The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy (NCT02527343), a randomized phase 2, phase 3 study. The primary outcome is Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG).

2. Clinical Question

3. Trial Design

The BROADEN study was a randomized, parallel-group, placebo-controlled Phase 2/3 study of volanesorsen in participants with familial partial lipodystrophy. The registry describes the study as double-blind and triple-masked. Enrollment was 40. Its status is listed as terminated; the reason for termination is not reported in the registry record.

In the randomized treatment period, the volanesorsen group received 300 mg subcutaneously once weekly, and the placebo group received matching placebo on the same weekly schedule. This period ran from Weeks 1–52. Dose adjustment based on monitoring rules was permitted. The randomized comparison included 21 participants in the volanesorsen group and 19 in the placebo group for the primary outcome.

After the randomized period, participants could enter an open-label extension. The registry describes continued volanesorsen treatment in the extension, including a period from Weeks 53–104 and an option for continued dosing through Week 156. Participants who did not enter the extension, and those who did not choose continued dosing after the described extension period, proceeded to post-treatment follow-up. The available arm descriptions are incomplete, so they do not fully describe the extension procedures or participant flow.

The primary result discussed in the registry is for the randomized treatment period only. It should not be treated as a comparison of long-term outcomes in the extension, where treatment was open-label and the randomized comparison no longer represents the same contrast. The registry gives the study start as 2015-12-28 and the primary completion date as 2018-06-30. Further details of the reasons for termination, recruitment flow, and conduct of the extension are 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.

Before assignment: A total of 40 participants were randomized into this study.

RT Period: Weeks 1 to 52

Reasons for not completing this period:

RT Post Treatment Follow-up: Weeks 54-65

Reasons for not completing this period:

OLE Period-Year 1: Week 53 to 104

Reasons for not completing this period:

OLE Period-Year 2: Week 105 to 156

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS included all participants who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting TG assessment. This outcome measure is reported here for the randomized treatment period only, as per the planned analysis.

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: Full Analysis Set (FAS) included all participants who were randomized and received at least one dose of study drug in the randomized treatment period, and who had a baseline fasting triglyceride (TG) assessment.

6. Primary Endpoint

The registry lists the primary outcome as Randomized Treatment Period: Percent Change From Baseline to Month 3 in Fasting Triglycerides (TG), measured over Baseline to Month 3.

The primary endpoint was percent change from baseline to Month 3 in fasting triglycerides. Fasting triglycerides are a continuous measure, and expressing change as a percentage places the result in terms of change relative to the baseline level rather than as an absolute concentration change. The registry reports least-squares means, which are model-adjusted estimates, for each randomized group.

For this analysis, baseline was defined as the average of the Day 1 predose fasting assessment and the last fasting measurement before that assessment. The Month 3 value was the average of the Week 12 and Week 13 fasting assessments during the randomized treatment period. The endpoint therefore uses averaged measurements at both time points rather than a single measurement at either time.

Fasting triglycerides were the primary measure of interest in the randomized period. The registry’s analysis used ANCOVA, incorporating treatment group, a randomization stratification factor based on disease diagnosis with or without genetics and family history, and log-transformed baseline fasting triglycerides. The endpoint can describe the size and uncertainty of the group difference in the observed trial population. By itself, it does not establish effects on clinical events or other outcomes, and its interpretation remains specific to the stated measurement period and analysis population.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous, so it is summarized with least-squares means and a between-group difference rather than only with event counts. The reported least-squares means are model-based estimates. They account for the covariates and factors specified in the analysis model, rather than being simple unadjusted averages. The registry reports the ANCOVA method and the variables included in it.

What does ANCOVA do?

As a general statistical explanation, analysis of covariance compares groups while accounting for specified baseline or design variables. In this trial, the model included treatment group and the randomization stratification factor as factors, with log-transformed baseline fasting triglycerides as a covariate. Accounting for baseline can improve the comparison when baseline values are related to the outcome. Including the stratification factor aligns the analysis with a feature used in the randomization design. The registry does not give further details of model diagnostics or assumptions.

