Safety and Efficacy of Mipomersen (ISIS 301012) As Add-on Therapy in High Risk Hypercholesterolemic Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Mipomersen (ISIS 301012) As Add-on Therapy in High Risk Hypercholesterolemic Patients (NCT00770146), a randomized phase 3 study. The primary outcome is Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group Phase 3 study comparing mipomersen with placebo as add-on therapy for high-risk patients with hypercholesterolemia. The official title describes a randomized, double-blind, placebo-controlled study; the registry also records quadruple masking. Enrollment was 158. The recorded study status is completed, with a start date of 2008-11 and primary completion in 2010-05. The sponsor is Kastle Therapeutics, LLC.

Participants in the mipomersen arm received 200 mg by subcutaneous injection once a week for 26 weeks. Participants in the placebo arm received a subcutaneous injection once a week for 26 weeks. All participants described in the study summary were on a maximally tolerated statin dose and had a diagnosis placing them at least at high risk of coronary heart disease. The registry record does not report additional details about how randomization was generated, how allocation was concealed, or how masking was maintained.

The primary outcome was percent change from baseline in LDL-C at the primary efficacy time point. Baseline was the average of screening and Day 1 pre-treatment assessments. The primary efficacy time point was Week 28 or the post-baseline visit closest to 14 days after the last dose. The primary analysis used the Full Analysis Set: randomized patients who received at least one injection and had a valid baseline and at least one post-baseline LDL-C measurement. The group summaries included 50 placebo participants and 101 mipomersen participants.

Enrollment and analysis populations are not interchangeable descriptions: the primary result applies to the stated Full Analysis Set, while adverse-event summaries use their own recorded at-risk group sizes. The registry record does not report a sample-size justification, detailed randomization procedures, or the full statistical analysis plan.

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.

Before assignment: Five hundred and seventy-seven patients were screened and 158 patients were randomized at 43 study centers in a 2:1 ratio to receive mipomersen or placebo once a week for 26 weeks. Participants who finished treatment or who discontinued prematurely from the study for any reason were assessed for safety for 24 weeks after the last study drug dose.

Treatment Period

Reasons for not completing this period:

Follow-up Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set, which consisted of all randomized patients who received at least 1 injection of study drug (mipomersen or placebo) and with a valid baseline and at least 1 post-baseline LDL-C measurement.

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.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point, measured over Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose)..

The primary endpoint measures each participant’s percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to the primary efficacy time point. Baseline was defined as the average of the screening and Day 1 pre-treatment assessments. The endpoint visit was Week 28 or the post-baseline visit closest to 14 days after the last dose of study treatment. LDL-C was measured in mg/dL after an overnight fast. For triglyceride values at or below 400 mg/dL, LDL-C was obtained using Friedewald’s calculation; at values above 400 mg/dL, the central laboratory directly measured LDL-C using ultracentrifugation.

Percent change expresses an individual’s follow-up measurement relative to that person’s baseline, making the outcome a measure of change rather than an endpoint value alone. LDL-C was the prespecified primary efficacy measure in the registry record, so it provides the main posted comparison between the randomized groups. The primary summaries are medians with inter-quartile ranges, and the reported group comparison uses a Wilcoxon (Mann-Whitney) test.

General: A change-from-baseline endpoint can account descriptively for where participants started, but it does not by itself establish that every participant changed in the same way. A group median describes the middle of the observed values, while the inter-quartile range describes the spread of the central half. Neither summary gives the full distribution or an individual-level prediction. The registry record does not report a primary between-group confidence interval, so the precision of the primary contrast cannot be read from an interval estimate in the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure: percent change from baseline in LDL-C at the primary efficacy time point. The registry reports median and inter-quartile range summaries for each arm and a Wilcoxon (Mann-Whitney) test for the comparison. The primary-analysis population was defined as randomized patients who received at least one injection and had a valid baseline and at least one post-baseline LDL-C measurement. This is the Full Analysis Set described in the record.

What do the medians and inter-quartile ranges describe?

General: The median is the middle value when observations are ordered. It is less affected by extreme observations than the arithmetic mean. The inter-quartile range describes the interval from the lower to the upper quartile, containing the central half of the observations. It indicates spread, but it is not a confidence interval for the median and does not describe the full range of individual values. In this trial, the registry chose these summaries for the primary outcome and reported the group medians and inter-quartile ranges.

