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 Impact of LDL-cholesterol Lowering on Platelet Activation (NCT03331666), a randomized phase 4 study. The primary outcome is Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03331666 |
| Phase | Phase 4 |
| Condition | Familial Hypercholesterolemia |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Double |
| Enrollment | 4 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Columbia University |
| Results posted | Yes |
2. Clinical Question
Population
Adults with a clinical diagnosis of familial hypercholesterolemia referred for PCSK9 inhibitor treatment were eligible according to the registry description. The description specifies LDL cholesterol levels ≥70 mg/dl while receiving baseline statins and/or ezetimibe, or intolerance to statin and/or ezetimibe. It then begins a statement about the four participants, but the population description is incomplete. Further details about who enrolled are not reported in the registry record.
Intervention
The intervention was evolocumab, described in the arm information as 140 mg every 14 days. The evolocumab arm description says participants would start with placebo and receive evolocumab beginning on Day 14, continuing until Day 196. These are the registry's stated schedule details; further information about treatment periods is not reported in the registry record.
Comparator
The comparator was placebo within a randomized, double-blind crossover design. The placebo arm description also says participants would start with placebo and receive evolocumab, beginning on Day 28 and continuing until Day 196. The two arm descriptions therefore specify different evolocumab start days, but do not fully explain the crossover sequence, period structure, or placebo schedule.
Primary question
The primary question was whether evolocumab treatment was associated with a change in platelet activation, assessed using platelet aggregation measures reported in PRU. The listed assessment days were Day 7, Day 14, Day 21, Day 28, and Day 84. No numerical primary outcome results or treatment-effect estimate are reported in the registry record, so the direction and precision of any difference cannot be described.
3. Trial Design
This was a Phase 4, randomized, double-blind crossover study sponsored by Columbia University. The registry record lists an enrollment of 4 and a status of terminated. The recorded study start was 2018-11-16, and the primary completion date was 2020-02-04. These record dates do not establish how many participants completed treatment or contributed outcome measurements.
The crossover model means participants are intended to receive more than one treatment condition over time, allowing comparisons within a participant. That general design can reduce the influence of stable differences between participants, but it also makes treatment sequence and period details important to interpretation. The registry record does not report the sequence-generation method, allocation concealment, period lengths, washout interval, or a detailed crossover schedule. The arm descriptions state that evolocumab began on Day 14 in one arm and Day 28 in the other, with placebo at the start; additional schedule details are not reported in the registry record.
The study was double blind, but the identity of the people kept unaware of treatment assignment and the procedures used to maintain masking are not reported in the registry record. The record describes the study as randomized, but does not report the randomization procedure or the number allocated to each sequence. The planned enrollment and any rationale for choosing it are not reported in the registry record.
The primary measure concerned platelet activation assessed in PRU at Day 7, Day 14, Day 21, Day 28, and Day 84. The study also listed a secondary goal concerning the rs3184504 polymorphism. The specific analysis planned for that goal is not reported in the registry record. The record indicates two outcome measures, but the available description gives the primary measure and does not provide the second measure's definition or results.
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.
Overall Study
| Stage | Evolocumab | Placebo |
|---|---|---|
| STARTED | 2 | 2 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 2 | 2 |
Reasons for not completing this period:
| Reason | Evolocumab | Placebo |
|---|---|---|
| Due to Covid-19 pandemic, the trial was prematurely terminated | 2 | 2 |
Analysis population for the primary outcome, as defined in the registry: Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms).
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.
Population: Patients who have a clinical diagnosis of familial hypercholesterolemia and are referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe.
| Characteristic | Unit | Evolocumab | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 2 | 2 | 4 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 | 0 | 1 |
| Age, Categorical: >=65 years | Participants | 1 | 2 | 3 |
| Sex: Female, Male: Female | Participants | 1 | 1 | 2 |
| Sex: Female, Male: Male | Participants | 1 | 1 | 2 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 2 | 0 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 0 | 2 | 2 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 2 | 2 | 4 |
6. Primary Endpoint
The registry lists the primary outcome as Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)), measured over Day 7, Day 14, Day 21, Day 28, Day 84.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | PRU |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is described as adenosine di-phosphate (ADP)-induced, P2Y12-dependent, and arachidonic acid-induced platelet activation, measured in P2Y12 Reaction Units (PRU). The registry description says ADP- or arachidonic acid-stimulated platelet aggregation would be assessed using the commercially available VerifyNow P2Y12 test. Assessments were scheduled for Day 7, Day 14, Day 21, Day 28, and Day 84.
