Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I (NCT01004406), a randomized phase 3 study. The primary outcome is Change in the Total Atheroma Volume of the Target Coronary Artery From Baseline to 12 Weeks Post-PCI as Assessed Via Intravascular Ultrasound With Virtual Histology (IVUS-VH).

2. Clinical Question

3. Trial Design

The registry identifies PREMIER as a randomized, single-masked, parallel-group trial. Participants were assigned to intensive LDL-lowering therapy or standard statin monotherapy. The intervention descriptions specify LDL-apheresis plus statin treatment in the intensive arm and statin treatment without LDL-apheresis in the comparator arm. The registry describes the study as multi-site, but the number and locations of participating sites are not reported in the registry record.

The trial concerned patients with acute coronary syndrome undergoing PCI. Its primary outcome was assessed at baseline and 12-week follow-up, and the outcome description identifies the baseline measurement as occurring during index PCI. The primary outcome results are described as based on an intention-to-treat approach. The registry record does not report the details of the randomization sequence, concealment procedures, who was masked, or how masking was maintained.

The record lists 59 participants as enrolled. For the primary outcome, the reported group sizes are 21 in the intensive LDL-lowering therapy arm and 10 in the standard statin monotherapy arm. The registry record does not explain the relationship between the enrollment figure and these outcome group sizes, or why the reported numbers differ. It also does not report participant flow or the amount and handling of missing outcome data.

The registry phase field lists PHASE3, while the trial title includes “Phase I.” That difference is present in the record, and a reconciliation is not reported in the registry record. The study status is COMPLETED. The registry lists the start as 2011-09 and primary completion as 2013-01. The sponsor is the VA Office of Research and Development.

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: There were 59 subjects consented and enrolled into the study before entering catheterization lab to have the PCI procedure, but 28 subjects were not randomized to treatment assignments with the major exclusion reasons as not referred for PCI or not able to comply with study protocol based on the inclusion/exclusion criteria.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Reported results are based on Intent-to-Treat (ITT) approach.

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 Change in the Total Atheroma Volume of the Target Coronary Artery From Baseline to 12 Weeks Post-PCI as Assessed Via Intravascular Ultrasound With Virtual Histology (IVUS-VH), measured over baseline and 12-week follow-up.

The primary endpoint is change in total atheroma volume within a ≥ 20 mm long segment of the target coronary artery, measured by intravascular ultrasound with virtual histology. Measurements were taken at baseline during index PCI and at 12-week follow-up. The registry reports this continuous outcome as a mean change, with standard deviation describing the spread of individual measurements within each arm.

In general, an imaging measure of plaque volume provides a quantitative way to compare changes in the target artery over the specified follow-up interval. It is a measure of a vessel characteristic, not itself a count of cardiovascular events. The endpoint was selected to address the trial’s stated question about plaque-volume change under the two treatment strategies. The endpoint description does not establish that a change in this imaging measure necessarily corresponds to a change in clinical outcomes.

The observed mean change was -3.7 mm^3 in the intensive arm and 10.79 mm^3 in the standard-statins arm. The comparison focuses on the difference between those group means, rather than on whether either group’s mean change alone establishes a treatment effect. The confidence interval for that difference is important because it describes the range of estimates compatible with the posted data under the analysis assumptions.

7. Results Posted in the Registry

• Intensive LDL-lowering Therapy (ILLT): mean -3.70 versus 10.79 on control; difference -14.49 (95% CI -37.72 to 8.74), standardized effect d = -0.58; z-test p = 0.221.

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.

Change in % Necrotic Core (NC) Component of Atheroma From Baseline to 12 Weeks Post-PCI as Assessed Via IVUS-VH

• 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 deviations.
• Result:
  • Intensive LDL-lowering Therapy (ILLT): mean 0.01 versus -0.01 on control; difference 0.01 (95% CI -0.01 to 0.04), standardized effect d = 0.43; z-test p = 0.259.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Intensive LDL-lowering Therapy (ILLT) and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists three secondary outcomes: change in the necrotic-core component of atheroma, endothelial progenitor cell colony-forming units per milliliter of peripheral blood across time, and major adverse cardiovascular events. A numerical comparison is posted for the necrotic-core endpoint. Numerical results for endothelial progenitor cell colony-forming units and major adverse cardiovascular events are not reported in the registry record. The secondary outcomes therefore do not provide a complete numerical picture of every additional question named in the record.

The posted necrotic-core comparison has the same broad inferential limitation as the primary comparison: its estimate is uncertain, and its interval includes zero. It does not independently settle whether the treatment groups differed on that aspect of plaque composition. Viewed alongside the primary result, the available quantitative outcomes do not supply a precise, conclusive separation between the strategies. The secondary outcomes are related to the trial’s broader aims, but they measure distinct features and should not be treated as substitutes for the primary endpoint.

