A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653C in Japanese Participants With Hypercholesterolemia (MK-0653C-384): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653C in Japanese Participants With Hypercholesterolemia (MK-0653C-384) (NCT02460159), a non-randomized phase 3 study. The primary outcome is Percentage of Participants Who Experience 1 or More Adverse Event (AE).

2. Clinical Question

The clinical question is about safety and tolerability after participants received a combination of ezetimibe and atorvastatin. It is not a randomized test of whether one dose combination is superior to the other, and the primary endpoint is not an LDL-C efficacy outcome. The official title describes participants with inadequate LDL-C control on monotherapy, but the registry record does not provide a numerical LDL-C result for this primary endpoint.

The registry record lists 135 participants enrolled overall. It describes two treatment arms and reports serious and other adverse-event counts by arm. Numerical results for the primary endpoint itself are not reported in the registry record. Therefore, the stated clinical question can be described from the endpoint definition, but its primary numerical answer cannot be recovered from the posted results.

3. Trial Design

This was a Phase III, parallel, non-randomized clinical trial sponsored by Organon and Co. The registry record lists the study as completed. It gives a start date of 2015-06-23 and a primary completion date of 2016-12-22, with enrollment of 135 participants. The study concerned Japanese participants with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia.

Participants received one of two ezetimibe/atorvastatin fixed-dose combinations. One arm took ezetimibe 10 mg/atorvastatin 10 mg, and the other took ezetimibe 10 mg/atorvastatin 20 mg. Each regimen is described as one tablet orally with food once daily for 52 weeks. The primary endpoint timeframe is stated as up to 54 weeks. The reason for the difference between the treatment duration and endpoint timeframe is not reported in the registry record.

Allocation was non-randomized and masking was none. The registry record therefore does not describe a blinded or randomized comparison. It explicitly cautions that the arms are not a like-for-like control comparison. The precise mechanism for choosing a participant’s arm, and whether arm choice reflected participant characteristics or clinical considerations, is not reported in the registry record. This limits how directly differences between arm-level outcomes can be attributed to the dose combination.

The study summary says its purpose was to assess safety and tolerability in participants whose hypercholesterolemia was uncontrolled with ezetimibe 10 mg or atorvastatin up to 20 mg monotherapy. It also states that there was no formal hypothesis. The registry record lists 12 outcome measures, but no posted analyses are recorded. A detailed statistical analysis plan, including planned comparisons and any prespecified adjustments, is not reported in the registry record.

The primary endpoint population was defined as participants who received at least one dose of study drug and had available data for the endpoint. The registry record does not give further details about screening, follow-up visits, treatment discontinuation, or how participants without endpoint data were handled. Those omissions matter when interpreting the reported safety counts and when judging how completely the endpoint represents all enrolled participants.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants that received at least 1 dose of study drug and had available data for endpoint.

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 Percentage of Participants Who Experience 1 or More Adverse Event (AE), measured over up to 54 Weeks.

The primary endpoint is the percentage of participants who experienced one or more adverse events, with a timeframe of up to 54 weeks. An adverse event was defined as an untoward medical occurrence that did not necessarily have a causal relationship with treatment. The definition includes an unfavorable or unintended sign, including an abnormal laboratory finding, symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to that product.

This type of endpoint is used to describe the frequency of participants with at least one recorded adverse event during the specified observation period. It gives a participant-level summary: a participant with multiple events still meets the endpoint of experiencing one or more events. It is a broad safety measure, not a measure of event severity, treatment causation, or clinical benefit. More detailed event categories are needed to understand the nature of reported events.

The endpoint population includes participants who received at least one dose and had available endpoint data. That definition is important: the percentage does not necessarily describe every enrolled participant if some did not receive treatment or lacked endpoint data. The registry record does not report the numerical primary endpoint results, confidence intervals, or a detailed account of missing endpoint data. As a result, the endpoint’s definition is available, but the posted results do not give its numerical value for either arm.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s primary outcome is binary at the participant level: each participant either experienced at least one adverse event during the specified follow-up or did not. A percentage summarizes the share of participants meeting that definition. In general, binary endpoints are commonly described with counts and percentages because those summaries show both the number of participants affected and the proportion of an analysis population affected. Here, the registry record defines the endpoint but does not report its numerical result.

