Dose-ranging Efficacy and Pharmacokinetics Study of Intravenous Atorvastatin in Hypercholesterolemic Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-ranging Efficacy and Pharmacokinetics Study of Intravenous Atorvastatin in Hypercholesterolemic Patients (NCT03611010), a non-randomized phase 2 study. The primary outcome is Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C.

2. Clinical Question

3. Trial Design

This Phase II study evaluated the efficacy dose response and pharmacokinetics of atorvastatin in patients with hypercholesterolemia previously controlled on oral atorvastatin. It is listed as completed, with enrollment of 40. The registry classifies the study as open-label, non-randomized, and sequential. These design features matter when interpreting differences between cohorts: treatment assignment was not randomized, there is no stated concurrent control group, and participants and study personnel were not masked.

The cohort descriptions identify an oral atorvastatin lead-in followed by study drug for up to 15 days. Cohort 1 had a baseline daily oral dose of 10 mg; Cohorts 2 and 3 had 20 mg and 40 mg, respectively. Cohort 4 also had a baseline daily oral dose of 20 mg. The first three cohorts are described as receiving intravenous study drug, while Cohort 4 is described as receiving subcutaneous study drug. The official title refers to intravenous atorvastatin, so the route description for Cohort 4 differs from that title; the registry record does not explain the distinction.

The primary outcome focuses on Day 15 LDL-C relative to baseline. Secondary outcomes listed include a Day 15 HDL-C threshold, change in LDL-C concentration, and pharmacokinetic measures. The record lists nine outcome measures but no analysis entries. It does not report the actual primary efficacy counts, cohort-specific efficacy results, or statistical comparisons. The sequential classification alone does not establish how cohort progression was determined; those criteria 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.

Period 1: Lead-In

Period 2: 15 Day Treatment

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy Population: A completed group of subjects that 1) finished the two-week treatment period, 2) provided a Day 15 LDL-C level, and 3) took the final targeted dose for that cohort comprised the four efficacy populations.

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: Safety Population: All subjects who received at least a partial dose of investigational medicinal product. No treated subjects were excluded from the safety population.

6. Primary Endpoint

The registry lists the primary outcome as Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C, measured over Baseline, 15 Days.

The primary endpoint is the number of participants in each cohort whose Day 15 LDL-C was no more than 125% of their baseline LDL-C. LDL-C is measured before treatment and at the end of the 15-day treatment period, and the endpoint expresses the Day 15 value relative to each participant’s own baseline. The registry description defines a cohort as meeting its efficacy criterion when eleven or more participants satisfy the threshold.

This endpoint turns a continuous laboratory measurement into a binary participant-level outcome: each participant either meets the specified LDL-C threshold or does not. Counting participants makes the result interpretable as the number meeting the criterion, but it does not retain the full range of LDL-C changes. Participants just on either side of the cutoff are classified differently, even if their measurements are close; participants with different magnitudes of change can be grouped together if both meet the criterion.

The endpoint is used to assess whether the cohort’s Day 15 LDL-C remained within the stated limit relative to baseline. It is not a direct estimate of the average LDL-C change, nor does the threshold alone describe variation across participants. Although the registry states the efficacy definition, it does not report how many participants in any cohort met it. The evidence needed to judge the primary endpoint’s observed result is therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the primary outcome as a participant count, not a continuous estimate of LDL-C change. It also lists change in LDL-C concentration as a secondary outcome. Those are different summaries: a threshold count records whether each participant meets a specified condition, whereas a change measure retains information about the magnitude and direction of the laboratory value’s movement. The registry does not post the results for either outcome.

What a threshold count captures

General statistical explanation: converting a measurement to a yes-or-no outcome can make a criterion straightforward to interpret, but it discards information about how far each participant’s value lies from the cutoff. A participant slightly above the threshold and one substantially above it are both classified as not meeting the criterion. Likewise, meeting the threshold does not show the size of any change within that category. The count should therefore be understood as a tally of participants satisfying the stated rule, not as a complete description of LDL-C values.

The registry defines efficacy as eleven or more participants in a dosing cohort having a Day 15 LDL-C no more than 125% of baseline. This cohort-level rule is distinct from the individual participant classification: the individual either meets the LDL-C threshold or does not, while the cohort criterion depends on the number meeting it. The record does not report the observed number in any cohort, so it is not possible to determine whether the stated cohort criterion was reached.

What uncertainty would mean

General statistical explanation: a confidence interval describes the range of values reasonably compatible with observed data under a specified statistical model. Its width reflects precision, and its interpretation depends on the design and analysis assumptions. A point estimate without an interval gives less information about uncertainty; a count without the relevant denominator and analysis details is more limited still. No confidence interval for the primary outcome is reported in the registry record.

