A Study of RO4607381 in Patients With Coronary Heart Disease (CHD) or a CHD Risk Equivalent.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of RO4607381 in Patients With Coronary Heart Disease (CHD) or a CHD Risk Equivalent. (NCT00353522), a randomized phase 2 study. The primary outcome is Absolute Change From Baseline in HDL-C.

2. Clinical Question

The question concerns a change in a continuous blood lipid measure over the study treatment period. It is narrower than asking whether either treatment changes the likelihood of a clinical event: the reported primary endpoint is HDL-C, not a cardiovascular event or a measure of symptoms. The record also lists cholesterol ester transfer protein (CETP) measures and other lipid outcomes as secondary outcomes. Their roles and limitations are discussed separately from the primary comparison.

3. Trial Design

This was a Phase II, randomized, double-blind, placebo-controlled, parallel-group study of RO4607381, identified in the intervention record as dalcetrapib. The registry describes two treatment arms: dalcetrapib and placebo. The study status is completed, and enrollment is reported as 135. The sponsor is Hoffmann-La Roche.

The treatment period is described as 24 weeks. The brief study summary also describes a pre-randomization phase of 5-12 weeks and anticipated time on study treatment of 3-12 months. The reported primary endpoint timeframe is baseline and Week 24. The registry record lists the study start as 2006-07 and primary completion as 2008-10.

The primary outcome is a continuous measure: absolute change from baseline in HDL-C, expressed in mg/dL. The posted group summaries are least-squares means with standard errors. The primary result includes 89 participants in the dalcetrapib group and 45 in the placebo group. The registry record does not explain why these outcome counts differ from enrollment, or describe participant flow, exclusions, or the analysis population.

Randomization and double masking are design features intended, in general, to reduce differences in treatment assignment and knowledge of assignment that could affect comparisons. The registry record does not describe the randomization procedure, who was masked, the original sample-size justification, or the detailed statistical analysis plan. Those details should not be inferred from the posted outcome summaries.

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

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 Absolute Change From Baseline in HDL-C, measured over Baseline and Week 24.

The primary endpoint is absolute change from baseline in HDL-C at Week 24, measured in mg/dL. HDL-C is a blood lipid measure. In general, measuring change from baseline allows a study to describe how a continuous measurement differs after treatment from its starting value; comparing changes across randomized groups provides an estimate of the between-group contrast over the stated period.

The registry reports least-squares means for the two groups. In general, a least-squares mean is an estimate from a statistical model rather than simply an unadjusted arithmetic average. The registry record does not describe the model or list covariates used to obtain these estimates, so the specific adjustment cannot be characterized.

HDL-C is a laboratory measure, not a direct count of cardiovascular events or an assessment of symptoms. The endpoint can describe the direction and size of the reported lipid change, but it does not by itself establish what that change means for clinical outcomes. The record's primary endpoint is specifically an absolute change, not a percent change. The posted time point is Week 24; longer-term primary endpoint results are not reported in the registry record.

7. Results Posted in the Registry

• Dalcetrapib: mean 12.76 versus 0.50 on control; difference 12.26 (95% CI 8.55 to 15.97), standardized effect d = 1.15; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percent Change From Baseline in Cholesterol Ester Transfer Protein (CETP) Mass

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Dalcetrapib: mean 86.45 versus -4.93 on control; difference 91.38 (95% CI 70.93 to 111.83), standardized effect d = 2.07; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Dalcetrapib than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in Cholesterol Ester Transfer Protein (CETP) Activity

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Dalcetrapib: mean -56.50 versus -5.69 on control; difference -50.81 (95% CI -67.25 to -34.37), standardized effect d = -1.42; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Dalcetrapib than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary findings include measures of CETP mass and CETP activity. Their posted directions differ: the dalcetrapib group has an increase in CETP mass and a decrease in CETP activity relative to placebo. In general, measures related to the same biological pathway can help characterize how a treatment affects that pathway, while still representing outcomes distinct from the primary HDL-C endpoint.