What does a percentage describe?

A percentage is meaningful only alongside its denominator and the population from which that denominator was drawn. The primary endpoint population is described as all participants who received at least one dose and had endpoint data available. That is narrower than all enrolled participants if anyone did not receive treatment or did not have endpoint data. The registry record does not provide the number included in the primary endpoint analysis for either arm, nor does it report how missing endpoint data were handled. The separate numbers at risk in the adverse-event record should not automatically be assumed to be the denominators for every endpoint or event category.

For a binary outcome, uncertainty depends in part on the amount of information in the data. In general, estimates from smaller groups tend to be less precise than estimates from larger groups, all else equal. A confidence interval is a range of values compatible with the data under a specified statistical method and its assumptions; it communicates uncertainty rather than guaranteeing that the true value lies within the interval. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from that endpoint result.

Why does allocation matter?

Random allocation is intended, in general, to make treatment groups comparable with respect to both measured and unmeasured factors on average. This study is listed as non-randomized, and the registry record cautions that its arms are not a like-for-like control comparison. Differences in observed adverse-event counts could reflect differences between participants or in their care, as well as any effect associated with treatment. The record does not describe the allocation process, report baseline comparisons, or provide adjusted estimates that would help address such concerns.

Masking is listed as none. In general, awareness of the treatment can affect reporting, investigation, or classification of symptoms and events. That is a potential consideration for interpreting adverse-event reporting, not evidence that reporting was biased in this study. The registry record does not describe procedures used to assess or adjudicate events.

What can the posted safety counts show?

The record gives serious-event and other-event counts for each arm, alongside the numbers at risk. These are descriptive summaries. They indicate how many participants were recorded in those categories, but they do not provide time-to-event estimates, event rates per unit of follow-up, or an adjusted comparison. The record does not specify whether participants could contribute to both categories or how recurrent events were handled. The primary endpoint counts and percentages are also not reported, so the safety counts cannot substitute for that primary result.

The registry lists selected serious adverse-event terms with percentages. In general, a term-level percentage may use a participant denominator, an event denominator, or another defined population; the denominator must be known to interpret it. The registry record does not clarify the denominators or link the listed term percentages to a particular treatment arm. It is not possible to make a treatment-group comparison from those term entries alone.

What can be inferred from the analysis record?

The study summary explicitly states that there was no formal hypothesis, and the registry record contains no posted analyses. Thus, a reader should not infer that a particular statistical test, model, adjustment, or decision threshold was used. The detailed statistical plan, including any interim analysis plan, is not reported in the registry record. The record also does not report a sample-size justification. The enrollment count is not, by itself, evidence that the study was designed to achieve a stated level of precision or power.

In general, sample-size planning depends on a target effect or precision, assumptions about the outcome, and the chosen analysis. A planning illustration is not the same as an observed result or an observed power calculation. The registry’s own design rationale and the assumptions behind any formal planning exercise are not reported in the registry record. No conclusion about the adequacy of the study’s sample size for the primary endpoint can be made from enrollment alone.

Finally, statistical interpretation must distinguish description from causation. A within-arm count describes events recorded among participants in that arm. A comparison between non-randomized arms is vulnerable to confounding and cannot automatically be interpreted as the effect of changing the atorvastatin dose. Without the primary endpoint values, an analysis plan, and information on participant comparability, the posted record supports a limited descriptive account rather than a precise comparative conclusion.

