Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy (NCT04219826), a randomized phase 2 study. The primary outcome is Incidence of Adverse Events (AEs).

2. Clinical Question

3. Trial Design

NCT04219826 was a Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study sponsored by Cytokinetics. The registry record gives an enrollment of 96 and a status of COMPLETED. The recorded start date is 2020-01-10, and the primary completion date is 2023-02-28. These record dates and enrollment describe the trial as registered; they do not, by themselves, establish how many participants contributed to each posted outcome.

The study evaluated CK-3773274, identified in the arm descriptions as aficamten. In Cohort 1, participants with oHCM received aficamten at 5 - 15 mg once daily, with dose levels guided by echocardiography assessments, or placebo. Cohort 2 was also described as oHCM and included aficamten at 10 - 30 mg once daily, guided by echocardiography assessments, or placebo. The intervention descriptions state that treatment was given for up to 10 weeks.

Cohort 3 included participants with oHCM receiving aficamten at 5 - 15 mg once daily, with dose levels guided by echocardiography assessments, while taking disopyramide. Cohort 4 included participants with nHCM receiving aficamten at 5 - 15 mg once daily, also with dose levels guided by echocardiography assessments. The arm descriptions do not report placebo comparators for these cohorts. The registry record does not report the allocation procedures within each cohort, the planned numbers for each group, or the rationale for the dose ranges.

Although the trial is described as randomized and double-blind overall, those design labels do not mean every active-treatment group can be compared with a placebo group in the posted results. The primary safety analysis population included participants who received at least 1 dose of aficamten or placebo. The endpoint timeframe was 14 weeks, while the intervention descriptions specify dosing for up to 10 weeks; the record does not explain the relationship between those timeframes.

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: Safety Analysis Set included all participants who received at least 1 dose of investigational product (IP), aficamten or placebo

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: One participant in the placebo group was discontinued from the study prior to receiving treatment.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Adverse Events (AEs), measured over 14 weeks.

The primary endpoint was the incidence of reported adverse events (AEs), measured as a count of participants. The registry describes the purpose as determining the safety and tolerability of aficamten in participants with HCM. Its analysis population was the Safety Analysis Set: participants who received at least 1 dose of investigational product, either aficamten or placebo. The endpoint timeframe was 14 weeks.

For a participant-level binary endpoint, each participant is classified according to whether an event was reported during the endpoint period. The resulting count describes how many participants in a group had at least one reported event; it is not a count of all event episodes. This distinction matters because a participant can experience more than one event, whereas a participant-incidence endpoint counts that person as an affected participant. The registry record describes the measure as participant incidence, but does not report additional operational details about event coding or the handling of repeated events.

Adverse-event incidence is used in a safety and tolerability assessment because it records reported harms during study participation. By itself, an incidence count does not establish that an event was caused by the study drug. Nor does a count alone describe event severity, duration, or clinical consequences. Serious adverse events are reported separately in the registry record and should not be treated as interchangeable with the primary endpoint’s overall AE count.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A participant-incidence endpoint is a binary outcome at the participant level: a participant either had at least one recorded event during the specified period or did not. The group count is the number classified as having an event, and the arm size is the number assessed for that result. This is different from counting every event episode. If a participant has repeated events, an incidence count still represents that participant once; the record does not state whether a separate event-count analysis was also performed.

What can an arm-specific count tell us?

An arm-specific count is a descriptive result. It tells the reader how many participants in that arm were recorded as having an AE, alongside the arm’s reported analysis size. The posted results give counts rather than an adjusted estimate for a treatment contrast. Counts should therefore be interpreted within their own cohort and arm, rather than compared across groups as if all participants had been assigned to a common active-versus-placebo experiment. Cohort differences and the lack of placebo groups for some active-treatment cohorts constrain direct comparisons.

For a binary endpoint, a statistical comparison commonly estimates a difference or another contrast between event frequencies. An uncertainty interval around such a contrast would communicate the range of values compatible with the data under the analysis assumptions. A confidence interval is not a guarantee that the true effect lies within its limits; it is a method for expressing sampling uncertainty. The registry record does not report a confidence interval or an estimable two-arm comparison for the primary endpoint. No inferential precision measure should be inferred from the counts alone.

Why does a missing comparison matter?