The overall pattern is compatible with a set of changes in lipid-related measures, but secondary outcomes do not independently establish the meaning of the primary HDL-C comparison. The record lists additional outcomes involving mesenteric lymph nodes, total cholesterol, triglycerides, HDL-C, LDL-C, and apolipoproteins A1 and B. Numerical results for those listed measures are not reported in the registry record. The CETP activity timeframe is listed as baseline and 48 Weeks, whereas the primary endpoint is assessed at Week 24; the record does not explain the difference.

Both posted secondary comparisons have unadjusted p-values reported as p < 0.001. Unadjusted results do not account for the number of secondary outcomes or comparisons that may have been considered. In general, testing many outcomes can increase the chance of observing apparently strong statistical evidence by chance, even when no single result is persuasive on its own. The registry record does not report a testing hierarchy, multiplicity adjustment, or confirmatory status for the secondary endpoints.

For that reason, the secondary findings are most useful as supporting or descriptive evidence about the measured outcomes, rather than as replacements for the primary comparison. Their interpretation also depends on the models, analysis populations, missing-data methods, and endpoint definitions, which are not fully described in the registry record. The results should be viewed as a pattern across distinct measures, with less inferential weight than would be warranted by a prespecified, multiplicity-controlled confirmatory analysis.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percent Change From Baseline in Cholesterol Ester Transfer Protein (CETP) Mass
• Change in Mesenteric Lymph Nodes
• Change From Baseline in Total Cholesterol (TC), Triglycerides (TG), HDL-C, LDL-C, Apolipoproteins A1 (ApoA1), Apolipoproteins B (ApoB)
• Change From Baseline in Cholesterol Ester Transfer Protein (CETP) Activity

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it records a measured quantity, HDL-C, and the change in that quantity from baseline. For continuous outcomes, summaries commonly include a group estimate and a measure of uncertainty. The registry reports least-squares means with standard errors for each group, followed by a mean difference and an interval for the between-group comparison. These statistics answer related but distinct questions: the group means describe estimated change within each arm, while the mean difference describes the estimated contrast between arms.

What does a least-squares mean represent?

In general, a least-squares mean is a model-based estimate of a group mean. Depending on the model, it can account for specified factors or covariates. The registry record names the estimate type but does not report the model formula, covariates, or other adjustment details. It is therefore appropriate to describe the reported estimates as least-squares means, but not to assert which variables they adjust for or how that adjustment was performed.

The reported least-squares mean change was 12.76 mg/dL for dalcetrapib and 0.5 mg/dL for placebo. The between-group mean difference was 12.26 mg/dL. A difference is useful because it puts the comparison on the original measurement scale: mg/dL of HDL-C change. It is not a ratio, percent change, or standardized effect. The comparison is reported against placebo.

How should standard errors be understood?

In general, a standard error describes the precision of an estimated quantity: it reflects uncertainty in the estimate, not the range of individual observations. The reported group standard errors are 1.17 for dalcetrapib and 1.49 for placebo. They should not be interpreted as standard deviations among participants. The registry identifies the dispersion measure as standard error and does not provide the individual-level outcome distribution.

The comparison record also includes an approximate pooled standard deviation of 10.7 and a standardized effect size d of 1.146. These are distinct from the mean difference in mg/dL. The pooled standard deviation is marked as approximate, so any standardized interpretation depends on that approximation. Such standardized quantities can support comparisons across measurement scales in general, but the endpoint's original-scale mean difference remains the most direct description of the posted HDL-C result.

What does the p-value say?

The primary comparison reports unadjusted p < 0.001. In general, a p-value describes how compatible the observed data are with a specified null hypothesis under the statistical test's assumptions. It is not the probability that the null hypothesis is true, and it does not measure the clinical importance of the endpoint change. Because the reported value is unadjusted, it does not indicate that a correction for testing multiple endpoints or comparisons was applied. The registry record does not describe the test, its assumptions, or a multiplicity procedure.