What does the Wilcoxon (Mann-Whitney) test compare?

The registry names the Wilcoxon (Mann-Whitney) method for the primary two-group comparison and reports p < 0.001. General: This rank-based test compares the ordering of observations across groups. It does not directly test a difference between means, and its result is not automatically a test of a median difference unless additional assumptions about the distributions are appropriate. A p-value does not state the magnitude of a contrast or its precision. No primary between-group confidence interval is reported in the registry record.

How was the primary measurement defined?

LDL-C was measured in mg/dL after an overnight fast. The endpoint was percent change from a baseline defined as the average of screening and Day 1 pre-treatment assessments. The primary efficacy time point was Week 28 or the post-baseline visit closest to 14 days after the last dose. LDL-C was calculated using Friedewald’s method for patients with triglycerides at or below 400 mg/dL and directly measured by the central laboratory using ultracentrifugation for patients with triglycerides above 400 mg/dL. These details matter because the endpoint depends on both the measurement method and the visit used for the comparison.

What does the secondary re-calculation represent?

A separate posted secondary endpoint is percent change from baseline in total cholesterol. Its summaries are means and standard deviations: -2.7 with standard deviation 14.58 in the placebo group, and -26.4 with standard deviation 18.65 in the mipomersen group. A simple unadjusted re-calculation from those summary statistics gives a mean difference of -23.7, with a 95% confidence interval from -29.14 to -18.26, and an unadjusted p-value of p < 0.001. This is a re-calculation for the total-cholesterol secondary endpoint, not a re-analysis of the primary LDL-C endpoint.

General: A confidence interval gives a range of values compatible with the estimate under the method used, and its width reflects statistical precision. It does not account for every possible source of bias or uncertainty. The total-cholesterol re-calculation is unadjusted: it does not account for testing multiple outcomes or comparisons. The sponsor’s reported test for that endpoint is a two-sided t-test with p < 0.001. The registry record does not provide the sponsor’s numerical between-group estimate or confidence interval for this secondary comparison.

What are the planning illustrations?

The planning illustrations are based on the observed total-cholesterol effect, not on the trial’s own design justification. Their stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation. They show participants per arm for 80% power and participants per arm for 90% power when planning for 100%, 75%, or 50% of the observed effect. The listed counts are 9 and 12 for 100% of the observed effect; 16 and 21 for 75% of the observed effect; and 34 and 46 for 50% of the observed effect. These are planning illustrations, not observed power and not evidence about the original design rationale. The registry record does not report the trial’s sample-size justification or the assumptions used by the sponsor to plan enrollment.

General: Power is a design quantity describing the chance of detecting a specified effect under a set of assumptions. An illustration calculated after a trial from its observed effect is sensitive to that observed estimate and does not tell whether the completed trial was adequately powered for a different effect. Planning for a smaller fraction of an observed effect requires more participants per arm under the stated assumptions. The calculations do not establish that any such sample size was planned or used in this study.

The registry record lists 20 outcome measures and 10 analyses. The posted secondary outcomes include percent change and measured values for apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol. The methods for handling missing data, the detailed analysis plan, and whether other modeling or adjustment methods were used are not reported in the registry record.

10. Analyses Reported by the Sponsor

The sponsor-reported primary comparison is a Wilcoxon (Mann-Whitney) test, with p < 0.001. The registry gives group medians and inter-quartile ranges for the primary LDL-C outcome but does not report a sponsor-estimated between-group contrast or its confidence interval. Accordingly, the primary result can be described using the reported group summaries and test, but its precision cannot be expressed as a primary confidence interval from the posted results.

The numerical re-calculation concerns a different endpoint: percent change from baseline in total cholesterol. It uses the posted group means and standard deviations and gives an unadjusted mean difference of -23.7, a 95% confidence interval from -29.14 to -18.26, and p < 0.001. The registry’s reported analysis for that secondary endpoint is a two-sided t-test, also with p < 0.001. The re-calculation is not a substitute for the sponsor’s primary LDL-C analysis, and its estimate should not be presented as a primary result.