The record indicates that values are missing or not estimable for a two-arm binary comparison. This means a formal comparison cannot be recovered from the posted information for that endpoint. Randomization is a feature of the trial design, but it does not supply the missing estimate, its uncertainty, or the analysis details. It also does not make active-treatment arms without reported placebo comparators suitable for a direct treatment comparison. The record does not report a reason for the comparison being unavailable, so the reason should not be guessed.

The registry identifies the trial as double-blind and randomized, but the available information does not describe the exact randomization method, allocation concealment, or how masking was maintained. These are method details that can affect assessment of bias, but they are not reported in the registry record. The parallel-group description indicates that participants were assigned to groups rather than being described as crossing through multiple treatment conditions; it does not answer how the outcome analysis was conducted.

How should safety counts be distinguished?

The primary endpoint counts participants with reported AEs. The separate serious-adverse-event information distinguishes serious events from other events and includes counts of affected participants by arm. Seriousness is a separate classification from whether an event occurred. A serious-event count is not the same as an overall AE count, and the listed serious-event terms are not a complete description of every safety outcome. The record does not report enough detail to establish how the serious-event terms were coded, whether terms could overlap within participants, or the denominator used for the listed term percentages.

The Cohort 4 summaries illustrate why endpoint definitions must remain distinct. The primary result reports 28 participants with AEs among 41, whereas the adverse-event summary reports 26 with other events among 41. The registry record does not explain this discrepancy in the reported counts. It is not appropriate to reconcile the numbers by assuming different event definitions, periods, or exclusions; those explanations are not reported. Readers should preserve the distinction between the two reported summaries.

What do the planning assumptions mean?

The record’s planning illustration is described as being computed from the observed effect rather than from the trial’s own design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. Such an illustration concerns how a future study might be planned under those assumptions. It is not observed power and does not establish that the completed trial had a particular probability of detecting an effect. No planning illustration values are included in the registry record for this analysis, so no target sample-size result can be stated.

For a binary endpoint, planning depends on assumptions about event frequency, the effect to detect, the significance threshold, and the desired power. Changing those assumptions changes the planning result. The illustration’s equal-allocation assumption is not evidence that the trial’s actual groups were equally allocated; the posted arm sizes are not equal. Nor does a calculation based on an observed effect independently validate that effect. It is a conditional planning exercise, not a finding about treatment efficacy, safety certainty, or the trial’s original sample-size justification. The registry record does not report that justification.

What do the secondary outcomes add?

The registry lists five secondary outcome descriptions concerning relationships between plasma concentration and changes in resting or post-Valsalva LVOT-G, changes in those gradients over time as a function of dose, and a relationship with change in resting LVEF. The registry entries also report 8 outcome measures and 12 analyses. The results and detailed analysis specifications for these secondary outcomes are not reported in the information available for this analysis. Their listing indicates that the study included pharmacokinetic and pharmacodynamic questions, but does not establish any particular result for them.

Overall, the most defensible statistical reading is descriptive: the posted AE counts indicate the number of participants recorded with an event in each reported arm. The record does not supply the inferential comparison, uncertainty estimates, or analysis details needed to extend those counts into 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("Cohort 1 (oHCM) - Aficamten", "Cohort 1 (oHCM) - Placbo", "Cohort 2 (oHCM) - Aficamten", "Cohort 2 (oHCM) - Placebo", "Cohort 3 (oHCM) - Aficamten & Background Disopyram", "Cohort 4 (nHCM) - Aficamten")
n      <- c(14, 7, 14, 6, 13, 41)
events <- c(10, 7, 11, 4, 9, 28)
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 (oHCM) - Aficamten  14  10  71.4  41.9  91.6  45.4  88.3  44.9  88.2
ARM  Cohort 1 (oHCM) - Placbo  7  7  100.0  59.0  100.0  64.6  100.0  63.1  99.7
ARM  Cohort 2 (oHCM) - Aficamten  14  11  78.6  49.2  95.3  52.4  92.4  51.9  92.2
ARM  Cohort 2 (oHCM) - Placebo  6  4  66.7  22.3  95.7  30.0  90.3  29.0  90.1
ARM  Cohort 3 (oHCM) - Aficamten & Background Disopyram  13  9  69.2  38.6  90.9  42.4  87.3  41.9  87.2
ARM  Cohort 4 (nHCM) - Aficamten  41  28  68.3  51.9  81.9  53.0  80.4  52.9  80.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity plan for the primary and secondary outcomes, including whether any outcomes were designated for confirmatory testing or how multiple analyses were handled. This matters because examining multiple outcomes or contrasts can increase the chance of a seemingly notable result occurring by chance. General statistical approaches can control or describe that issue, but no particular approach should be attributed to this study without a report in the registry record.

