This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C) (NCT02597127), a randomized phase 2 study. The primary outcome is Percentage Change in LDL-C From Baseline to Day 180.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02597127 |
| Phase | Phase 2 |
| Condition | Atherosclerotic Cardiovascular Disease, Familial Hypercholesterolemia, Diabetes |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 501 |
| Arms in the primary outcome | 8 |
| Lead sponsor | The Medicines Company |
| Results posted | Yes |
2. Clinical Question
Population
Participants had atherosclerotic cardiovascular disease or an ASCVD-risk equivalent, such as diabetes or familial hypercholesterolemia, and elevated LDL-C despite maximum tolerated LDL-C-lowering therapy. The primary outcome is described for the modified intent-to-treat population. The brief summary describes 480 participants, while the registry lists enrollment of 501; the relationship between those figures is not reported in the registry record.
Intervention
Participants were assigned to ALN-PCSSC at different doses and schedules. The single-dose regimens were administered once at Day 1. The other regimens were administered at Day 1 and Day 90. The listed doses were 100 mg, 200 mg, 300 mg, and 500 mg, though not every dose appears in both schedules.
Comparator
Normal saline served as placebo, with a single-dose schedule and a schedule with administrations at Day 1 and Day 90. The registry’s outcome groups label these comparators as single-dose and double-dose placebo.
Primary question
The primary question was how percentage change in LDL-C from baseline to Day 180 differed across the ALN-PCSSC dose and schedule groups and their placebo groups. The registry reports least-squares means and 95% confidence intervals for the modified intent-to-treat population. It also records one-sided sponsor-reported t-tests comparing each active group with the corresponding placebo group.
3. Trial Design
The registry describes a randomized, double-blind, parallel-group, placebo-controlled Phase II trial. It lists The Medicines Company as sponsor and gives the trial status as completed. The recorded start is 2016-01, and the primary completion date is 2017-06-07.
The study compared ALN-PCSSC dose and schedule groups with normal-saline placebo groups. The single-dose groups received one administration at Day 1. The other active groups and placebo group received administrations at Day 1 and Day 90. The registry calls these schedules bi-annual dosing and quarterly dosing in its arm descriptions, while the results use single-dose and double-dose labels. These schedule labels describe the administrations specified in the record; no additional dosing details are reported in the registry record.
The registry lists enrollment of 501. Its brief summary describes a study in 480 participants. These are different figures in the record, and the reason for the difference is not reported in the registry record. The primary outcome specifies a modified intent-to-treat population, with group denominators shown alongside the posted estimates. The registry does not report the allocation procedure, concealment details, or further eligibility criteria beyond the description of cardiovascular risk and elevated LDL-C despite maximum tolerated LDL-C-lowering therapy.
The outcome set includes the primary percentage change in LDL-C at Day 180 and secondary outcomes addressing LDL-C at other time points, LDL-C response thresholds, PCSK9, other lipid measures, and attainment of lipid targets. The registry lists 10 outcome measures and posts 9 secondary outcomes. More detail about how the secondary outcomes were analyzed is not reported in the registry record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Only the first 6 of 8 groups are shown.
Overall Study
| Stage | Inclisiran 200 mg (Single-dose) | Inclisiran 300 mg (Single-dose) | Inclisiran 500 mg (Single-dose) | Placebo (Single-dose) | Inclisiran 100 mg (Double-dose) | Inclisiran 200 mg (Double-dose) |
|---|---|---|---|---|---|---|
| STARTED | 60 | 62 | 66 | 65 | 62 | 63 |
| Treated | 60 | 61 | 65 | 65 | 61 | 62 |
| COMPLETED | 59 | 59 | 58 | 60 | 57 | 59 |
| NOT COMPLETED | 1 | 3 | 8 | 5 | 5 | 4 |
Analysis population for the primary outcome, as defined in the registry: Modified intent-to-treat (MITT) population
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Only the first 6 of 9 groups are shown.