As a general statistical and measurement point, a laboratory platelet aggregation measure is a biological response endpoint, not a direct count of clinical events. It can be used to describe platelet activity under specified test conditions. Its interpretation depends on how the measurement is collected, summarized, and compared between treatment conditions. The registry record does not report the measurement values, their variability, or the method used to combine the listed stimulation conditions and assessment times into an analysis.
No treatment contrast, confidence interval, or test result for this endpoint is reported in the registry record. Accordingly, the endpoint definition identifies what the investigators intended to measure, but the record does not show the magnitude or precision of any observed difference.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a randomized, double-blind crossover study with an enrollment of 4 and a status of terminated. It identifies platelet activation in PRU as the primary outcome and lists five assessment days. However, it reports no numerical primary outcome values, no treatment-effect estimate, and no statistical analysis results. The direction, size, and precision of any difference between evolocumab and placebo therefore cannot be assessed from the registry record.
The analysis count recorded in the registry is zero. This means there are no analyses listed in the record; it does not by itself establish what analyses may have been conducted outside the record. No p-value or confidence interval is reported. As a general statistical explanation, a confidence interval describes a range of estimates compatible with the data and analysis assumptions. Without a reported estimate and interval, readers cannot assess statistical uncertainty or distinguish a precise estimate from an imprecise one.
The primary outcome has several components and assessment times, and the registry record does not reduce these to one comparison. This matters because a single treatment-effect summary cannot be inferred just from a list of endpoints and visit days. A complete interpretation would require knowing which measurements were analyzed, how repeated observations within participants were handled, and how the treatment contrast was defined. These analysis details are not reported in the registry record.
The enrollment is very small, and the status is terminated. Those details constrain what can be learned from the record, but they do not reveal why the study ended or whether the planned enrollment was achieved. The reason for termination, the number completing each treatment period, and the number with usable outcome measurements are not reported in the registry record. No explanation of the termination or account of missing measurements is available.
The registry lists a secondary objective concerning whether platelet activation or response to evolocumab varied with rs3184504 polymorphism. It reports no genotype-specific results or analysis plan. The record therefore does not permit assessment of that secondary objective. Overall, the registry information establishes the study question and broad design, but does not provide the outcome evidence needed to quantify an effect or its uncertainty.
9. Statistical Methods Explained
What does a crossover design compare?
In a crossover trial, participants receive multiple treatment conditions in sequence. A general advantage is that each participant can serve as their own comparator. Stable characteristics that differ between people may then have less influence on the treatment comparison than in a design that compares separate groups alone. The benefit depends on having interpretable measurements under each condition and an analysis that respects the repeated observations from the same participant.
Crossover studies also require attention to sequence and period. A period effect is a difference associated with when a measurement is taken, rather than the treatment itself. Carryover occurs when an earlier treatment has an influence during a later treatment period. General methods may address these issues through design features and analysis choices, but the registry record does not report period lengths, a washout interval, sequence details, or the planned method for handling period or carryover effects. The arm descriptions give different evolocumab start days, but do not supply enough detail to reconstruct the full schedule.
What does randomization contribute?
Randomization is intended to assign treatment sequence by chance, reducing systematic differences in assignment. In a crossover trial, randomization generally concerns the order in which treatment conditions are received. The registry identifies the study as randomized, but does not report how the sequence was generated, whether allocation was concealed, or how many participants were assigned to each sequence. Those omissions limit assessment of the implementation of randomization.
What does double blinding mean for interpretation?
Blinding is intended to reduce the influence of knowledge about treatment assignment on participant behavior, care, outcome assessment, or analysis. The record labels the trial double blind, but does not identify which parties were blinded or describe how masking was maintained. The PRU endpoint is a laboratory measure, yet the record does not report whether outcome assessment was performed without knowledge of treatment assignment. The design label alone does not document the practical success of masking.
How should the PRU outcome be understood?
The outcome description identifies ADP- or arachidonic acid-stimulated platelet aggregation assessed with the VerifyNow P2Y12 test and expressed in PRU. These are repeated measurements planned at Day 7, Day 14, Day 21, Day 28, and Day 84. As a general measurement principle, repeated outcomes from the same participant are correlated: one participant's measurements tend to be more alike than measurements from different participants. Analyses should account for this dependence rather than treating every visit as an independent observation.