Five secondary outcome descriptions are listed, spanning concentration-response relationships and dose-related changes in cardiac measures. The registry entries also report 8 outcome measures and 12 analyses, but do not give the results or specify how those analyses relate to one another. Without a prespecified testing hierarchy or adjustment method, the family of analyses and the interpretation of any secondary finding are not clear from the registry record. No secondary-outcome result should be inferred from the outcome descriptions alone.

Missing-data methods are not reported in the registry record. The primary safety population is defined as participants who received at least 1 dose of investigational product, but the record does not explain how missing AE information, incomplete follow-up, or participants who discontinued were handled. It also does not report the extent or pattern of missing endpoint data. The absence of those details does not establish that data were missing; it limits assessment of how completeness was evaluated.

The stated analysis population is a safety population based on exposure to at least 1 dose, not a reported intention-to-treat population. The registry record does not report an intention-to-treat analysis or an alternative analysis population for the primary endpoint. It also does not report a statistical analysis plan, interim-analysis approach, or sample-size justification. These items should be treated as unreported rather than inferred from the trial’s randomized designation or its enrollment.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypotension (14.3%), stress cardiomyopathy (14.3%), syncope (14.3%), acute respiratory failure (14.3%), pulmonary oedema (14.3%).

The serious-adverse-event summary reports participants at risk and participants affected in each arm. Serious events were reported for 1 of 14 participants in Cohort 1 aficamten, 1 of 7 in Cohort 1 placebo, 1 of 14 in Cohort 2 aficamten, 0 of 6 in Cohort 2 placebo, 0 of 13 in Cohort 3 aficamten with background disopyramide, and 4 of 41 in Cohort 4 aficamten. The record reports no deaths in the first five groups and 1 death in Cohort 4. These are descriptive counts, not estimates of comparative risk.

The serious-event terms listed include Hypotension, Stress cardiomyopathy, Syncope, Acute respiratory failure, Pulmonary oedema, and Acute coronary syndrome. The record gives percentages of 14.3% for each of the first five terms and 7.1% for Acute coronary syndrome. It does not report the denominator or explain whether a participant could contribute to more than one term, so these percentages should not be used to infer term-specific participant counts.

Serious events are distinct from the primary endpoint’s broader AE incidence. The Cohort 4 serious-event count does not replace its overall AE count, and the record does not establish that reported events were caused by treatment. Small arm sizes and the absence of a reported comparative estimate limit what can be concluded about differences between groups.

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

The posted results describe reported adverse events among participants who received study treatment and were included in the Safety Analysis Set. They show that participants with AEs were recorded in each reported active-treatment group and in the placebo groups that were included for Cohort 1 and Cohort 2. The serious-adverse-event information separately reports affected-participant counts and a death count for Cohort 4. These findings are relevant to the safety description of the enrolled study groups, but they do not establish a comparative effect.

The registry record does not report an estimable two-arm binary comparison, a confidence interval, or a p-value for the primary endpoint. Consequently, the counts cannot establish whether the observed group values differ beyond what could be due to sampling variation. They also cannot establish that groups are equivalent. Lack of a reported comparison is a limitation of the available result, not a finding that there is no difference.

The study’s randomized, double-blind design is important context, but it does not remove the need for reported analysis methods and estimates. The reported groups include different HCM descriptions, different dose ranges, and a cohort receiving background disopyramide. Placebo arms are described for Cohort 1 and Cohort 2, not for Cohort 3 or Cohort 4. The results therefore should not be treated as a single pooled comparison or as direct evidence about differences between every cohort.

Adverse-event counts also do not determine causation. Events reported during a trial may or may not be attributable to the investigational product, and the record does not provide event-by-event causal assessments. Nor do participant-incidence counts convey the number of episodes, duration, severity beyond the separate serious classification, or longer-term outcomes. The outcome timeframe is 14 weeks, and the intervention descriptions specify dosing for up to 10 weeks; the record does not describe additional follow-up details.