The study is non-randomized and open-label. General statistical explanation: random assignment can help balance participant characteristics across treatment groups, while masking can reduce the influence of knowledge of treatment assignment on care or measurement. When those features are absent, a difference between groups may reflect differences in who entered each cohort, the order or circumstances of treatment, or other factors as well as treatment. This is why cohort contrasts in this study should not be interpreted as randomized comparisons. The registry record does not report an adjustment strategy that would address such differences.

Sequential cohorts and dose response

The registry classifies the model as sequential and describes cohorts with different oral lead-in doses, followed by study drug. General statistical explanation: dose-ranging studies can explore whether outcomes vary with dose, but a dose-response interpretation depends on the actual outcome data and on how cohorts were formed and treated. The registry record does not report the rules for moving between cohorts, the timing or rationale for those decisions, or a statistical model for dose response. The cohort labels and dose descriptions alone do not establish a dose-response pattern.

The listed primary outcome is binary, while several secondary outcomes concern pharmacokinetic quantities such as maximum concentration, time to maximum concentration, exposure, distribution volume, and half-life. These outcomes address different aspects of drug concentration and effect. Their presence in the outcome list does not establish that results were reported or that a particular statistical method was used. The record lists nine outcome measures and zero analysis entries.

Planning calculations are not trial findings

General statistical explanation: sample-size calculations are planning tools. They depend on assumptions about an effect, variability, allocation, significance level, and target power. A planning illustration based on an observed effect is not the same as a prespecified design justification, and it is not observed power. The registry describes its planning illustration as using a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a fraction of the observed effect. It also specifies that non-time-to-event illustrations are expressed as participants per arm. The registry record does not report a trial-specific sample-size justification, and no observed-effect results are posted from which to interpret the illustration.

In general, over-dispersion means that observed variability is greater than a statistical model assumes. If present, a model that fails to account for it can understate uncertainty. The registry record does not identify an over-dispersion assessment or a model for the primary endpoint. No particular statistical test, regression model, variance assumption, or confidence-interval method is reported, so none should be inferred from the endpoint definition.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1", "Cohort 2", "Cohort 3", "Cohort 4")
n      <- c(11, 13, 2, 9)
events <- c(9, 9, 1, 7)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1  11  9  81.8  48.2  97.7  52.3  94.9  51.6  94.5
ARM  Cohort 2  13  9  69.2  38.6  90.9  42.4  87.3  41.9  87.2
ARM  Cohort 3  2  1  50.0  1.3  98.7  9.5  90.5  9.4  90.6
ARM  Cohort 4  9  7  77.8  40.0  97.2  45.3  93.7  44.4  93.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures, including the primary LDL-C threshold outcome and secondary lipid and pharmacokinetic outcomes. It does not report a multiplicity strategy, such as how the chance of false-positive findings across multiple outcomes would be handled. Nor does it report a hierarchy of testing or an analysis plan specifying which secondary outcomes would be confirmatory. Since the record contains zero analysis entries, it does not provide results that could be reviewed in light of a multiplicity plan.

Missing-data handling is also not reported in the registry record. The efficacy population is defined using completion of the treatment period, availability of a Day 15 LDL-C value, and receipt of the final targeted dose. That definition indicates who was included in the efficacy population, but it does not explain how many participants were excluded for each reason, whether missing measurements were imputed, or how incomplete follow-up was handled in any analysis. The posted entry does not report a separate intention-to-treat analysis or another analysis population.

These details matter because excluding participants without a Day 15 measurement can affect the composition of the analyzed group. General statistical explanation: missingness can influence an estimate when the likelihood of having a measurement is related to participant characteristics or outcomes. Without counts and a stated handling approach, the direction or magnitude of any such influence cannot be assessed. The registry record does not report sensitivity analyses for missing data.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety entries list no serious adverse events and no deaths in any of the four cohorts. The groups at risk for serious adverse events are 14 in Cohort 1, 14 in Cohort 2, 2 in Cohort 3, and 10 in Cohort 4; the corresponding serious-event counts are zero. These are descriptive counts in the registry record, not evidence that the risk of serious events is absent.

Other adverse events are listed for the same group sizes: 4 in Cohort 1, 1 in Cohort 2, 1 in Cohort 3, and 3 in Cohort 4. The registry entry does not provide event terms for these counts, severity detail, timing, or an analysis comparing cohorts. Cohort 3 has only 2 participants at risk in the posted safety grouping, so its count should be read in that limited context. The groups were not randomized comparator arms, and differences in counts should not be interpreted as causal treatment effects.

General statistical explanation: an observed count of zero does not prove that an event cannot occur; it describes only the events recorded in the observed group. A safety assessment also depends on the number followed, duration of observation, definitions, and completeness of reporting. The registry lists treatment for up to 15 days, but does not report further safety-analysis details.