| Characteristic | Unit | Placebo (Single-dose) | Inclisiran 200 mg (Single-dose) | Inclisiran 300 mg (Single-dose) | Inclisiran 500 mg (Single-dose) | Placebo (Double-dose) | Inclisiran 100 mg (Double-dose) |
|---|---|---|---|---|---|---|---|
| Participants analysed | 65 | 60 | 62 | 66 | 62 | 62 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 40 | 30 | 27 | 32 | 32 | 24 |
| Age, Categorical: >=65 years | Participants | 25 | 30 | 35 | 34 | 30 | 38 |
| Age, Continuous | years | 62.0 (SD 11.4) | 63.9 (SD 10.8) | 64.1 (SD 12.8) | 62.1 (SD 12.4) | 62.8 (SD 10.3) | 65.2 (SD 9.4) |
| Sex: Female, Male: Female | Participants | 23 | 21 | 20 | 19 | 29 | 23 |
| Sex: Female, Male: Male | Participants | 42 | 39 | 42 | 47 | 33 | 39 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 7 | 4 | 3 | 1 | 2 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 58 | 56 | 59 | 65 | 60 | 60 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 1 | 0 | 1 | 1 | 0 | 2 |
| Race (NIH/OMB): Asian | Participants | 0 | 2 | 2 | 2 | 1 | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 1 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 4 | 4 | 2 | 0 | 3 | 2 |
| Race (NIH/OMB): White | Participants | 59 | 53 | 56 | 63 | 58 | 57 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 | 1 | 0 | 0 | 0 | 0 |
| Region of Enrollment: Canada | Participants | 8 | 8 | 7 | 12 | 10 | 10 |
| Region of Enrollment: Netherlands | Participants | 22 | 21 | 21 | 21 | 20 | 20 |
| Region of Enrollment: United States | Participants | 12 | 10 | 10 | 12 | 8 | 10 |
| Region of Enrollment: United Kingdom | Participants | 11 | 11 | 11 | 11 | 10 | 9 |
| Region of Enrollment: Germany | Participants | 12 | 10 | 13 | 10 | 14 | 13 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage Change in LDL-C From Baseline to Day 180, measured over Baseline to 180 days.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | Percent change |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is percentage change in LDL-C from baseline to Day 180, measured by beta-quantification. The registry reports the outcome as a least-squares mean with a 95% confidence interval for the modified intent-to-treat population. Percentage change expresses the outcome relative to each participant’s baseline, rather than as an absolute LDL-C concentration. A lower or more negative percentage change represents a greater reduction from baseline in the measure being analyzed.
LDL-C is the trial’s target laboratory measure, and the registry identifies elevated LDL-C as part of the study population’s description. A Day 180 assessment provides a specified time point for comparing the groups after the assigned injection schedules. The outcome is continuous, so the posted group estimates summarize average percentage change rather than the number of participants crossing a response threshold. The registry also records secondary outcomes at other time points and outcomes based on thresholds, but those are distinct from the primary endpoint.
Least-squares means are model-based adjusted group summaries, but the model specification and covariates are not reported in the registry record. The confidence interval conveys uncertainty around each group estimate. It does not, by itself, provide a direct interval for the difference between an active group and placebo. The registry’s sponsor-reported tests address those group comparisons separately.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary estimates show a different pattern for placebo and ALN-PCSSC groups. The placebo estimates are close to zero: 2.1% for single-dose placebo and 1.8% for double-dose placebo. The ALN-PCSSC group estimates are negative. For example, the 200 mg single-dose group estimate is -27.9%, and the 300 mg double-dose group estimate is -52.6%. The confidence intervals for the active-group estimates are also negative, while the placebo intervals extend across zero. These are group estimates, not direct estimates of a between-group difference.
The registry reports a one-sided t-test for each active dose group against its corresponding placebo group. Each reported p-value is p < 0.001. These are sponsor-reported inferential results. The registry does not report a multiplicity adjustment for the set of comparisons, so the p-values should be read as individual reported tests rather than as evidence that a family-wise error procedure was applied.