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("EZ 10 mg/Atorva 10 mg FDC", "EZ 10 mg/Atorva 20 mg FDC")
n      <- c(117, 18)
events <- c(97, 16)
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  EZ 10 mg/Atorva 10 mg FDC  117  97  82.9  74.8  89.2  75.1  88.7  75.0  88.6
ARM  EZ 10 mg/Atorva 20 mg FDC  18  16  88.9  65.3  98.6  67.2  96.9  66.9  96.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 12 outcome measures, but no posted analyses are recorded. It does not report a plan for controlling multiplicity, such as how to interpret multiple outcome tests or comparisons. The study summary states that there was no formal hypothesis, so the record does not establish a formal hypothesis-testing framework for the outcomes. A reader should not infer that statistical significance testing, adjustment for multiple comparisons, or a hierarchy among outcomes was performed.

Missing-data handling is also not reported in the registry record. The primary endpoint population is defined as participants who received at least one dose and had available endpoint data, but the record does not give the number lacking data, reasons for missingness, or methods used to address missing outcomes. It does not report whether participants with incomplete follow-up were included in any other analysis population. In general, excluding participants without endpoint data can affect interpretation if their outcomes differ from those with observed data; the size and direction of any such effect cannot be assessed without information about missingness.

The record does not describe imputation, sensitivity analyses, or assumptions about missing data. It also does not provide a detailed analysis population beyond the primary endpoint definition. Accordingly, the reported adverse-event counts should not be taken as a complete account of endpoint availability or follow-up completeness. The absence of these details limits assessment of both the primary result and the robustness of any comparisons between arms.

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: extradural haematoma (5.6%), subdural haematoma (5.6%), lung neoplasm malignant (5.6%), angina pectoris (0.9%), myocardial ischaemia (0.9%).

The registry’s adverse-event record lists 7 participants affected by serious adverse events among 117 at risk in the ezetimibe 10 mg/atorvastatin 10 mg arm, and 2 among 18 at risk in the ezetimibe 10 mg/atorvastatin 20 mg arm. For other adverse events, it lists 77 among 117 and 16 among 18, respectively. No deaths are listed in either arm. These counts are descriptive, and the registry record does not establish that events were caused by the study treatment.

The record also lists selected serious adverse-event terms: extradural haematoma, subdural haematoma, and lung neoplasm malignant at 5.6% each; and angina pectoris, myocardial ischaemia, and colitis ischaemic at 0.9% each. The denominators and arm attribution for these term-level percentages are not reported in the registry record. The terms may not represent separate participants, and the record does not explain whether one participant could contribute to more than one listed term. These entries should therefore be read as reported safety details, not as directly comparable arm-specific risks.

Serious adverse events are a category distinct from the broad primary endpoint of at least one adverse event. The primary endpoint’s numerical result is not reported in the registry record, and no confidence intervals or adjusted arm comparison are reported for the safety counts.

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

The record establishes the purpose and broad structure of a safety and tolerability study of two ezetimibe/atorvastatin fixed-dose combinations in Japanese participants with hypercholesterolemia. It defines the primary endpoint as the percentage experiencing at least one adverse event during follow-up of up to 54 weeks and describes the endpoint population. It also reports selected arm-level adverse-event counts and serious-event terms.

Those details do not provide the numerical result for the primary endpoint. The registry record does not report the primary endpoint percentage for either arm, its uncertainty, or a statistical comparison. It therefore cannot support a numerical statement about how frequently participants experienced at least one adverse event under the primary endpoint definition, based on the posted results.

The study is non-randomized, unmasked, and explicitly described as not having a like-for-like control comparison. As a general statistical principle, differences between non-randomized groups may reflect group composition or other factors rather than treatment alone. The record does not report enough information about assignment or participant comparability to separate those possibilities. The safety counts should be interpreted as descriptive observations, not proof of a causal difference between regimens.

The registry also states that there was no formal hypothesis. No posted analyses are recorded, and the record does not report a detailed statistical plan, multiplicity approach, or missing-data methods. These omissions mean that the intended inferential framework and the robustness of any potential comparison cannot be evaluated from the record.