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

The study asks whether participants in each dosing cohort meet a prespecified Day 15 LDL-C threshold relative to baseline. The registry record gives the threshold and the cohort-level criterion, but does not give the primary outcome counts. As a result, the posted information cannot show whether any cohort met the efficacy criterion, how outcomes varied across participants, or how precisely an effect was estimated.

The study’s design can support descriptive reporting of results from the enrolled cohorts, but its non-randomized, open-label, sequential structure does not provide a randomized comparison. The cohorts also differ in oral lead-in dose, and Cohort 4 is described with a different route from the other cohorts. Without reported analysis methods and outcome data, cohort contrasts cannot be separated from potential differences in cohort composition or study conduct.

The safety entries report zero serious adverse events and zero deaths, alongside other adverse-event counts. These counts describe what is recorded for the specified groups; they do not establish comparative safety or rule out events beyond those observed and reported. The registry record does not provide enough detail to assess the nature or timing of the other events.

In statistical terms, the record is informative about the question the trial set out to ask and the way its cohorts were structured, but not about the primary efficacy result. It does not establish that atorvastatin did or did not achieve the LDL-C criterion, and it does not quantify a treatment effect or its uncertainty. No clinical recommendation follows from the endpoint definition or the posted safety counts alone.

14. Why This Trial Matters Statistically

This study illustrates how a clear endpoint definition and a reported result are separate parts of statistical evidence. The primary criterion is explicit: count participants with Day 15 LDL-C no more than 125% of baseline, with a cohort-level efficacy definition of eleven or more participants. Yet the outcome counts themselves are not reported. Without those counts, readers cannot assess whether the criterion was reached or quantify the result.

The design also highlights why treatment allocation and cohort structure matter. A non-randomized, open-label, sequential study may be useful for describing dose-ranging and pharmacokinetic questions, but it does not create a randomized control comparison. Differences between cohorts cannot automatically be attributed to dose, especially when the cohorts have different oral lead-in doses and one cohort has a different route description. The registry does not report the procedures or analyses needed to evaluate those distinctions.

Finally, the record shows the limits of interpreting safety counts in small cohort groups. Zero serious events and deaths are useful descriptive observations, but event counts alone do not establish a risk comparison or exclude uncommon harms. Together, these features make the trial a useful example of reading registry information cautiously: endpoint definitions, design labels, and adverse-event counts answer different questions, and none substitutes for unreported efficacy results, uncertainty estimates, or a detailed analysis plan.

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 most important limitation for interpretation is that the registry record does not report results for the primary efficacy endpoint. It also does not report a primary effect estimate, confidence interval, or test. Although the primary endpoint is defined in detail, the actual number of participants meeting its threshold in each cohort is absent, so its result cannot be assessed.

The non-randomized and open-label design limits causal interpretation of cohort differences. The record does not describe the criteria for cohort progression or explain how participants were assigned to the cohorts. Cohorts also have different oral lead-in doses, and the Cohort 4 description specifies subcutaneous study drug while the study title describes intravenous atorvastatin. The registry does not resolve this difference.

The efficacy population requires completion, a Day 15 LDL-C value, and receipt of the final targeted dose, but the number of participants satisfying these conditions is not reported. Missing-data procedures, analysis populations beyond that definition, and sensitivity analyses are not reported in the registry record. The statistical analysis plan, multiplicity approach, and trial-specific sample-size justification are also not reported.

Safety reporting is limited to group counts for serious events, other adverse events, and deaths. The record does not provide the terms for other events, their severity or timing, or comparative safety analyses. Cohort 3 has 2 participants at risk in the posted safety entries, which restricts what its event count can convey. The posted information therefore supports a limited descriptive account, not a comprehensive assessment of efficacy, safety, or comparative effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose-ranging Efficacy and Pharmacokinetics Study of Intravenous Atorvastatin in Hypercholesterolemic Patients — NCT03611010.
• Registry record last updated 2022-07-15; status last verified 2022-05.
• Results first posted 2022-07-15.
• 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.

19. Record Summary

NCT03611010 is a completed Phase II dose-ranging study of atorvastatin in patients with hypercholesterolemia previously controlled on oral atorvastatin. The registry lists enrollment of 40, non-randomized allocation, no masking, and a sequential model. Its primary outcome is the number of participants with Day 15 LDL-C no more than 125% of baseline; the cohort-level efficacy definition is eleven or more participants meeting that threshold.

The cohorts are described with oral lead-in doses of 10 mg, 20 mg, 40 mg, and 20 mg, followed by study drug for up to 15 days. The first three are described as intravenous and Cohort 4 as subcutaneous. The registry lists nine outcome measures and zero analysis entries. Primary efficacy results are not reported in the registry record. Safety entries list zero serious adverse events and zero deaths in each cohort, with other adverse-event counts of 4, 1, 1, and 3 for Cohorts 1 through 4, respectively.