In general, secondary outcomes are often evaluated in addition to a primary outcome, and multiple testing can increase the chance of at least one apparently noteworthy result arising by chance. The registry does not report a multiplicity adjustment, a hierarchy for testing secondary outcomes, or a prespecified strategy for interpreting them. The posted secondary result is therefore best treated as exploratory context rather than as a stand-alone confirmatory finding. The record also does not report analyses for all listed secondary outcomes, so conclusions should not be extended to cell measurements or cardiovascular events on the basis of the available numerical results.

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

• Change in % Necrotic Core (NC) Component of Atheroma From Baseline to 12 Weeks Post-PCI as Assessed Via IVUS-VH
• Endothelial Progenitor Cell Colony Forming Units (EPC-CFU) Per Milliliter of Peripheral Blood Across Time
• Major Adverse Cardiovascular Events

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant contributes a measured change in total atheroma volume. The registry reports the mean change and standard deviation in each arm, then gives a mean difference between arms. For this comparison, the contrast is intensive LDL-lowering therapy minus standard statin monotherapy. The estimated difference is -14.49 mm^3, with a 95% confidence interval from -37.72 to 8.738 mm^3 and an unadjusted p-value of 0.221.

What does a mean difference express?

In general, a mean difference expresses the difference between the average outcome in one group and the average outcome in another. The sign depends on the order of subtraction. Here, the comparison is expressed as intensive therapy minus standard statin monotherapy, so a negative value means the observed mean change was lower in the intensive arm. The sign alone does not say whether a change should be considered clinically important; that requires substantive interpretation of the endpoint and a prespecified threshold, which is not reported in the registry record.

A group mean gives a compact description of the observed outcomes, but it does not show how individual observations are distributed. The standard deviation describes how spread out observations are around the group mean. For the primary endpoint, the reported standard deviations are 18.52 mm^3 for intensive therapy and 35.23 mm^3 for standard statin monotherapy. A larger standard deviation means more variation among observed values, not that the mean is necessarily less valid or that every participant had a change of that size.

How should the confidence interval be understood?

In general, a confidence interval describes statistical uncertainty around an estimate under the assumptions of the method used to calculate it. It is not a range containing a known share of individual participant outcomes, and it is not a guarantee that the true value lies inside the particular interval. The primary interval extends from -37.72 to 8.738 mm^3 and includes zero. That breadth means the posted summary does not pin down the population mean difference precisely. The interval is more informative about uncertainty than the point estimate alone.

In general, a p-value measures how compatible the observed data are with a specified null model, under the assumptions of the test. The primary unadjusted p-value is 0.221. It should not be interpreted as the probability that there is no treatment difference, nor as a measure of the size or clinical importance of a difference. A p-value also does not account for every uncertainty in the trial, such as missing outcome data or potential problems in implementation.

What do the analysis labels tell us?

The primary outcome description says the results are based on an intention-to-treat approach. In general, an intention-to-treat analysis aims to preserve the randomized group assignment in the analysis. The registry does not give additional information about how that approach was implemented, the availability of measurements, or the treatment of missing data. The reported group sizes are 21 and 10, while overall enrollment is 59; the participant flow that connects these figures is not reported in the registry record.

The comparison includes an unadjusted p-value. The registry record does not report a covariate-adjusted primary estimate or identify covariates used in a model. It also does not report the statistical analysis plan, the original sample-size justification, or whether there were interim analyses. Those details cannot be inferred from the reported means and standard deviations.

Why can over-dispersion matter?

In general, over-dispersion means that outcome variability is greater than a model assumes. For continuous outcomes, a large spread relative to the average treatment contrast can make the estimate less precise because observations provide less consistent information about the mean difference. This trial’s reported standard deviations indicate notable spread in both groups, particularly in the standard-statins arm. The contrast is uncertain in the confidence interval, but the registry record does not identify an over-dispersion model or any special correction for it. This explanation is general, rather than a claim that a particular model was used in the trial.

The results should be read as summary statistics for the stated endpoint and follow-up, not as a complete account of the analysis. Methods not described in the record—including data handling, model choices beyond the posted summary, and any sensitivity analyses—are not reported in the registry record. The absence of those details limits independent assessment of how robust the reported comparison is to analytical choices.

11. Confidence Intervals and Precision

The primary mean difference is -14.49 mm^3, with a 95% confidence interval from -37.72 to 8.738 mm^3. The interval includes zero and spans values on both sides of it. Thus, although the point estimate lies below zero, the data do not precisely determine the direction or size of the underlying mean difference. The confidence interval is the central precision result: it communicates a range of estimates compatible with the observed data and analysis assumptions, rather than just a single number.

