted statistical analyses use the intent-to-treat (ITT) population. In an ITT analysis, participants are analyzed according to their randomized treatment assignment rather than being reassigned according to subsequent treatment exposure. This preserves the treatment comparison created by randomization as the basis of the efficacy analysis.
ANCOVA
The registry reports analysis of covariance (ANCOVA) for both primary endpoints and all six secondary analyses reported in the ClinicalTrials.gov record. ANCOVA is a linear-model approach that can compare treatment groups while accounting for relevant covariate information specified by the analysis.
For this record, the reported treatment effect is expressed as a least squares mean difference from placebo. The ClinicalTrials.gov record does not identify the individual covariates included in the ANCOVA model, so none are added to the analysis description.
Least squares mean difference
The effect measure is reported as Mean Difference (Final Values), normalized to mean difference. The analysis notes clarify that the estimate represents the least squares mean difference from placebo.
Because the reported endpoint is percentage change in LDL-C, a negative estimate indicates a lower modeled percentage-change value in the inclisiran group relative to placebo.
Two-sided confidence intervals
Every posted statistical analysis reported in the ClinicalTrials.gov record reports a 95% two-sided confidence interval. The interval describes statistical uncertainty around the estimated treatment difference under the analysis model and sampling framework. It does not describe the range of individual participant responses.
Superiority testing
All eight analyses are labeled as superiority analyses. This means the statistical question is whether the treatment groups differ rather than whether one treatment remains within a prespecified non-inferiority or equivalence margin.
7. Primary Results
ClinicalTrials.gov reports formal statistical analyses for both registered primary endpoints. Both analyses were performed in the ITT population using ANCOVA and report least squares mean differences from placebo.
Primary Endpoint 1: Percentage Change in LDL-C From Baseline to Day 510
Least squares mean difference from placebo
95% CI: -60.86 to -54.43 · P < .0001
Analysis population: Intent-to-treat (ITT) · Method: ANCOVA
| Feature | Reported result |
|---|---|
| Endpoint | Percentage Change in LDL-C From Baseline to Day 510 |
| Time frame | Baseline, Day 510 |
| Groups | Inclisiran vs Placebo |
| Analysis population | Intent-to-treat (ITT) |
| Method | ANCOVA |
| Effect measure | Mean Difference (Final Values) |
| Estimate | -57.64 |
| 95% CI | -60.86 to -54.43 |
| P-value | <.0001 |
| Hypothesis type | Superiority |
The reported estimate of -57.64 is a least squares mean difference from placebo for the percentage change in LDL-C from baseline to Day 510. The negative sign indicates that the modeled percentage-change outcome was lower in the inclisiran group than in the placebo group by 57.64 percentage points on the reported effect scale.
The estimate is not a hazard ratio, relative risk, probability of response, or percentage of participants who benefited. It also does not mean that every participant experienced exactly the same change.
The 95% confidence interval of -60.86 to -54.43 quantifies uncertainty around the estimated least squares mean difference. Its relatively narrow span provides information about the statistical precision of this estimate; it does not describe individual-level biological variability.
The P-value of <.0001 addresses the strength of evidence against the null hypothesis under the specified statistical framework. A p-value is not a measure of effect size and does not tell us how clinically important an effect is. The magnitude of the estimated difference and its confidence interval are needed to understand the size and precision of the observed treatment-group difference.
Because the analysis is ANCOVA rather than a time-to-event model, proportional-hazards assumptions are not relevant to this particular endpoint. The result is also an ITT analysis, so the comparison remains anchored to randomized treatment assignment.