The comparison also reports an interval from 8.547 to 15.97. In general, a confidence interval expresses uncertainty about an estimated parameter under a specified method. The confidence level and method are not reported in the registry record. The interval gives a range of values associated with the estimated between-group contrast, but it does not encompass uncertainty about every design or analysis choice.

Why do randomization and masking matter?

In general, random allocation is intended to make treatment groups comparable with respect to measured and unmeasured characteristics, on average. Double masking is intended to limit the influence of treatment knowledge on care or outcome assessment. These design features support interpretation of a between-group comparison, but they do not guarantee that the analysis is free of bias. The registry does not describe the allocation sequence, concealment, masking roles, or whether masking was maintained.

The registry reports outcome counts of 89 and 45 for the primary endpoint, while overall enrollment is 135. The record does not explain the difference, provide a participant flow, or describe missing-data handling. In general, the way missing outcomes are handled can affect both the estimate and its uncertainty. The analysis population and any sensitivity analyses are not reported in the registry record.

The secondary measures are also continuous outcomes and include CETP mass and CETP activity. Their reported estimates and comparisons use the same general statistical language: least-squares means, standard errors, a mean difference, an interval, and an unadjusted p-value. The timeframes differ: CETP mass is listed at baseline and Weeks 24, while CETP activity is listed at baseline and 48 Weeks. The registry record does not explain the latter timeframe in relation to the 24-week treatment period. Secondary outcomes and their unadjusted p-values should be interpreted with attention to the number of outcomes considered and to the absence of a reported multiplicity plan.

11. Confidence Intervals and Precision

The primary between-group mean difference is 12.26 mg/dL, with a reported interval from 8.547 to 15.97. The interval gives a range around the estimated contrast and helps show its precision; it is more informative about uncertainty than the point estimate alone. The interval's bounds are on the same side of zero, consistent with the positive direction of the posted contrast. The confidence level and calculation method are not reported in the registry record, so the interval should not be assigned a confidence level by assumption.

The group estimates have standard errors of 1.17 for dalcetrapib and 1.49 for placebo. In general, smaller standard errors indicate more precise estimates when the underlying quantity and method are comparable. These values describe uncertainty in the estimated group means, not participant-to-participant variability. The registry does not report standard deviations for the primary outcome directly; the pooled standard deviation in the comparison record is marked approximate.

Precision is also bounded by the available outcome data. The endpoint counts are 89 and 45, and the record does not report why these counts differ, how missing observations were treated, or whether participants were analyzed according to original assignment. Without those details, it is not possible to assess from the record whether missingness could have affected the estimate or interval. The interval also does not address issues such as endpoint selection, analysis choices, or multiple testing.

The reported interval and p-value describe statistical uncertainty under the analysis used, but the interval does not establish clinical importance. That judgment would require a relevant clinical context or threshold, neither of which is reported in the registry record. The result is best read as a relatively precise estimate of the posted between-group HDL-C change within the stated analysis, while recognizing the unreported analysis details and endpoint scope.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total event counts. They are illustrations based on the observed effect, rather than a report of the trial's original design calculation. The registry record does not report the trial's own sample-size assumptions or justification.

The listed assumptions for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. The rows therefore ask how many participants per arm would be needed under the planning assumptions if the target effect were the full observed effect, 75% of it, or 50% of it. The columns for 80% and 90% power express the chance, under those assumptions and if the target effect were the true effect, of detecting a difference at the specified significance level. The 90% column corresponds to a higher chance of detection and generally requires more participants than the 80% column for a given target effect.

The sample-size curve presents the same planning idea across effect sizes: as the effect to be detected becomes smaller, more participants are needed. This relationship is a feature of statistical planning, not evidence that a smaller effect occurred in the trial. Estimates based on the observed result can be optimistic or uncertain, particularly when the observed effect itself is estimated from a finite study.