The endpoint title includes more than one stimulation condition, and multiple days are listed. A statistical analysis could define a primary time point, compare trajectories across time, or use another prespecified summary. Those are general possibilities, not a description of the analysis used in this study. The registry record does not report which summary or contrast was planned, whether the two stimulation conditions were analyzed separately, or how repeated observations were modeled. It also does not report means, distributions, or measures of spread for the PRU values.
What can the analysis record establish?
No analyses are listed in the registry record. Thus there is no reported estimate, standard error, confidence interval, or hypothesis-test result for the primary endpoint. General statistical interpretation relies on an estimate to describe the observed contrast and an uncertainty measure to show how precisely it is known. Neither can be reconstructed from the endpoint description alone.
The sample-size planning assumptions describe illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. Such illustrations are planning calculations, not observed power and not evidence that a treatment difference was established. The record does not identify a single reduced primary comparison, and no numerical planning values are reported in the registry record. A sample-size illustration cannot substitute for an outcome analysis.
As a general concept, over-dispersion occurs when observed variability is greater than a statistical model assumes. It can make standard errors too small if a model fails to account for the extra variation. The registry record does not report a fitted model or variability estimates, so there is no basis for saying over-dispersion occurred in this trial. More broadly, the available record does not identify the statistical model, covariate adjustments, handling of incomplete repeated measures, or prespecified analysis population.
10. Multiplicity, Missing Data and Analysis Populations
The primary endpoint includes multiple assessment days and refers to platelet activation under more than one stimulation condition. When several outcomes, time points, or contrasts are examined, the chance of obtaining an apparently notable result by chance can increase. As a general statistical principle, multiplicity may be addressed through a prespecified primary contrast, a hierarchy of tests, an adjustment procedure, or a clearly exploratory interpretation. The registry record does not report a multiplicity strategy or identify one primary comparison among the listed measurements.
The registry identifies a secondary goal involving rs3184504 polymorphism, but the planned comparisons and any multiplicity approach for that goal are not reported in the registry record. The record also indicates two outcome measures, while the available outcome description does not define the second measure. Its relationship to the primary endpoint and any analysis priority are not reported in the registry record.
Missing-data handling is not reported in the registry record. This is important for a crossover study with repeated assessments: participants may have measurements for some days or periods but not others. The record does not state how incomplete visits, withdrawal, or unavailable assay results were handled, nor does it give the number of participants with outcome data at each assessment.
The analysis population is also not reported in the registry record. It is therefore unclear whether any intended analysis would include all randomized participants, participants who received treatment, or only participants with measurements in both conditions. No claim about the degree or consequences of missing data can be made from the available information.
11. 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 |
|---|---|---|---|
| Evolocumab | 0 | 2 | 0.0% |
| Placebo | 0 | 2 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Evolocumab | 0 of 2 |
| Placebo | 0 of 2 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Evolocumab | 0 of 2 |
| Placebo | 0 of 2 |
The registry record lists 2 participants at risk in the Evolocumab group and 2 in the Placebo group for serious adverse events. It reports 0 serious adverse events in each group. For other adverse events, it likewise lists 2 at risk in each group and 0 affected in each. Deaths are listed as 0 in both groups, and no serious adverse-event terms are listed.
These are the recorded counts, not a detailed safety analysis. The record does not report exposure time, event surveillance procedures, event severity beyond the serious-event classification, or the completeness of adverse-event reporting. In a crossover study, participants may contribute experience under multiple conditions; the record does not explain how the group counts relate to individual treatment sequences. The group counts should not be added or treated as independent sets of participants without that information.
As a general statistical point, observing no recorded events in a small study does not establish that an event cannot occur or precisely quantify its frequency. The safety figures describe what the registry record lists for this trial; they do not support a broad safety conclusion.
12. What the Result Does, and Does Not, Mean
The record establishes that a randomized, double-blind crossover trial was registered to examine evolocumab and platelet activation in people with familial hypercholesterolemia. It identifies PRU-based platelet aggregation as the primary endpoint and lists assessment days. It also records an enrollment of 4 and a terminated status. These details describe the trial question and its broad conduct, not the result of the primary comparison.