Primary Endpoint 2: Time-adjusted Percentage Change in LDL-C After Day 90 and up to Day 540
Least squares mean difference from placebo
95% CI: -56.23 to -51.33 · P < 0.0001
Analysis population: Intent-to-treat (ITT) · Method: ANCOVA
| Feature | Reported result |
|---|---|
| Endpoint | Time-adjusted Percentage Change in LDL-C Levels From Baseline After Day 90 and up to Day 540 |
| Time frame | Baseline, Day 90 to Day 540 |
| Groups | Inclisiran vs Placebo |
| Analysis population | Intent-to-treat (ITT) |
| Method | ANCOVA |
| Effect measure | Mean Difference (Final Values) |
| Estimate | -53.78 |
| 95% CI | -56.23 to -51.33 |
| P-value | <0.0001 |
| Hypothesis type | Superiority |
The reported estimate of -53.78 represents the least squares mean difference from placebo for the time-adjusted percentage change in LDL-C over the registry-defined period after Day 90 and up to Day 540.
As with the first primary endpoint, the negative estimate describes a lower modeled percentage-change value in the inclisiran group relative to placebo. It is not a statement that 53.78% of participants responded, nor does it represent a relative risk or hazard ratio.
The 95% confidence interval of -56.23 to -51.33 indicates the uncertainty associated with the estimated treatment difference. Confidence intervals should be interpreted as properties of the statistical estimation procedure rather than as a prediction interval for individual patients.
The P-value of <0.0001 indicates strong statistical evidence against the null hypothesis in the reported superiority analysis. It should not be interpreted as a probability that the null hypothesis is true or as a direct measure of the magnitude of the treatment effect.
The time-adjusted nature of the endpoint is important: it is not simply another single-day LDL-C measurement. The registry specifically defines the endpoint over the period after Day 90 and up to Day 540, with the time-adjusted percent change at Day 540 reported.
8. Primary Results in Context
| Primary endpoint | Estimate | 95% CI | P-value |
|---|---|---|---|
| Percentage Change in LDL-C From Baseline to Day 510 | -57.64 | -60.86 to -54.43 | <.0001 |
| Time-adjusted Percentage Change in LDL-C From Baseline After Day 90 and up to Day 540 | -53.78 | -56.23 to -51.33 | <0.0001 |
Both primary analyses point in the same direction on the reported mean-difference scale: the estimated least squares mean difference from placebo is negative. Both confidence intervals are entirely below zero, and both analyses have p-values below the reported thresholds.
The visual comparison above is intended only to display the reported point estimates on a common scale. It is not a substitute for the confidence intervals and formal analyses, and it does not establish whether the two endpoint estimates are statistically different from one another.
9. Secondary Endpoint Results
The registry supplies six secondary statistical analyses. All use the ITT population, compare inclisiran with placebo, use ANCOVA, report a least squares mean difference from placebo, and use a superiority hypothesis framework.
| Secondary endpoint | Estimate | 95% CI | P-value |
|---|---|---|---|
| Absolute Change in LDL-C From Baseline to Day 510 | -54.12 mg/dL | -57.37 to -50.88 | <0.0001 |
| Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540 | -53.28 mg/dL | -55.75 to -50.80 | <0.0001 |
| Percentage Change in PCSK9 From Baseline to Day 510 | -83.80 | -89.25 to -77.34 | <0.0001 |
| Percentage Change in Total Cholesterol From Baseline to Day 510 | -33.13 | -35.30 to -30.97 | <0.0001 |
| Percentage Change in Apolipoprotein B (ApoB) From Baseline to Day 510 | -43.09 | -45.50 to -40.67 | <.0001 |
| Percentage Change in Non-HDL-C From Baseline to Day 510 | -47.36 | -50.25 to -44.47 | <0.0001 |
How to read the secondary results
The six secondary estimates are all negative on their reported mean-difference scales. For the absolute LDL-C endpoints, the outcome unit is mg/dL; for the PCSK9, total cholesterol, ApoB, and non-HDL-C endpoints, the outcome unit is percent change.
The estimates should therefore not be compared as if they were interchangeable quantities. For example, -54.12 mg/dL for absolute LDL-C and -83.80 for percentage change in PCSK9 are expressed on different scales and represent different biological variables.
10. Secondary Results: What the Effect Measures Mean
Absolute LDL-C change
The absolute LDL-C analyses are reported in mg/dL. A mean difference of -54.12 mg/dL for the Day 510 endpoint means that the estimated least squares mean change in the inclisiran group was 54.12 mg/dL lower than the corresponding placebo value on the reported analysis scale.