These calculations are not observed power. They are planning illustrations using the stated assumptions, not a measure of the probability that the completed study found a result because of its sample size. They should not be read as a substitute for the unreported original sample-size rationale.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 12.260; pooled standard deviation σ = 10.702.
2. n = 2 × (1.96 + 0.842)² × 10.702² / 12.260² = 12.0, rounded up to 12 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 12.26                      # observed difference in means
sigma <- 10.7015372727473                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(353522)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 12 (80% power), 17 (90% power)
 75% of observed effect: n per arm = 22 (80% power), 29 (90% power)
 50% of observed effect: n per arm = 48 (80% power), 65 (90% power)
power.t.test: 13 
Simulated power at n = 12 per arm: 0.759 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record reports an unadjusted p-value for the primary comparison and unadjusted p-values for the posted secondary comparisons. It does not report whether the analysis plan controlled the chance of false-positive findings across multiple endpoints, whether a hierarchy of outcomes was specified, or whether any secondary results were intended to be confirmatory. In general, when several outcomes are tested, the chance of at least one apparently notable result can rise. Without a reported multiplicity strategy, the individual p-values should not be treated as if they necessarily represent a single isolated test.

The record names several additional secondary outcomes, but numerical results for some listed measures are not reported in the registry record. It also does not describe whether all planned outcomes were reported, whether analyses were changed after data were reviewed, or whether there were interim analyses. These matters are not established by the posted comparisons and should not be inferred.

Missing-data methods and analysis populations are also not reported in the registry record. The primary outcome counts are 89 for dalcetrapib and 45 for placebo, while enrollment is reported as 135. The record does not explain the participant flow, the reasons for any difference between enrollment and outcome counts, or whether missing values were imputed, excluded, or handled by another method. The secondary outcome counts differ from the primary outcome counts, but the reasons are not reported.

The record does not specify whether an intention-to-treat population, a per-protocol population, or another population was used. It does not report sensitivity analyses for missing data or alternative modeling choices. In general, these details help readers judge how robust an estimate may be to assumptions about participants without an observed outcome. Their absence limits assessment of the analysis beyond the reported estimates, intervals, and p-values.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: lymphadenopathy (4.3%), atrial fibrillation (2.2%), non-cardiac chest pain (2.2%), coronary artery disease (2.2%), arthritis (2.2%).

The serious adverse event summaries report 11 affected participants among 89 at risk in the dalcetrapib group and 6 among 46 at risk in the placebo group. The registry's other adverse-event category records 0 affected participants in each group, with 89 at risk for dalcetrapib and 46 at risk for placebo. These are counts and denominators as recorded; they do not by themselves describe event timing, duration, severity beyond the serious classification, or causal relationship to treatment.

The registry lists serious event terms with percentages: Lymphadenopathy, 4.3%; Atrial Fibrillation, 2.2%; Non-Cardiac Chest Pain, 2.2%; Coronary Artery Disease, 2.2%; Arthritis, 2.2%; and OsteoArthritis, 2.2%. The listing does not specify an arm for each term or provide further detail about how the percentages were calculated. The number of participants affected by each listed term should not be inferred from the percentages alone.

Deaths are not reported in the registry record. The safety summaries are limited to the posted categories and follow-up information. They do not establish whether an event was caused by treatment, and they should be interpreted as descriptive registry data rather than as a complete assessment of comparative safety.

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

The primary result describes a greater mean increase in HDL-C from baseline to Week 24 in the dalcetrapib group than in the placebo group, with a reported between-group mean difference of 12.26 mg/dL and interval from 8.547 to 15.97. The unadjusted p-value is p < 0.001. This is evidence about the measured HDL-C endpoint under the reported analysis, not a direct result about cardiovascular events, symptoms, or survival.

In general, a laboratory marker can be useful for describing biological or biochemical change, but a change in a marker does not automatically establish a corresponding change in a clinical outcome. The registry record does not report a primary clinical event endpoint or longer-term primary outcome assessment. It also does not report a threshold for what size of HDL-C change would be considered clinically important. The statistical comparison therefore should not be translated into a claim about patient benefit or lack of benefit.