Confidence intervals show the uncertainty associated with each group estimate under the analysis used. Their width gives a sense of precision, but a confidence interval for a group mean is not interchangeable with a confidence interval for a treatment contrast. Nor does a p-value describe the size of an effect or its practical importance. The registry does not post sponsor-reported contrast estimates or confidence intervals for these primary comparisons, so the magnitude of each adjusted contrast cannot be read directly from the reported tests.
Patterns across dose groups and schedules may be descriptively informative, but the registry does not report a formal dose-response test or a test comparing schedules. The numerical ordering of the group estimates should not be treated as a separate inferential finding without such analyses. The group estimates also do not establish how individual participants responded; some secondary outcomes address response thresholds, but they do not replace the primary mean outcome.
Overall, the posted primary results describe substantially more negative mean LDL-C percentage changes in the ALN-PCSSC groups than in the placebo groups at Day 180. The sponsor’s reported tests find each listed active group different from its corresponding placebo group under the stated one-sided tests. Interpretation remains bounded by the registry’s limited reporting of the analysis model, multiplicity approach, missing-data handling, and details of the analysis population.
9. Statistical Methods Explained
The primary outcome is continuous: each participant has a percentage change in LDL-C, and the registry summarizes the groups using least-squares means. A mean describes the central average of the measurements. Least-squares means usually arise from a statistical model and can account for specified factors, but the registry record does not describe the model or identify any covariates. It is therefore not possible to establish from the record which adjustments were made or how the model handled any departures from its assumptions.
A 95% confidence interval expresses the range of values compatible with the data and analysis under repeated use of the same statistical procedure. It communicates precision around each reported group estimate. A narrower interval indicates more precision than a wider interval, all else equal. The intervals reported for each arm concern that arm’s estimate; they are not automatically the intervals for a difference between arms. A direct comparison needs its own estimate and uncertainty calculation.
The registry’s sponsor-reported primary comparisons use one-sided t-tests and report p < 0.001 for each active group versus its corresponding placebo. A t-test evaluates evidence against a specified null hypothesis about a mean contrast, using the test’s assumptions. A one-sided test addresses evidence in a specified direction rather than either direction. The registry gives the test type and p-values but does not report the test statistic, contrast estimate, degrees of freedom, or further details of the test implementation. The p-value is not the probability that the null hypothesis is true, and it does not quantify the treatment contrast’s size.
The posted group estimates and confidence intervals can be used to understand the direction and precision of the within-group results. However, the registry does not post enough information to reproduce the model-based primary contrasts. A simple difference between two arm estimates would not necessarily equal the sponsor’s adjusted contrast and would not reproduce its standard error or test. No recalculated primary comparison is available in the registry record, and no discrepancy between a recalculation and the sponsor’s primary analysis is flagged.
The secondary outcome for percentage change in PCSK9 is presented as a mean with standard deviation. A standard deviation describes participant-to-participant spread within a group; it is not the uncertainty of the group mean. The posted secondary comparison calculations include mean differences, confidence intervals, and unadjusted p-values for selected comparisons. These are simple unadjusted re-calculations from the posted summary statistics, not sponsor-reported results. They do not account for possible covariate adjustment or multiplicity, and the registry does not report sponsor analyses for those particular comparisons.
The secondary binary outcome records the number of participants meeting the threshold of at least 50% LDL-C reduction by Day 180. A count alone does not show the precision of a proportion or the evidence for a comparison. The posted recalculated risk differences and confidence intervals for selected comparisons provide a contrast on the absolute probability scale. Those calculations are unadjusted and should not be interpreted as adjusted trial estimates. No sponsor-reported analyses are listed for that outcome.
Planning illustrations based on the PCSK9 comparisons use the observed effect as a reference and show participants per arm for 80% power and participants per arm for 90% power at the stated effect fractions. The assumptions specify a two-sided significance level of 0.05, equal allocation, and a normal approximation. For example, for 100% of the observed effect in the 200 mg single-dose comparison, the illustration gives 4 participants per arm for 80% power and 5 participants per arm for 90% power. These values are planning illustrations, not observed power, and do not describe the trial’s original design. The sample-size justification for the trial is not reported in the registry record.