In short, the results support a descriptive account of the events recorded in the trial arms. They do not, on their own, establish efficacy, comparative safety, a causal relationship for individual events, or generalizability beyond the study population and treatment conditions. Those stronger conclusions would require information and analyses not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a randomized design and a reported comparative result. Randomization is intended to support fair comparisons, but a reader still needs an outcome estimate, its uncertainty, and a clear account of which groups and participants contributed. The registry reports arm-level safety counts but says a two-arm binary comparison is not estimable from the posted information. That distinction prevents descriptive observations from being mistaken for an inferential conclusion.

The study also has multiple clinical contexts within one trial record. The cohorts include oHCM and nHCM, different dose ranges, placebo arms in some cohorts, and background disopyramide in one cohort. Those features make it important to keep cohort-specific results separate unless the analysis explicitly justifies combining them. A pooled summary could conceal differences in population or treatment context, while a cross-cohort comparison could confound cohort features with the treatment contrast.

Safety reporting benefits from separating overall AE incidence from serious events and deaths. Each measure answers a different question, and the Cohort 4 counts show why definitions and summaries need to be read carefully: the primary endpoint and the separate adverse-event summary report different overall affected-participant counts for that arm. The registry record does not explain the difference. Statistical interpretation depends not only on arithmetic, but also on knowing what each outcome represents and how it was assembled.

Finally, the dose-finding and pharmacokinetic/pharmacodynamic aims make the listed secondary outcomes relevant, but outcome titles alone are not findings. The registry lists concentration-response and dose-related questions without reporting their results in the registry record for this analysis. For biostatisticians and clinical researchers, the key lesson is to distinguish a registered question, a descriptive result, and a supported comparison. The available safety counts are useful descriptions, while the missing comparative and analysis details set clear limits on interpretation.

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 affect interpretation of the posted safety results. The main endpoint is participant incidence of AEs, and the record does not provide an estimable two-arm binary comparison. It also does not report a confidence interval, p-value, adjusted estimate, or detailed statistical analysis plan for the endpoint. The arm counts therefore offer a descriptive account without a reported measure of comparative uncertainty.

The cohort structure limits cross-group interpretation. Placebo is described for the oHCM groups in Cohort 1 and Cohort 2, but not for the cohorts receiving background disopyramide or involving nHCM. Cohort 2 uses a different dose range from the other active-treatment cohorts, and Cohort 3 includes background disopyramide. A direct comparison across these groups would require analysis details that are not reported in the registry record.

The registry record does not explain the difference between the Cohort 4 primary AE count, 28 of 41 participants, and the separate count of 26 of 41 participants with other events. It also does not report the denominator or overlap rules underlying the listed serious-event term percentages. These uncertainties make it important to preserve the measure-specific numbers rather than reconcile them through assumptions.

Missing-data handling, event coding details, causal attribution, and follow-up after treatment are not reported in the information available for this analysis. The record defines a safety population based on receipt of at least 1 dose, but does not explain how incomplete observation was addressed. The outcome timeframe of 14 weeks and treatment duration of up to 10 weeks are both stated, but their relationship is not explained. These reporting gaps limit assessment of completeness and precision without showing that any particular bias occurred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy — NCT04219826.
• Registry record last updated 2026-02-24; status last verified 2025-12.
• Results first posted 2026-02-24.
• 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

NCT04219826 is a completed Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled dose-finding study sponsored by Cytokinetics. It enrolled adults with symptomatic HCM and evaluated CK-3773274, also called aficamten in the arm and endpoint descriptions. The registry gives an enrollment of 96, a start date of 2020-01-10, and a primary completion date of 2023-02-28.

The primary endpoint was participant incidence of reported AEs over 14 weeks in the Safety Analysis Set, defined as participants who received at least 1 dose of investigational product. Treatment descriptions include dose-guided aficamten regimens and placebo in Cohort 1 and Cohort 2; other cohorts include background disopyramide or nHCM without a described placebo group.

The posted primary results are arm-specific counts, but the record indicates that a two-arm binary comparison is missing or not estimable. Serious-event counts and listed serious-event terms are reported separately. Confidence intervals, multiplicity procedures, missing-data methods, and detailed analysis specifications are not reported in the registry record.