The study was Phase II and randomized, double-blind, and placebo-controlled. These features support a treatment-group comparison in general, but the record does not provide implementation details or enough information to evaluate the analysis population and handling of missing values. The reported safety counts and secondary lipid measures add context but do not remove those limitations. Serious adverse event counts alone do not establish a causal relationship or provide a full safety profile.

The result is most appropriately understood as a registry-reported estimate of a short-term change in HDL-C in the studied groups. It does not by itself answer whether the observed measurement change persists, applies to other populations, corresponds to changes in clinical outcomes, or balances against all potential risks. Those broader questions are not answered by the posted primary endpoint.

17. Why This Trial Matters Statistically

This study illustrates the distinction between a measured biomarker endpoint and a clinical outcome. The primary estimate is expressed in the endpoint's original unit, mg/dL, which makes the reported between-group contrast interpretable as a difference in HDL-C change. The interval adds information about statistical precision, while the unadjusted p-value addresses a different question about compatibility with a null comparison under the test assumptions.

The randomized, double-blind, placebo-controlled parallel design is relevant to how a group contrast can be interpreted. At the same time, details of allocation, masking, modeling, and analysis populations are not reported. Statistical conclusions are shaped not only by the point estimate but also by how participants and missing observations are handled, and by whether multiple outcomes are considered together.

The registry also illustrates why secondary results require careful weighting. CETP measures add biological context, but several outcomes are listed without numerical results and the multiplicity strategy is not reported. An unadjusted p-value for one measure does not settle the evidential status of a family of related outcomes.

Finally, the planning illustrations are not a retrospective measure of the completed study's power. They show how assumed target effects and stated planning conditions relate to participant requirements; the original design rationale is not reported. Taken together, these features make the study a useful example of reading an estimated treatment contrast while keeping endpoint scope, precision, multiplicity, and reporting gaps in view.

18. 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 trial-specific details needed to assess the result are not reported in the registry record. These include eligibility criteria beyond the broad CHD or CHD risk equivalent description, participant characteristics, allocation procedures, masking roles, and the statistical model used for the least-squares means. The record also does not explain the difference between enrollment of 135 and the primary outcome counts of 89 and 45.

The analysis population, participant flow, missing-data approach, and sensitivity analyses are not reported. This means the relationship between the reported endpoint estimates and all randomized participants cannot be established from the record. The confidence level and calculation method for the primary interval are also not reported, limiting technical interpretation of that interval.

The outcome record has other limits. It reports a Week 24 primary HDL-C measure but does not report a longer-term primary result. CETP activity is listed at baseline and 48 Weeks, and the reason for that timeframe is not described. Several other listed secondary outcomes lack numerical results in the registry record. No multiplicity plan or original sample-size justification is reported, so the inferential status of the secondary p-values and the basis for the planned enrollment cannot be assessed.

The serious adverse event summary gives counts and selected terms but does not report event-level details, term-specific arm assignments, or deaths. It does not establish causality. These limitations mean the posted information supports a focused reading of the reported endpoint estimates and safety counts, but not a complete reconstruction of the trial's conduct or analysis.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of RO4607381 in Patients With Coronary Heart Disease (CHD) or a CHD Risk Equivalent. — NCT00353522.
• Registry record last updated 2020-01-27; status last verified 2020-01.
• Results first posted 2020-01-27.
• 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.

22. Record Summary

The registry describes a completed Phase II, randomized, double-blind, placebo-controlled, parallel-group study of dalcetrapib in patients with coronary heart disease or a CHD risk equivalent. Enrollment is reported as 135, and the sponsor is Hoffmann-La Roche. Treatment is described as dalcetrapib 900mg po daily or placebo po daily for 24 weeks, with concomitant atorvastatin described in the study summary.

The primary endpoint is absolute change from baseline in HDL-C at Week 24. The reported mean difference is 12.26 mg/dL, with an interval from 8.547 to 15.97 and unadjusted p < 0.001. The record also posts CETP mass and activity results and serious adverse event counts. Original sample-size assumptions, multiplicity procedures, missing-data methods, and detailed analysis populations are not reported in the registry record.