No discrepancy is indicated between the posted and re-calculated secondary result. Even so, the sponsor’s reported analysis remains the trial’s reported analysis; the re-calculation is a simple, unadjusted check based on summary statistics. It does not reproduce any analysis that may have used participant-level data or additional procedures. Such procedures, if any, are not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The primary outcome is identified as percent change from baseline in LDL-C at the primary efficacy time point, and the posted analysis reports a Wilcoxon (Mann-Whitney) test. The registry also lists 20 outcome measures and 10 analyses, with secondary outcomes covering apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol. The record does not report a multiplicity adjustment, testing hierarchy, or other procedure for controlling the overall chance of false-positive findings across outcomes. The unadjusted secondary p-value should therefore not be treated as though it had been adjusted for the broader set of tests.

The analysis population is described for the primary endpoint: randomized patients who received at least one injection and had a valid baseline and at least one post-baseline LDL-C measurement. This definition clarifies who contributed to the primary result, but it does not explain how missing measurements were handled, how many participants lacked endpoint data, or why data were missing. Those details are not reported in the registry record. Imputation, sensitivity analyses, and other missing-data procedures are not reported in the registry record.

The primary summaries include 50 participants in the placebo group and 101 in the mipomersen group. The safety summaries use at-risk group sizes of 52 for placebo and 105 for mipomersen. These are the populations and counts recorded for the respective summaries; the registry does not explain in the posted results why the denominators differ. They should not be treated as interchangeable analysis sets.

The registry record does not report interim analyses, a stopping rule, or a detailed statistical analysis plan. It also does not report a sample-size justification. Their absence from the posted record does not establish that a procedure was or was not used; it means the available description does not permit that assessment. The total-cholesterol planning illustrations are retrospective calculations based on the observed effect under stated assumptions, not evidence about the study’s original design plan.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute coronary syndrome (1.9%), acute myocardial infarction (1.9%), cardiogenic shock (1.9%), non-cardiac chest pain (1.9%), electrocardiogram abnormal (1.9%).

The safety summaries report serious adverse events among 4 of 52 participants at risk in the placebo group and 7 of 105 participants at risk in the mipomersen group. The registry also reports 42 participants in the placebo group and 97 in the mipomersen group in its other adverse-event category. These are counts with the stated at-risk denominators; they are not estimates adjusted for exposure time or other factors. The registry record does not provide a basis in these summaries for attributing an event to study treatment.

The listed serious-event terms are acute coronary syndrome, acute myocardial infarction, cardiogenic shock, non-cardiac chest pain, electrocardiogram abnormal, and dyspnoea exertional. Each is reported as 1.9%. The posted list does not provide further detail about event timing, severity beyond the serious-event classification, or whether a participant experienced more than one listed event. The deaths field has no reported value; deaths are not reported in the registry record.

General: Adverse-event counts describe events recorded in the study groups; they do not by themselves establish causation. Group sizes and follow-up duration matter when comparing safety patterns, and summaries do not replace detailed event-level assessment. These figures should be read as registry-reported counts and categories, not as a complete assessment of risks or a basis for treatment decisions.

13. What the Result Does, and Does Not, Mean

The primary result describes a difference between the observed LDL-C change distributions in the analyzed groups at the stated efficacy time point. The placebo group had a median percent change of -3.4, with an inter-quartile range from -14.8 to 11.8; the mipomersen group had a median percent change of -40.2, with an inter-quartile range from -56.4 to -19.1. The registry reports p < 0.001 from a Wilcoxon (Mann-Whitney) comparison. This is evidence of a statistical difference under the reported test, not a direct measure of clinical importance.

The result applies to the Full Analysis Set as defined in the registry: randomized participants who received at least one injection and had a valid baseline and at least one post-baseline LDL-C measurement. It concerns percent change in a laboratory measure at Week 28 or the post-baseline visit closest to 14 days after the last dose. It does not describe every randomized or enrolled participant irrespective of available data, and it does not establish what happened beyond the recorded assessment period.

The group medians and inter-quartile ranges do not reveal every individual response, the full shape of either distribution, or the precision of a between-group effect estimate. The primary result does not include a confidence interval for the contrast. The p-value cannot be interpreted as the probability that there is no difference, nor does it quantify the magnitude or practical importance of the result.

The primary outcome is LDL-C. The record also lists secondary lipid outcomes, but numerical results for all those outcomes are not reported in the registry record. The reported total-cholesterol re-calculation is unadjusted and pertains to a secondary outcome. Neither it nor the primary LDL-C result establishes effects on coronary events or other clinical outcomes. Safety summaries are counts of reported events and do not, by themselves, establish causation or provide a complete characterization of safety.