Normal-approximation planning calculations depend on the effect size and variability used as inputs. Observed effects can be unstable, particularly when estimated in a study that is not designed to estimate that effect independently. The illustrations therefore do not establish what sample size would be suitable for a future study without assumptions about the target effect, variability, design, and analysis. Over-dispersion is a general concern when the variability in data exceeds what a model assumes: standard errors can then be too small and uncertainty understated. Whether over-dispersion is relevant to these outcomes cannot be determined from the registry record.
Finally, multiple outcomes and comparisons create a multiplicity issue. When many hypotheses are tested, the chance of at least one apparently unusual result can increase if no adjustment or testing hierarchy is used. The record reports several primary comparisons and multiple secondary outcomes, but does not report a multiplicity strategy. Consequently, individual unadjusted secondary p-values carry less inferential weight than results from a prespecified, fully described testing plan. The analysis plan, interim analyses, and missing-data methods are not reported in the registry record.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| t-test, 1 sided | not reported | < 0.001 | |
| t-test, 1 sided | not reported | < 0.001 | |
| t-test, 1 sided | not reported | < 0.001 | |
| t-test, 1 sided | not reported | < 0.001 | |
| t-test, 1 sided | not reported | < 0.001 | |
| t-test, 1 sided | not reported | < 0.001 |
The registry reports sponsor analyses for the primary endpoint: one-sided t-tests comparing each ALN-PCSSC group with its corresponding placebo group. Each reported test has p < 0.001. These tests are the sponsor’s inferential results in the registry. The group-level least-squares means and 95% confidence intervals provide context for the direction and precision of the arm estimates, but they are not themselves the sponsor’s between-group contrast estimates.
No recalculated primary pairwise contrasts are posted. The information available for the primary endpoint does not support reproducing the sponsor’s model-based comparisons, and the record does not flag a discrepancy between a recalculation and the sponsor analysis. Therefore, the sponsor-reported tests should be described as the available primary comparison results, while noting the limits of the registry’s reporting. The contrast estimates, contrast confidence intervals, test statistics, model details, and multiplicity procedure are not reported in the registry record.
For selected secondary outcomes, separate unadjusted calculations based on posted summary statistics are available, but the registry lists no sponsor-reported analyses for those comparisons. They are not substitutes for the sponsor’s primary analysis, and their unadjusted nature and limited scope should remain explicit.
11. Multiplicity, Missing Data and Analysis Populations
The registry reports several active-versus-placebo primary comparisons and a broader set of secondary outcomes, including outcomes at multiple time points. It does not report whether the primary comparisons were adjusted for multiplicity, whether a testing hierarchy was used, or whether a particular secondary outcome was designated as confirmatory. The sponsor-reported p-values should therefore be understood as the reported results of individual one-sided tests; the record does not establish family-wise error control across the set.
Multiplicity matters because repeated testing increases the opportunity for chance findings. Adjustment methods and prespecified hierarchies can address that issue, but different methods answer different questions and can affect interpretation. No such method is reported in the registry record, so none should be inferred. The unadjusted secondary calculations have an additional limitation: they are not sponsor-reported analyses and do not account for a trial-wide testing plan.
The primary outcome identifies the modified intent-to-treat population, but the registry does not describe the population definition in detail or explain how participants were included or excluded from that analysis. It also does not report how missing Day 180 measurements were handled, whether imputation was used, or whether sensitivity analyses examined missingness assumptions. The number of participants shown for an arm’s outcome is not, by itself, an explanation of missing-data handling.
The registry lists enrollment of 501 while the brief summary describes 480 participants. It does not explain the difference between the enrollment figure and the figure in the summary. The primary endpoint’s arm-specific denominators are also reported, but the record does not provide a reconciliation of those denominators with enrollment or the brief-summary figure. This limits assessment of the analysis population and participant flow.