In general, the absence of a reported result is not evidence that no adverse events occurred; it means the primary numerical summary is unavailable in the registry record. Similarly, a count of zero deaths in the posted arm summaries does not establish that a regimen is free of risk. The record supports a description of what was registered and which safety counts were posted, but not a conclusion about treatment efficacy, comparative safety, or the certainty of a treatment effect.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a registered safety question and the results needed to answer it quantitatively. The primary outcome is clearly framed as the percentage of participants with at least one adverse event, and the registry defines what counts as an adverse event. Yet numerical results for that primary endpoint are not reported in the registry record. Knowing the endpoint definition alone is not enough to judge its observed frequency or precision.

The non-randomized design is also central to interpretation. A parallel-arm study can describe what happened in each arm, but without random allocation the groups are not necessarily comparable. The registry’s explicit warning against treating the arms as a like-for-like comparison is an important limit on any arm-to-arm interpretation. It illustrates why design information must be considered alongside event counts rather than treating those counts as direct evidence of a dose effect.

The record makes another useful distinction between broad adverse-event experience and serious adverse events. The primary endpoint covers at least one adverse event, while the safety record separately lists serious and other events and selected serious-event terms. These summaries answer different descriptive questions. They should not be combined or substituted for one another, especially when definitions and denominators are not fully reported.

For clinical researchers and biostatisticians, the record highlights the value of complete reporting: primary endpoint values, analysis populations, uncertainty estimates, missing-data handling, and the planned approach to multiple outcomes. Without those elements, readers can identify the study question and some recorded safety counts, but cannot assess the primary result’s precision or conduct a well-supported comparative interpretation. This is a limit on what can be concluded from the registry record, not a claim about whether results exist elsewhere.

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.

Several trial-specific limitations constrain interpretation. First, the registry record does not report numerical results for the primary endpoint, even though it defines the endpoint and its timeframe. Without those values, the main stated safety outcome cannot be quantitatively assessed. The record also does not report confidence intervals or another measure of uncertainty for that endpoint.

Second, allocation was non-randomized, and the record cautions that the arms are not a like-for-like control comparison. The arm-assignment process and relevant participant characteristics are not reported in the registry record. This prevents assessment of whether the groups differed in ways that could influence adverse-event experience and limits causal interpretation of between-arm differences.

Third, masking is listed as none. The registry record does not describe event assessment or adjudication procedures. Awareness of treatment can, in general, influence reporting or classification, although the record does not establish that this occurred. The serious-event term percentages are presented without denominators or clear arm attribution, which further limits interpretation of those entries.

Finally, the registry record does not report a detailed statistical analysis plan, multiplicity strategy, missing-data methods, or sample-size justification. It gives an endpoint population definition but does not report the numbers with missing endpoint data or how incomplete follow-up was handled. No formal hypothesis is stated, and no posted analyses are recorded. Together, these omissions limit evaluation of the planned inference, the completeness of endpoint ascertainment, and the precision of any comparative conclusions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653C in Japanese Participants With Hypercholesterolemia (MK-0653C-384) — NCT02460159.
• Registry record last updated 2024-05-16; status last verified 2022-02.
• Results first posted 2018-01-11.
• 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

NCT02460159 is a completed Phase III, parallel, non-randomized trial sponsored by Organon and Co. It enrolled 135 Japanese participants with hypercholesterolemia and assessed ezetimibe 10 mg/atorvastatin 10 mg and ezetimibe 10 mg/atorvastatin 20 mg fixed-dose combinations, each taken once daily for 52 weeks.

The primary endpoint was the percentage of participants with at least one adverse event through up to 54 weeks. The study summary states that there was no formal hypothesis. The registry record lists serious and other adverse-event counts by arm, and no deaths in either arm, but does not report numerical results for the primary endpoint. Allocation was non-randomized, and the record cautions that the arms are not a like-for-like comparison. Detailed analysis, multiplicity, and missing-data methods are not reported in the registry record.