Why use a transformed baseline measure?

The baseline covariate was log-transformed. As a general explanation, transformation can make a skewed measurement more suitable for a model or represent relationships on a different scale. The registry does not report the distribution of baseline triglycerides, the reason for choosing this transformation, or diagnostic results. The endpoint itself is reported as percent change, while the model’s baseline covariate is specified on the log-transformed scale; these are distinct parts of the analysis.

How should the confidence interval be read?

As a general explanation, a confidence interval communicates the uncertainty of an estimate under the analysis method and its assumptions. The primary between-group estimate is -66.83, and its 95% confidence interval runs from -104.17 to -29.48. The interval’s position relative to zero is relevant to whether the data are compatible with no between-group difference under this model. Its width is also informative: a result can be statistically distinguishable from zero while the range still allows uncertainty about the size of the difference. A confidence interval is not a range containing every participant’s response.

What does the p-value add?

The reported p-value for the primary comparison is 0.001. In general, a p-value measures how unusual results at least as incompatible with a specified null hypothesis would be if that hypothesis and the model assumptions held. It is not the probability that the null hypothesis is true. It also does not measure effect size, precision, or clinical importance. Those aspects require reading the estimate and confidence interval as well as the p-value.

What is the role of the secondary binary analysis?

The registry also reports a Month 6 secondary outcome requiring participants to meet both a triglyceride reduction threshold and a hepatic fat reduction threshold. In the placebo group, 1 of 19 participants met the combined criterion; in the volanesorsen group, 9 of 21 did. The posted percentages are 5.3% and 42.9%, respectively. An unadjusted recalculation reports a risk difference of 0.376, with a 95% confidence interval from 0.142 to 0.610 and an unadjusted p-value of 0.006. This is a separate endpoint and time point from the primary Month 3 continuous endpoint. It should not be treated as another estimate of the primary outcome.

General caution applies to such recalculations: they use the posted summary counts and do not replace a sponsor’s prespecified analysis. The registry lists no sponsor-reported analysis for this secondary comparison. The recalculated interval and p-value are unadjusted, and the registry does not report a multiplicity adjustment for this result. The planning illustrations based on this observed binary effect are hypothetical design calculations, not observed power and not a statement about the original trial’s design.

Why can over-dispersion matter?

As a general explanation, over-dispersion arises when observed variability is greater than a statistical model expects. For count or proportion outcomes, ignoring it can make uncertainty estimates too small. The primary endpoint is analyzed as a continuous outcome using ANCOVA, and the registry does not report an over-dispersion assessment. No conclusion about over-dispersion should therefore be inferred from the posted primary result.

The registry does not report the detailed missing-data method, sensitivity analyses, model diagnostics, or a full statistical analysis plan. These omissions limit independent assessment of how robust the estimates are to alternative modeling choices or missing outcome measurements.

10. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary comparison using ANCOVA. It gives a difference in least-squares means of -66.83, a 95% confidence interval from -104.17 to -29.48, and p < 0.001. The group-specific least-squares means are -21.64 for placebo and -88.47 for volanesorsen. These are the reported primary analysis results, not an independent recalculation from summary counts.

No discrepancy is flagged for the posted primary result. The sponsor’s analysis therefore remains the relevant reported analysis for the primary endpoint; there is no competing recalculated primary estimate to set against it. The outcome definition and ANCOVA model are described in the registry, although further analysis-plan details are not reported.

For the binary secondary outcome at Month 6, the registry posts group percentages and counts but no sponsor-reported comparison. The unadjusted comparison derived from those posted counts is a recalculation, not the sponsor’s own inferential analysis. It is useful as a transparent descriptive comparison, but it should not be given the same status as a reported prespecified analysis. Its unadjusted p-value also does not account for the broader set of outcomes and analyses.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures and 7 analyses, and it identifies 15 secondary outcomes. These counts indicate that the record covers more than the primary endpoint, but do not establish the number of statistical tests that formed any particular inferential family. The registry does not report a multiplicity adjustment for the secondary result, nor does it describe a hierarchy or gatekeeping strategy for interpreting multiple outcomes.