Interim analyses, stopping rules, the statistical analysis plan, and sample-size justification are not reported in the registry record. Without these details, it is not possible to determine the planned control of type I error, the prespecification of the reported comparisons, or whether the posted analyses fully represent the intended analysis plan.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Placebo (Single Dose) | 3 | 65 | 4.6% |
| Inclisiran 200 mg (Single Dose) | 11 | 60 | 18.3% |
| Inclisiran 300 mg (Single Dose) | 11 | 61 | 18.0% |
| Inclisiran 500 mg (Single Dose) | 8 | 65 | 12.3% |
| Placebo (Double Dose) | 7 | 62 | 11.3% |
| Inclisiran 100 mg (Double Dose) | 13 | 61 | 21.3% |
| Inclisiran 200 mg (Double Dose) | 8 | 62 | 12.9% |
| Inclisiran 300 mg (Double Dose) | 9 | 61 | 14.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Placebo (Single Dose) | 0 of 65 |
| Inclisiran 200 mg (Single Dose) | 0 of 60 |
| Inclisiran 300 mg (Single Dose) | 0 of 61 |
| Inclisiran 500 mg (Single Dose) | 1 of 65 |
| Placebo (Double Dose) | 0 of 62 |
| Inclisiran 100 mg (Double Dose) | 0 of 61 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Placebo (Single Dose) | 50 of 65 |
| Inclisiran 200 mg (Single Dose) | 49 of 60 |
| Inclisiran 300 mg (Single Dose) | 49 of 61 |
| Inclisiran 500 mg (Single Dose) | 54 of 65 |
| Placebo (Double Dose) | 51 of 62 |
| Inclisiran 100 mg (Double Dose) | 47 of 61 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo (Single Dose) | Inclisiran 200 mg (Single Dose) | Inclisiran 300 mg (Single Dose) | Inclisiran 500 mg (Single Dose) | Placebo (Double Dose) | Inclisiran 100 mg (Double Dose) |
|---|---|---|---|---|---|---|---|
| Angina pectoris | Cardiac disorders | 0 of 65 | 1 of 60 | 1 of 61 | 1 of 65 | 0 of 62 | 0 of 61 |
| Myocardial infarction | Cardiac disorders | 0 of 65 | 1 of 60 | 0 of 61 | 2 of 65 | 0 of 62 | 0 of 61 |
| Syncope | Nervous system disorders | 0 of 65 | 1 of 60 | 1 of 61 | 0 of 65 | 1 of 62 | 0 of 61 |
| Non-cardiac chest pain | General disorders | 0 of 65 | 0 of 60 | 1 of 61 | 0 of 65 | 0 of 62 | 1 of 61 |
| Urinary tract infection | Infections and infestations | 0 of 65 | 0 of 60 | 1 of 61 | 0 of 65 | 1 of 62 | 0 of 61 |
| Post procedural haemorrhage | Injury, poisoning and procedural complications | 0 of 65 | 0 of 60 | 0 of 61 | 1 of 65 | 1 of 62 | 0 of 61 |
| Prostate cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 65 | 2 of 60 | 0 of 61 | 0 of 65 | 0 of 62 | 0 of 61 |
| Anameia | Blood and lymphatic system disorders | 0 of 65 | 0 of 60 | 0 of 61 | 1 of 65 | 0 of 62 | 0 of 61 |
| Angina unstable | Cardiac disorders | 1 of 65 | 0 of 60 | 0 of 61 | 0 of 65 | 0 of 62 | 0 of 61 |
| Atrial flutter | Cardiac disorders | 0 of 65 | 0 of 60 | 0 of 61 | 1 of 65 | 0 of 62 | 0 of 61 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo (Single Dose) | Inclisiran 200 mg (Single Dose) | Inclisiran 300 mg (Single Dose) | Inclisiran 500 mg (Single Dose) | Placebo (Double Dose) | Inclisiran 100 mg (Double Dose) |
|---|---|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 4 of 65 | 8 of 60 | 9 of 61 | 9 of 65 | 8 of 62 | 8 of 61 |
| Back pain | Musculoskeletal and connective tissue disorders | 5 of 65 | 4 of 60 | 4 of 61 | 4 of 65 | 2 of 62 | 6 of 61 |
| Myalgia | Musculoskeletal and connective tissue disorders | 3 of 65 | 2 of 60 | 6 of 61 | 3 of 65 | 3 of 62 | 7 of 61 |
| Headache | Nervous system disorders | 6 of 65 | 2 of 60 | 2 of 61 | 2 of 65 | 5 of 62 | 5 of 61 |
| Fatigue | General disorders | 5 of 65 | 2 of 60 | 4 of 61 | 2 of 65 | 6 of 62 | 2 of 61 |