In general, confidence intervals become narrower when estimates are based on more information and less variable measurements, and wider when information is limited or outcomes vary substantially. Here, the primary outcome group sizes are 21 and 10, and the observed standard deviations are 18.52 and 35.23 mm^3. These features provide context for the broad interval, but the registry does not report a precision target or the intended confidence-interval width during trial planning.

The interval does not establish equivalence, and it does not mean that all values inside it are equally plausible in every practical sense. It also does not describe the range of individual changes. The posted p-value of 0.221 is consistent with the interval’s inclusion of zero, but the interval conveys more than a binary test result by displaying the range of uncertainty. The registry record does not report a prespecified threshold for a clinically important mean difference, so the interval cannot be classified against such a threshold.

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 illustrations based on the observed effect, not a report of the trial’s original sample-size design. For this continuous-outcome planning display, the values refer to participants per arm, not total events. In general, a power column describes the planned chance of detecting a specified effect under a set of assumptions if that effect is present. The 80% power column and the 90% power column therefore represent different planning targets: the latter aims for a higher chance of detecting the chosen effect, all else held constant, and requires more participants per arm.

The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record. The displayed estimates should not be interpreted as the number needed for any unreported protocol target.

The rows illustrate planning for 100%, 75%, and 50% of the observed effect. As the assumed effect becomes smaller, more participants per arm are needed to detect it at the same power target under these assumptions. This is a general feature of sample-size planning: a subtle difference is harder to distinguish from background variation than a larger difference. These figures are not observed power; they are planning illustrations based on the posted effect estimate and stated assumptions. Because that observed estimate is uncertain, planning figures derived from it are uncertain too.

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 = -14.490; pooled standard deviation σ = 24.935.
2. n = 2 × (1.96 + 0.842)² × 24.935² / -14.490² = 46.5, rounded up to 47 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 <- -14.49                      # observed difference in means
sigma <- 24.9345239819592                     # 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(1004406)
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 = 47 (80% power), 63 (90% power)
 75% of observed effect: n per arm = 83 (80% power), 111 (90% power)
 50% of observed effect: n per arm = 186 (80% power), 249 (90% power)
power.t.test: 47.5 
Simulated power at n = 47 per arm: 0.792 (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 lists one primary outcome and several secondary outcomes, but it does not report a statistical analysis plan describing how those outcomes were to be tested together. A multiplicity procedure, such as a prespecified adjustment or an ordered testing strategy, is not reported in the registry record. In general, when multiple hypotheses are tested, the chance of at least one false-positive result can rise unless the analysis accounts for the number and structure of tests. Without a stated plan, the inferential status of secondary findings cannot be judged as confirmatory from the registry information alone.

The record gives a primary outcome population described as intention-to-treat, but it does not report detailed participant flow, the number with measurements available at each time point, or reasons for unavailable measurements. Overall enrollment is 59, while the reported primary outcome group sizes are 21 and 10. How the randomized participants relate to those outcome counts is not explained. The record does not report imputation methods, a missing-data sensitivity analysis, or whether any participants were excluded from the outcome analysis.

The registry record does not report the original sample-size justification, protocol-level statistical assumptions, interim analyses, or stopping rules. Nor does it report whether the primary comparison was adjusted for baseline characteristics or other covariates. These omissions do not prove that such methods were absent from the trial’s full documentation; they mean those details are not reported in the registry record. The posted summary statistics can be described, but they do not answer questions about the complete analysis plan or the robustness of results to alternative assumptions.

15. 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 4% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chest pain (20.0%), coronary artery disease (10.0%), drug hypersensitivity (10.0%), dyspnoea (10.0%), peripheral vascular disorder (10.0%).

The registry reports serious adverse events in 10 of 21 participants in the intensive LDL-lowering therapy group and 4 of 10 participants in the standard statin monotherapy group. Other adverse events are reported in 17 of 21 and 8 of 10 participants, respectively. Deaths are listed as 0 in each group. These are descriptive counts in the registry record; they do not, by themselves, establish whether the groups differ in safety.

The serious-event terms listed include Chest pain at 20.0%, Coronary artery disease at 10.0%, Drug hypersensitivity at 10.0%, Dyspnoea at 10.0%, Peripheral vascular disorder at 10.0%, and Angina unstable at 4.8%. The registry record does not provide further detail in the registry record about event timing, duration, severity grading, attribution, or whether a participant could contribute more than one event term. Such details are important to interpretation and are not reported in the registry record.

In general, adverse-event counts should be interpreted with the group sizes and event definitions in view. These figures are not an estimate of a causal treatment effect on safety, and no medical recommendation follows from them. They describe the posted safety summaries only.

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

The primary result describes the observed change in target-coronary-artery atheroma volume between baseline and 12-week follow-up among the reported outcome groups. The group means differed in direction, and the estimated mean difference was -14.49 mm^3 for intensive therapy relative to standard statin monotherapy. The confidence interval, from -37.72 to 8.738 mm^3, is broad and includes zero. The posted data therefore leave substantial uncertainty about the underlying between-group difference.