Multiplicity matters because repeated testing can increase the chance of at least one small p-value even when the underlying effects are absent. As a general statistical principle, methods such as adjusted significance thresholds or hierarchical testing can address that issue, but the registry record does not say that any such procedure was used. The primary p-value should be distinguished from an unadjusted secondary p-value, and secondary findings should be interpreted with the number and role of analyses in mind.

The primary analysis population is defined as participants who were randomized, received at least one dose during the randomized treatment period, and had a baseline fasting triglyceride assessment. The registry calls this the full analysis set. It does not describe an intention-to-treat population that includes all randomized participants regardless of treatment received or baseline availability. The primary outcome group counts are 19 for placebo and 21 for volanesorsen.

Missing outcome data can affect both the estimate and its uncertainty, particularly when the likelihood of missingness is related to treatment or outcome. The registry does not report how many Month 3 values were missing, whether missing data were imputed, which assumptions were used, or whether sensitivity analyses were conducted. It also does not report the handling of missing values for the Month 6 secondary endpoint. These gaps prevent assessment of how sensitive the results may be to missing-data assumptions.

The registry describes the ANCOVA covariates and factors but does not report a full statistical analysis plan, details of any interim analyses, or sample-size justification. These items are not reported in the registry record. Their absence means that prespecification, decision rules, and the rationale for the analysis cannot be independently assessed from the available record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: constipation (14.3%), medical device site inflammation (11.1%), abdominal pain (8.3%), pancreatitis (8.3%), pancreatitis acute (8.3%).

During the randomized treatment period, serious adverse events were reported for 3 of 19 participants in the placebo group and 6 of 21 participants in the volanesorsen group. The registry reports other adverse events for 18 of 19 participants in the placebo group and 21 of 21 participants in the volanesorsen group. No deaths are reported in either randomized group.

These figures are descriptive counts within the listed groups. They do not establish that an event was caused by study treatment, and differences in counts should not be treated as adjusted comparisons. The record also lists post-treatment and open-label extension groups with their own at-risk counts and adverse-event counts. Those periods have different treatment histories and should not be combined casually with the randomized comparison.

The registry lists serious adverse event terms including constipation, medical device site inflammation, abdominal pain, pancreatitis, acute pancreatitis, and anaphylactic reaction, with percentages attached to the terms. The available record does not give enough context to assign those term percentages to a particular randomized arm. They should therefore be read as reported event listings, not as comparative risks for the randomized groups. The safety summaries do not resolve the overall balance of harms and benefits.

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

The primary finding is an adjusted comparison of percent change in fasting triglycerides during the randomized treatment period. The volanesorsen group had a more negative least-squares mean estimate than the placebo group, and the reported difference was -66.83 with a 95% confidence interval from -104.17 to -29.48. The p-value was 0.001. These figures describe the observed trial result under the registry’s stated ANCOVA model.

The result does not show that every participant had a similar response. Group means conceal individual variation, and the confidence interval describes uncertainty in the estimated group difference rather than the range of individual changes. Nor does the p-value indicate the probability that the treatment is ineffective or that the observed difference is clinically important. Those conclusions cannot be drawn from statistical significance alone.

The primary endpoint is a laboratory measure at Month 3, not a clinical event or a long-term outcome. The secondary combined response measure is at Month 6 and is defined by meeting two reduction criteria. Its unadjusted analysis is a separate, less confirmatory result. The registry’s outcome list includes additional measures, but numeric results for most of them are not reported in the available record.

The randomized comparison applies to the stated analysis population and period. It does not directly answer what happened during the open-label extension, where participants continued on volanesorsen and the original placebo-controlled contrast was no longer maintained. The registry status is terminated, but the reason is not reported in the registry record. No conclusion about why the study ended should be inferred.