| Influenza | Infections and infestations | 3 of 65 | 3 of 60 | 4 of 61 | 5 of 65 | 2 of 62 | 3 of 61 |
| Cough | Respiratory, thoracic and mediastinal disorders | 2 of 65 | 4 of 60 | 7 of 61 | 3 of 65 | 3 of 62 | 1 of 61 |
| Upper respiratory tract infection | Infections and infestations | 2 of 65 | 2 of 60 | 4 of 61 | 5 of 65 | 2 of 62 | 2 of 61 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 2 of 65 | 4 of 60 | 4 of 61 | 4 of 65 | 1 of 62 | 2 of 61 |
| Dizziness | Nervous system disorders | 3 of 65 | 1 of 60 | 2 of 61 | 2 of 65 | 6 of 62 | 3 of 61 |
Serious events with the highest arm-level rate: prostate cancer (3.3%), coronary artery disease (3.3%), post procedural complication (3.2%), myocardial infarction (3.1%), angina pectoris (1.7%).
The registry reports serious adverse events by arm, including the number at risk and the number affected. For example, serious adverse events are listed for 3 of 65 participants in the single-dose placebo group, 11 of 60 in the 200 mg single-dose group, and 7 of 62 in the double-dose placebo group. Serious adverse events are also listed for the other active groups. These are descriptive counts; the registry does not provide a formal comparative safety analysis or uncertainty estimates for differences between groups.
Deaths are reported as 1 in the 500 mg single-dose group and 1 in the 200 mg double-dose group; the other listed groups report 0. The record also lists other adverse events and leading serious-event terms with percentages. The percentages attached to those terms are registry summaries, not risk comparisons between assigned groups. The record does not provide enough detail to infer causality from these summaries or to compare safety statistically.
Safety counts should be read alongside the trial’s group sizes and the reporting period, but the registry summary does not give a detailed account of event timing, severity beyond the serious-event classification, relatedness assessments, or follow-up completeness. These figures describe reported events; they do not establish that an event was caused by a study treatment.
13. What the Result Does, and Does Not, Mean
The primary outcome describes average percentage change in LDL-C from baseline to Day 180 in the modified intent-to-treat population. The posted group estimates are negative in the ALN-PCSSC arms and close to zero in the placebo arms. The sponsor reports one-sided t-tests with p < 0.001 for each active group compared with its corresponding placebo. Together, these findings describe a clear separation in the reported group-level results at that assessment time.
That result does not, by itself, establish the precise size of each sponsor-adjusted treatment contrast, because the registry does not report those contrast estimates or their confidence intervals. Nor does it establish the durability of the pattern beyond the reported assessment, effects on cardiovascular events, or the relationship between changes in LDL-C and outcomes not included in the posted primary endpoint. The record’s secondary outcomes address selected additional measures, but they do not answer every such question.
The findings also should not be interpreted as a claim about every participant. A group mean can coexist with varied individual responses, and the primary endpoint does not show the distribution of individual changes. Threshold-based secondary outcomes provide a different view, but the registry does not report a multiplicity plan for the secondary analyses. Missing-data handling and the analysis model details are also not reported.