Percentage change in PCSK9
The PCSK9 analysis reports an estimated mean difference of -83.80. This is a percentage-change endpoint, so the estimate is expressed on a percentage-change scale rather than an absolute concentration scale.
Total cholesterol, ApoB, and non-HDL-C
The same statistical framework was applied to percentage changes in total cholesterol, ApoB, and non-HDL-C. Their respective estimated differences were -33.13, -43.09, and -47.36. The negative direction is consistent across these reported endpoints, but each estimate pertains to a different outcome.
Point estimate
Describes the estimated treatment-group difference on the endpoint's own measurement scale.
Confidence interval
Shows the statistical uncertainty around that estimated difference.
P-value
Addresses evidence against the null hypothesis; it does not quantify effect magnitude.
Outcome scale
Determines how the numerical estimate should be interpreted. mg/dL and percent change are not interchangeable.
11. Safety Results
The ClinicalTrials.gov record reports serious adverse events by treatment arm. The affected and at-risk counts are provided directly for the two groups.
| Safety measure | Inclisiran | Saline Solution |
|---|---|---|
| Serious adverse events | 175 / 781 | 205 / 778 |
Reported serious adverse events
Inclisiran vs Saline Solution
The reported serious-adverse-event data should be kept separate from the efficacy analyses. The efficacy results use the ITT population and ANCOVA, whereas the ClinicalTrials.gov record is summarized as affected participants divided by participants at risk in each arm.
The ClinicalTrials.gov record does not provide a formal statistical comparison, confidence interval, or p-value for serious adverse events. It would therefore be inappropriate to manufacture a comparative safety test from the counts alone when the task is to reproduce the posted statistical evidence.
12. Statistical Methods Explained
Why was ANCOVA used for these endpoints?
ANCOVA is a linear-model framework suited to continuous quantitative outcomes such as changes measured on an LDL-C scale. It estimates a treatment-group difference while allowing the model to account for specified covariate information. The ORION-10 registry record reports ANCOVA for all eight posted analyses.
What does a least squares mean difference of -57.64 mean?
It is the reported adjusted treatment-group difference for the percentage change in LDL-C from baseline to Day 510, expressed as the inclisiran least squares mean minus the placebo least squares mean. The negative value indicates a lower modeled percentage-change outcome for inclisiran on this scale.
Why does the confidence interval matter?
The estimate alone gives a single best estimate from the model. The 95% confidence interval adds information about statistical precision. For the Day 510 primary endpoint, the reported interval is -60.86 to -54.43, showing the uncertainty around the point estimate of -57.64.
Why doesn't the p-value measure the size of the treatment effect?
A p-value is a measure of how compatible the observed data are with a specified null hypothesis under the statistical model. It is affected by both the estimated effect and the amount of information in the analysis. A very small p-value therefore does not, by itself, tell a reader whether an effect is small, moderate, or large.
What does ITT contribute to the analysis?
The ITT framework keeps participants associated with their randomized assignment for the efficacy comparison. This protects the interpretability of randomization as the basis for the treatment comparison and avoids changing the primary comparison simply because participants' treatment exposure differs after randomization.
Why are the Day 510 and Day 90-to-Day 540 endpoints not the same analysis?
The first primary endpoint is a percentage change from baseline to a specified Day 510 assessment. The second is explicitly time-adjusted over the period after Day 90 and up to Day 540, with the registry defining the reported time-adjusted percent change at Day 540. They therefore summarize different aspects of the LDL-C trajectory.
Does a negative estimate automatically mean clinical importance?
No. A negative estimate establishes direction on the reported statistical scale, not clinical importance by itself. Clinical interpretation requires consideration of the endpoint, its measurement scale, the magnitude of the difference, uncertainty, study population, and the broader clinical context. The ClinicalTrials.gov record supports the statistical estimates but do not provide a separate clinical-importance threshold.