General: A clinical trial result is most informative when interpreted alongside its population, outcome definition, measurement timing, analysis method, precision, and limitations. A statistically significant result does not settle questions about generalizability, long-term outcomes, or the balance of possible benefits and harms. Those questions cannot be answered from the posted primary comparison alone.

14. Why This Trial Matters Statistically

This trial illustrates why the endpoint definition and analysis method matter when reading a clinical result. The primary outcome is a percent change from baseline, not a follow-up LDL-C value alone. Baseline is defined using the average of two assessments, and the primary efficacy time point is tied to the last dose and a specified follow-up visit. The record also describes different LDL-C measurement procedures depending on triglyceride level. These details determine what the reported outcome represents.

The primary summaries use medians and inter-quartile ranges, and the sponsor-reported comparison is rank-based. That pairing is distinct from the mean-and-standard-deviation summaries and two-sided t-test reported for the total-cholesterol secondary outcome. A reader should not treat estimates or tests from different endpoints as though they were interchangeable. In particular, the unadjusted total-cholesterol re-calculation is not an alternative estimate of the primary LDL-C result.

The record also demonstrates the difference between a statistical signal and a measure of precision. The primary test reports p < 0.001, but no primary confidence interval for a between-group contrast is posted. The secondary re-calculation does include a confidence interval, but it belongs to total cholesterol. Keeping endpoint, method, and estimate together prevents a secondary result from being mistaken for the primary result.

Finally, the registry defines a primary analysis population and reports separate at-risk counts for safety. Its posted results do not explain missing-data handling, multiplicity procedures, or the original sample-size justification. These omissions limit the ability to assess the full analysis strategy. Statistical interpretation depends not only on the headline p-value, but also on the population analyzed, how uncertainty is expressed, and which questions the record leaves unanswered.

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.

The primary result is reported as arm-level medians and inter-quartile ranges with a Wilcoxon (Mann-Whitney) p-value. A primary between-group estimate and confidence interval are not reported in the registry record. Consequently, the posted primary result does not directly quantify the magnitude and precision of a contrast between groups using an interval estimate. The inter-quartile ranges describe within-group spread and are not substitutes for such an interval.

The primary analysis population required treatment exposure and post-baseline LDL-C data in addition to randomization. The registry does not report how many participants were excluded from this population, the reasons for missing measurements, or how missing data were handled. It also does not report sensitivity analyses for the primary result. These omissions constrain assessment of how incomplete outcome data may affect the estimate.

The record lists multiple outcome measures and analyses, but does not report whether multiplicity was addressed or how secondary results were prioritized. Numerical results for some listed secondary outcomes are not reported in the registry record. The total-cholesterol re-calculation is unadjusted and should not be treated as confirmatory evidence independent of the primary result.

Safety counts use at-risk groups that differ from the primary-analysis group sizes, and the registry does not explain the difference in the posted results. The deaths field has no reported value. The serious adverse-event summaries do not provide event-level timing or attribution. Finally, the efficacy time point is a specified post-treatment assessment; the registry record does not provide longer-term outcome results in the registry record. The sample-size illustrations are based on the observed secondary effect and stated assumptions, not the trial’s original sample-size justification.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Mipomersen (ISIS 301012) As Add-on Therapy in High Risk Hypercholesterolemic Patients — NCT00770146.
• Registry record last updated 2016-09-09; status last verified 2016-08.
• Results first posted 2013-03-20.
• 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.

19. Record Summary

NCT00770146 is a completed randomized, parallel-group, placebo-controlled Phase 3 study of mipomersen as add-on therapy in high-risk patients with hypercholesterolemia. Participants received weekly subcutaneous mipomersen 200 mg or placebo for 26 weeks. The primary outcome was percent change from baseline in LDL-C at the primary efficacy time point.

In the Full Analysis Set, the placebo median change was -3.4 (inter-quartile range -14.8 to 11.8) and the mipomersen median change was -40.2 (inter-quartile range -56.4 to -19.1). The reported Wilcoxon (Mann-Whitney) comparison had p < 0.001. The registry does not report a primary between-group confidence interval. Secondary outcomes include apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol; multiplicity and missing-data methods are not reported in the registry record.