No numerical platelet measurements, treatment-effect estimate, confidence interval, or p-value are reported in the registry record. It is therefore not possible to determine from this record whether measurements differed between treatment conditions, how large a difference may have been, or how precisely it was estimated. The absence of an analysis result is not evidence that the treatments produced the same measurements, and it is not evidence that a difference was present.
The registry describes a secondary interest in rs3184504 polymorphism, but does not report genotype-specific results. It also does not report the reason the study was terminated, how many participants completed the crossover, or how much outcome data were available. Those gaps prevent evaluation of completion, analysis populations, and the influence of missing data.
The study's platelet assay is a measure of a biological response. As a general distinction, a change in a laboratory measure is not by itself a demonstration of a change in clinical events. The registry summary mentions broader motivation involving atherothrombotic risk, but no clinical-event outcome results are reported in the registry record. The study description therefore cannot establish an effect on clinical events or support treatment decisions.
The most defensible reading is limited: the registered question was scientifically specific, but the record contains no reported primary outcome analysis with which to quantify an answer. The design and endpoint descriptions should not be mistaken for evidence of an observed treatment effect.
13. Why This Trial Matters Statistically
This trial illustrates why a registry description and a result are different kinds of evidence. A clear research question, a named assay, and planned assessment days explain what investigators intended to study. They do not reveal the observed values or whether the treatment conditions differed. Statistical interpretation requires outcome data and an analysis that estimates the contrast of interest.
The crossover design also highlights the importance of reporting sequence, treatment periods, and within-participant analysis. Because repeated observations from one participant are related, an analysis needs to account for that structure. Without the schedule and analysis details, readers cannot assess how period effects, carryover, or incomplete measurements were addressed. These are general considerations for crossover trials, not claims that a particular problem occurred in this study.
The enrollment of 4 and terminated status make transparent reporting especially important. The registry record does not state why the study ended or how many participants contributed complete measurements. Without those details and outcome results, readers cannot determine whether the planned question was answered or how much uncertainty surrounds any estimate.
The record also has a secondary genetic objective and multiple primary assessment days and stimulation conditions. Prespecifying and reporting the comparisons that matter helps readers distinguish confirmatory questions from exploratory ones and understand how multiple analyses were handled. Those details are not reported in the registry record.
For biostatistical interpretation, the central lesson is to separate design intent, measurement choice, and empirical result. The record documents the first two at a broad level, but does not report an outcome analysis. This distinction prevents missing information from being mistaken for a positive, negative, or definitive finding.
14. 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.
The principal limitation for interpreting this trial is that no numerical primary outcome results or statistical analyses are reported in the registry record. There is consequently no treatment-effect estimate or uncertainty interval to evaluate. The enrollment is 4, and the study status is terminated, but the reason for termination and the number of participants who completed assessments are not reported.
The endpoint is described across multiple assessment days and includes ADP- and arachidonic acid-stimulated aggregation. The record does not explain which time point or stimulation condition defined the principal treatment contrast, how repeated measurements were summarized, or what statistical model was planned. This leaves the intended estimand and handling of within-participant dependence unclear.
The crossover schedule is not fully described. The arm descriptions give different days for starting evolocumab, but do not report the complete sequence, treatment-period structure, or any washout interval. Randomization and double blinding are stated, while the implementation details are not reported in the registry record.
The record does not report the analysis population, missing-data approach, participant flow, or the number with usable outcome measurements at each visit. It also does not report a multiplicity strategy for the several endpoint conditions and times, or analysis details for the secondary polymorphism objective. A second outcome measure is indicated, but its definition is not reported in the available record. These omissions limit independent assessment of design execution and analysis choices.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Impact of LDL-cholesterol Lowering on Platelet Activation — NCT03331666.
- Registry record last updated 2021-04-01; status last verified 2021-03.
- Results first posted 2021-04-01.
- 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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18. Record Summary
NCT03331666 is a Phase 4 randomized, double-blind crossover study sponsored by Columbia University. It examined evolocumab and platelet activation among adults with familial hypercholesterolemia. The registry lists enrollment of 4, status terminated, a start date of 2018-11-16, and a primary completion date of 2020-02-04.
The primary endpoint was platelet aggregation in PRU, assessed using the VerifyNow P2Y12 test at Day 7, Day 14, Day 21, Day 28, and Day 84. The registry also describes a secondary interest in rs3184504 polymorphism. It reports no primary outcome estimates, analysis results, or reason for termination. Adverse-event listings show 0 serious events, 0 other events, and 0 deaths in each group.