13. Confidence Intervals and Statistical Precision
Confidence intervals are particularly useful in this trial because every posted analysis includes a 95% two-sided interval. They allow the reader to see the range of parameter values that remain compatible with the observed data under the specified statistical procedure more clearly than a p-value alone.
| Endpoint | Estimate | 95% confidence interval |
|---|---|---|
| LDL-C percentage change, Day 510 | -57.64 | -60.86 to -54.43 |
| Time-adjusted LDL-C percentage change | -53.78 | -56.23 to -51.33 |
| LDL-C absolute change, Day 510 | -54.12 mg/dL | -57.37 to -50.88 |
| Time-adjusted LDL-C absolute change | -53.28 mg/dL | -55.75 to -50.80 |
| PCSK9 percentage change | -83.80 | -89.25 to -77.34 |
| Total cholesterol percentage change | -33.13 | -35.30 to -30.97 |
| ApoB percentage change | -43.09 | -45.50 to -40.67 |
| Non-HDL-C percentage change | -47.36 | -50.25 to -44.47 |
Across the eight reported analyses, the confidence intervals remain entirely below zero. This is consistent with the reported superiority hypothesis tests and the corresponding p-values. The intervals also make clear that statistical significance and precision are related but distinct concepts: a confidence interval communicates the uncertainty and scale of the estimated effect, whereas a p-value summarizes evidence against a null hypothesis.
14. Reading the ANCOVA Results Correctly
The core result of ORION-10 is not simply that the p-values are small. The registry reports a coherent set of ANCOVA estimates showing negative least squares mean differences from placebo for both primary LDL-C endpoints and all six secondary biochemical endpoints reported in the ClinicalTrials.gov record.
The estimates quantify the modeled difference between inclisiran and placebo on each endpoint's specified scale. For example, the Day 510 LDL-C percentage-change estimate is -57.64, while the Day 510 absolute LDL-C estimate is -54.12 mg/dL.
These estimates do not describe the response of every participant, do not establish a probability that an individual participant will achieve a particular outcome, and should not be interpreted as interchangeable measures across different biomarkers or measurement scales.
The posted efficacy analyses use the ITT population. That means the reported estimates are treatment-assignment comparisons rather than comparisons restricted only to participants who adhered perfectly to treatment.
15. Primary vs Secondary Evidence
| Evidence level | Endpoints | Statistical interpretation |
|---|---|---|
| Primary | LDL-C percentage change to Day 510; time-adjusted LDL-C percentage change after Day 90 and up to Day 540 | Prespecified primary questions with formal ANCOVA analyses reported in the ITT population |
| Secondary | Absolute LDL-C, time-adjusted absolute LDL-C, PCSK9, total cholesterol, ApoB, non-HDL-C | Additional efficacy outcomes analyzed using the same reported ANCOVA framework |
| Safety | Serious adverse events | Reported as affected / at-risk counts by arm; no formal comparative analysis reported |
This hierarchy matters because a clinical trial can contain many statistically significant secondary findings without every one carrying the same confirmatory status as a primary endpoint. The ClinicalTrials.gov record identifies the endpoint roles but do not provide a multiplicity-adjustment scheme, so this page does not infer one.
16. Limitations and Interpretation Issues
- Registry-level statistical detail: the ClinicalTrials.gov record identifies ANCOVA, the ITT population, the mean-difference effect measure, confidence intervals, and p-values, but does not specify the complete ANCOVA model or all covariates. Those details are therefore not inferred here.
- Endpoint classification: the registry's inferred endpoint type is listed as binary for the two primary endpoints even though the reported outcome unit is percent change and the statistical method is ANCOVA. This page preserves the registry's classification rather than silently changing it.
- Multiplicity: two primary endpoints and six secondary analyses are reported, but the ClinicalTrials.gov record does not state how multiplicity across these tests was controlled. Individual p-values should therefore not be interpreted as evidence of an unreported familywise error strategy.
- Safety inference: serious adverse events are provided as affected/at-risk counts, but the ClinicalTrials.gov record does not report a formal between-group test or confidence interval for that safety outcome.
- Missing-data methods: the statistical analyses posted on ClinicalTrials.gov do not identify an imputation method or other missing-data strategy. No imputation procedure is therefore attributed to the trial.