That uncertainty matters for interpretation. The estimate should not be treated as an exact prediction of the contrast in another population, and the result does not establish that the two strategies are equivalent. Nor does the imaging endpoint directly answer whether the strategies differ in clinical events. Major adverse cardiovascular events are listed as a secondary outcome, but numerical results for that outcome are not reported in the registry record.

The study’s stated purpose also includes investigating endothelial progenitor cells. That outcome is listed in the registry, but numerical results are not reported in the registry record. Consequently, the posted primary endpoint cannot answer the cell-measurement question. The registry’s secondary-outcome listing and its available numerical results should be distinguished: an outcome being named does not mean its result is available for interpretation.

In general, randomized assignment supports a comparison between groups, but the strength of conclusions still depends on outcome information, precision, analysis choices, and follow-up. The registry identifies randomization and an intention-to-treat approach for primary results, while leaving important details about participant flow and missing observations unreported. The result supports a cautious description of the observed summaries, not a broad claim about all patients, longer follow-up, or outcomes not numerically reported.

No treatment recommendation follows from these statistical summaries. They describe the posted trial results and their uncertainty. Whether a measured change is clinically meaningful requires information and judgments beyond the point estimate alone, and a threshold for such a difference is not reported in the registry record.

17. Why This Trial Matters Statistically

This trial illustrates why a point estimate should not be read without its confidence interval. The observed primary mean difference is distinct from the uncertainty around that estimate: the interval extends across zero and covers a broad range of possible contrasts. A single direction in the group means is therefore not enough to establish a precise treatment difference. Reporting the interval alongside the mean difference and p-value gives a more informative account than relying on any one statistic.

The example also highlights how outcome variability and outcome group sizes affect precision. The reported standard deviations are substantial relative to the between-group estimate, while the outcome group sizes are 21 and 10. In general, greater variability and limited information make it harder to estimate a mean difference precisely. The record’s enrollment count of 59 does not remove the need to understand how many participants contributed to the reported outcome summaries and why those counts differ; that accounting is not reported in the registry record.

Finally, the trial connects a quantitative imaging endpoint with additional biological and clinical questions. The record lists secondary outcomes, but numerical results are not available for all of them. That distinction is important: a trial’s stated objectives, available outcome summaries, and the strength of statistical evidence are related but not interchangeable. The record is a useful example of interpreting the result that is posted without extending it to unreported outcomes or analyses.

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 limitations specific to this record constrain interpretation. First, the primary follow-up is 12 weeks. The registry does not report longer-term primary outcome results, so the posted imaging comparison addresses only the stated baseline-to-12-week interval. It cannot establish how the measure behaves beyond that follow-up.

Second, the overall enrollment is 59, while the primary outcome summaries report group sizes of 21 and 10. The registry record does not explain the difference, describe participant flow, or report the number of missing measurements and their reasons. Although the outcome population is described as intention-to-treat, the available record does not show how that principle was applied to participants without an observed measurement.

Third, the primary comparison is reported with an unadjusted p-value, and a broader analysis plan is not reported in the registry record. The record does not describe covariate adjustment, sensitivity analyses, multiplicity handling, or the original sample-size justification. These omissions limit assessment of the robustness and intended inferential status of the estimates.

Fourth, the outcome set is not fully represented by numerical results. Necrotic-core change has a posted comparison, but numerical results for endothelial progenitor cell colony-forming units and major adverse cardiovascular events are not reported in the registry record. Those unreported outcomes cannot be inferred from the primary imaging result.

Finally, the phase field lists PHASE3, while the title includes “Phase I.” The registry does not reconcile that difference. Further details about sites, masking procedures, treatment adherence, event adjudication, and adverse-event attribution are also not reported in the registry record. These limits concern the information available in the record and should not be mistaken for proof that the full study documentation lacked those details.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER), Phase I — NCT01004406.
• Registry record last updated 2019-07-30; status last verified 2019-07.
• Results first posted 2019-07-15.
• 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

PREMIER is listed as a completed, randomized, single-masked, parallel-group trial sponsored by the VA Office of Research and Development. It enrolled 59 participants with acute coronary syndrome undergoing PCI and compared intensive LDL-lowering therapy, involving LDL-apheresis plus statin treatment, with standard statin monotherapy. The primary endpoint was change in target-coronary-artery total atheroma volume from baseline to 12-week follow-up, measured by IVUS-VH.

The primary mean difference was -14.49 mm^3, with a 95% confidence interval from -37.72 to 8.738 mm^3 and an unadjusted p-value of 0.221. The interval includes zero and is broad, so the estimate is imprecise. Numerical results are not reported in the registry record for every listed secondary outcome. Important details about participant flow, missing data, multiplicity, and the original analysis and sample-size plans are not reported in the registry record.