Finally, the trial’s safety summaries are descriptive and do not establish causation or comparative safety. The registry record is a source of reported trial design and results, but its incomplete detail on analysis methods, participant flow, and outcome handling limits how fully the results can be independently evaluated. No treatment recommendation follows from these statistical summaries.
14. Why This Trial Matters Statistically
This trial is statistically informative because it reports a continuous primary endpoint across multiple dose and schedule groups with placebo comparators. The primary group estimates and confidence intervals allow readers to consider both direction and precision, while the sponsor’s reported tests address the active-versus-placebo comparisons. The registry also provides a set of secondary outcomes that spans related lipid measures and response definitions.
The design creates interpretive demands as well as opportunities. Comparisons involve multiple active groups, more than one dosing schedule, and several outcomes and time points. A prespecified multiplicity strategy would help clarify which inferences are confirmatory and how the chance of false-positive findings is controlled, but such a strategy is not reported in the registry record. Similarly, details about the statistical model, missing data, and participant flow are important for understanding how the estimates were produced and how robust they may be.
The distinction between a group estimate and a treatment contrast is especially important. The reported least-squares means describe each arm, while the sponsor’s t-tests report evidence for pairwise comparisons without posting the contrast estimates. Readers can see that the results differ descriptively, but cannot recover the sponsor’s adjusted effect size and uncertainty from the registry summary alone.
Finally, the record juxtaposes enrollment and summary-population figures without explaining their relationship. This illustrates why transparent accounting of analysis populations matters: denominators, exclusions, and missing measurements shape the interpretation of precision and potential bias. The trial is therefore useful not only for its posted outcome pattern, but also as an example of the limits of drawing detailed conclusions from registry results when methods and analysis documentation are incomplete.
15. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
Several limitations specific to this record constrain interpretation. The sponsor’s primary comparisons are reported as one-sided t-tests with p-values, but the registry does not provide contrast estimates, contrast confidence intervals, test statistics, or the model specification. The primary arm estimates have confidence intervals, yet those intervals do not supply the missing uncertainty for the pairwise contrasts.
The record lists enrollment of 501 and describes 480 participants in the brief summary without explaining the difference. It also identifies the primary population as modified intent-to-treat but does not define that population or reconcile its arm denominators with the other figures. Participant flow, exclusions, and reasons for missing outcomes are not reported.
Multiplicity handling is not described despite multiple active-versus-placebo comparisons and several secondary measures and time points. The registry does not identify a testing hierarchy or explain which secondary outcomes, if any, were confirmatory. Selected secondary recalculations are unadjusted and based on posted summary statistics; sponsor analyses for those comparisons are not listed.
The registry does not report the sample-size justification, the statistical analysis plan, interim analyses, or missing-data methods. The planning illustrations use observed secondary effects and should not be mistaken for the trial’s original design or observed power. The safety summary is also limited: it provides arm-level event counts and selected serious-event terms but does not give a comparative safety analysis or enough detail on timing and relatedness. These omissions do not negate the reported results, but they narrow the claims that can be assessed from the registry record.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C) — NCT02597127.
- Registry record last updated 2019-05-17; status last verified 2019-04.
- Results first posted 2019-05-17.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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19. Record Summary
The registry describes a completed, randomized, double-blind, parallel-group Phase II trial of ALN-PCSSC against normal-saline placebo in participants with elevated LDL-C and high cardiovascular risk. The primary endpoint was percentage change in LDL-C from baseline to Day 180 in the modified intent-to-treat population, reported as least-squares means with 95% confidence intervals.
Primary arm estimates were negative in the ALN-PCSSC groups and near zero in the placebo groups. The sponsor reported one-sided t-tests with p < 0.001 for each active group versus its corresponding placebo. Secondary outcomes cover additional LDL-C measures, PCSK9, other lipids, and target attainment. Serious adverse event counts and deaths are reported descriptively.
The registry does not report key details including the primary model specification, multiplicity handling, missing-data methods, sample-size justification, or the relationship between the enrollment and brief-summary participant figures. These limits should inform interpretation of both the primary comparisons and the secondary results.