Finally, the result does not settle safety or the overall balance of outcomes. Serious adverse events were reported in both randomized groups, and the posted counts are descriptive. Missing-data handling, multiplicity procedures, and several analysis-plan details are not reported. The most defensible interpretation is therefore specific: the posted primary model estimated a negative between-group difference in Month 3 fasting triglyceride percent change, with uncertainty quantified by the stated confidence interval.

14. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation requires more than comparing two central estimates. The primary outcome is reported as adjusted least-squares means, with a direct between-group estimate, confidence interval, and p-value. The group estimates alone would not communicate the uncertainty in the randomized contrast; the difference and its interval are central to interpreting the result.

The analysis also shows how the endpoint definition and model specification shape the question being answered. Baseline and Month 3 values are averages of specified fasting assessments, and the ANCOVA includes a stratification factor and log-transformed baseline triglycerides. The resulting estimate applies to this defined measure and model, not to every possible summary of triglyceride change.

Separating the primary result from secondary findings is especially important. The Month 6 combined responder outcome is binary, uses a different time point, and has an unadjusted recalculated comparison rather than a sponsor-reported analysis. Treating it as equivalent to the primary endpoint would blur differences in outcome, timing, and inferential status. The registry’s multiple outcome measures also make multiplicity and prespecification relevant to the strength of secondary claims.

The record further demonstrates the value of clear analysis-population and missing-data reporting. It defines the full analysis set, but does not report missing Month 3 values, their handling, or sensitivity analyses. Those details help readers judge how the analysis relates to all randomized participants and how robust the result might be to assumptions.

Finally, efficacy estimates and safety summaries answer different questions. The primary endpoint gives a modeled comparison of a laboratory measure, while adverse-event counts are descriptive and do not establish causation. Keeping those forms of evidence distinct makes the statistical reading more accurate and appropriately bounded.

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 registry record does not report the reason the study was terminated. Although the start and primary completion dates are listed, the available information does not explain how termination affected planned recruitment, follow-up, or analysis. The record also does not give a full participant-flow account for the randomized period and extension.

The primary analysis population excludes randomized participants who did not receive at least one dose or lacked a baseline fasting triglyceride assessment, according to its stated definition. The record does not provide further detail about the relationship between this population and all randomized participants. The number of missing Month 3 outcomes, the methods used to handle missing data, and sensitivity analyses are not reported.

The primary model is described at a high level, including ANCOVA, the stratification factor, treatment group, and log-transformed baseline triglycerides. Details such as model diagnostics and the assumptions used to estimate the least-squares means are not reported. The registry also does not report the full statistical analysis plan, sample-size justification, or interim analysis procedures.

Multiple secondary outcomes are listed, but numeric results for most are not available in the information. The registry does not report how multiplicity was handled or how secondary analyses were prioritized. The Month 6 binary comparison is an unadjusted recalculation from posted counts, rather than a sponsor-reported analysis, and should be interpreted with that limitation in mind.

Extension and post-treatment safety groups reflect different periods and treatment histories. Their adverse-event counts do not preserve the randomized comparison in the same way as the primary period. The available serious-event term percentages are not sufficiently contextualized to attribute them to a specific randomized arm. These limitations constrain conclusions about long-term outcomes and comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The BROADEN Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Partial Lipodystrophy — NCT02527343.
• Registry record last updated 2021-10-18; status last verified 2021-09.
• Results first posted 2021-10-18.
• 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

The BROADEN study was a randomized, parallel-group, double-blind, triple-masked Phase 2/3 study in participants with familial partial lipodystrophy. It compared weekly subcutaneous volanesorsen with matching placebo during a randomized treatment period lasting Weeks 1–52. The registry lists enrollment of 40 and status as terminated.

The primary endpoint was percent change in fasting triglycerides from baseline to Month 3. The reported ANCOVA difference in least-squares means was -66.83, with a 95% confidence interval from -104.17 to -29.48 and p < 0.001. The registry also describes an open-label extension and post-treatment follow-up.

The available record includes selected secondary and adverse-event results, but does not report several details needed to assess missing data, multiplicity, or the complete analysis plan. The reason for termination is not reported in the registry record.