- Model assumptions: ANCOVA relies on assumptions appropriate to the specified linear model. Because the ClinicalTrials.gov record does not describe diagnostic procedures or model-assumption checks, none are claimed here.
- Generalizability: the analysis describes the enrolled trial population and randomized comparison. The ClinicalTrials.gov record does not provide a detailed baseline-characteristics table from which broader population-representativeness claims could be made.
- Statistical versus clinical importance: the reported p-values establish statistical evidence under the posted analyses but do not, by themselves, establish the clinical importance of any estimated difference.
17. What Is Not Reported in the Supplied Statistical Data
The ClinicalTrials.gov record contains eight formal statistical analyses, but they do not provide several design and analysis details that are sometimes included in a full statistical-analysis report.
Not specified
Individual covariates included in the ANCOVA models.
Not specified
Formal missing-data or imputation strategy.
Not specified
Multiplicity-adjustment or alpha-allocation procedure.
Not specified
Interim-analysis framework or stopping boundary.
These omissions are not evidence that such procedures were absent from the underlying trial protocol or statistical analysis plan. They simply are not contained in the ClinicalTrials.gov record and therefore are not reconstructed here.
18. Why This Trial Matters Statistically
ORION-10 is a useful teaching example because the registry combines randomized treatment allocation, double masking, ITT efficacy analysis, ANCOVA, least squares mean differences, two-sided confidence intervals, superiority testing, and multiple biochemical endpoints in a single phase 3 trial.
| Concept | How it appears in ORION-10 |
|---|---|
| Randomization | Participants were randomized to two parallel treatment arms. |
| Blinding | The study is reported as double-masked. |
| Intention-to-treat | All eight posted statistical analyses use the ITT population. |
| ANCOVA | Reported as the statistical method for both primary and all six secondary analyses. |
| Least squares mean difference | The reported effect measure represents the least squares mean difference from placebo. |
| Confidence interval | Each analysis reports a 95% two-sided confidence interval. |
| P-value | Each formal analysis reports a superiority p-value. |
| Multiple endpoints | Two primary endpoints and six secondary outcomes are reported. |
| Safety analysis | Serious adverse events are reported as affected / at-risk counts by arm. |
The statistical lesson is that the numerical result is inseparable from its model and estimand. A point estimate such as -57.64 has meaning only because the reader knows the endpoint, time frame, treatment comparison, analysis population, statistical method, and effect-measure definition.
19. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: NCT03399370 — ORION-10. Official trial registry record and source for the trial data summarized on this page.
- PubMed record: PMID 41604274.
- PubMed record: PMID 38757725.
- PubMed record: PMID 38063346.
- PubMed record: PMID 37282500.
- PubMed record: PMID 32187462.
Continue through the Clinical Biostats statistical library
Use the related tutorials and calculators to explore the statistical concepts that underlie randomized trials, ANCOVA, confidence intervals, hypothesis testing, and intention-to-treat analysis.
22. Record Summary
ORION-10 provides a clear example of a randomized phase 3 treatment comparison analyzed with ANCOVA. The ClinicalTrials.gov record reports two primary LDL-C endpoints and six secondary biochemical endpoints, all analyzed in the ITT population with least squares mean differences from placebo, 95% two-sided confidence intervals, and superiority p-values. The primary Day 510 percentage-change analysis reports an estimate of -57.64 with a 95% CI of -60.86 to -54.43 and P <.0001; the time-adjusted primary endpoint reports -53.78 with a 95% CI of -56.23 to -51.33 and P <0.0001.
The broader statistical picture is equally important. The secondary analyses extend the same modeling framework to absolute LDL-C, PCSK9, total cholesterol, ApoB, and non-HDL-C. Serious adverse events are reported separately as affected/at-risk counts of 175/781 for inclisiran and 205/778 for Saline Solution. Together, these data illustrate how treatment effects should be interpreted through the combination of an explicitly defined endpoint, analysis population, model, effect measure, confidence interval, and hypothesis test rather than through a p-value alone.