Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM (NCT05186818), a randomized phase 3 study. The primary outcome is Change From Baseline in pVO2 at Week 24.

2. Clinical Question

The clinical question is about a measured difference between randomized groups, not whether every participant experienced the same change. The primary outcome is continuous: each participant’s pVO2 is measured, and the analysis compares group-level changes. The posted results report least-squares mean changes of 1.76 mL/kg/min for aficamten and 0.02 mL/kg/min for placebo. The sponsor’s reported comparison gives a mean difference of 1.74 mL/kg/min, with a 95% confidence interval from 1.04 to 2.44.

This result describes the trial’s measured endpoint over its treatment period. It does not by itself settle how the outcome relates to other measures, how durable any differences are beyond the reported timeframe, or how individual participants may respond. Those questions require evidence beyond this primary comparison.

3. Trial Design

This was a Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction. The registry record lists Cytokinetics as the sponsor and 282 participants as enrolled. The study is marked completed. Its listed start date is 2022-02-01 and its primary completion date is 2023-11-10.

Participants were assigned to aficamten or placebo. The aficamten arm included dose levels of 5 mg, 10 mg, 15 mg, and 20 mg, with dose levels guided by echocardiography assessments; treatment was given for up to 24 weeks. Participants in the comparison arm received placebo to match aficamten for up to 24 weeks. The registry describes masking as double, but further details about who was masked or how masking was maintained are not reported in the registry record.

The primary outcome was change from baseline in pVO2 at Week 24, measured in mL/kg/min. The primary analysis population is described as the Full Analysis Set, consisting of all randomized participants. The posted arm summaries include 142 participants in the aficamten group and 140 in the placebo group for this outcome. The registry record reports an ANCOVA comparison of final values, but the specific covariates, handling of repeated or missing measurements, and other model details are not reported in the registry record.

The record lists secondary outcomes covering a health-status score, New York Heart Association functional class, and Valsalva left ventricular outflow tract gradient, at Week 12 or Week 24. Although the registry lists 11 outcome measures and 15 analyses, the original protocol, the full statistical analysis plan, and the trial’s sample-size justification are not reported in the registry record. The posted planning illustrations discussed elsewhere on this page are not a substitute for those original design details.

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: Full Analysis Set (consisting of all randomized participants)

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 From Baseline in pVO2 at Week 24, measured over Baseline to Week 24.

The primary endpoint is change from baseline in peak oxygen uptake at Week 24. Peak oxygen uptake, abbreviated pVO2, is measured during cardiopulmonary exercise testing (CPET), using a treadmill or bicycle. The outcome is expressed in mL/kg/min. The registry describes a higher pVO2 as indicating better cardiorespiratory fitness.

Change from baseline focuses on how the measure differs from a participant’s starting value by the specified assessment time. Comparing the groups’ average changes can help describe whether their measured trajectories differed over the treatment period. The trial reports least-squares means, which are model-based group estimates; the exact covariates used to obtain them are not reported in the registry record.

Exercise capacity is a functional measure, so this endpoint addresses a different aspect of the trial than the listed health-status, functional-class, and outflow-tract-gradient outcomes. A continuous measure retains information about the size of changes across participants rather than reducing results to a simple event count. As with any group summary, an average does not describe every participant’s experience, and the endpoint alone does not establish how results translate to outcomes not measured in the trial.

The assessment is specified at Week 24, and the reported timeframe is baseline to Week 24. The registry record does not report additional details about CPET standardization, the specific baseline assessment schedule, or how measurements outside the planned assessment were handled.

7. Results Posted in the Registry

• Aficamten up to 20 mg: mean 1.76 versus 0.02 on control; difference 1.74 (95% CI 1.05 to 2.43), standardized effect d = 0.59; z-test p = <0.001.

8. Secondary Efficacy Endpoints

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

Change From Baseline in KCCQ-CSS at Week 24

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Aficamten up to 20 mg: mean 11.60 versus 4.30 on control; difference 7.30 (95% CI 4.53 to 10.07), standardized effect d = 0.61; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Aficamten up to 20 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in KCCQ-CSS at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Aficamten up to 20 mg: mean 11.10 versus 4.00 on control; difference 7.10 (95% CI 4.61 to 9.59), standardized effect d = 0.66; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Aficamten up to 20 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Proportion of Participants With ≥1 Class Improvement in New York Heart Association (NYHA) Functional Class From Baseline to Week 24

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Aficamten up to 20 mg: 58.5% (83/142) versus 24.3% (34/140) on control; risk difference 34.2 percentage points (95% CI 23.4 to 44.9), risk ratio 2.41 (1.74–3.33); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Aficamten up to 20 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes span several domains: health status measured by the KCCQ-CSS, improvement in NYHA functional class, and Valsalva left ventricular outflow tract gradient. The listed assessments occur at Week 12 or Week 24. The posted summaries include results for the health-status score at both listed timepoints and the proportion with at least one class improvement at Week 24. The available numerical secondary summaries therefore point in a direction broadly consistent with the primary comparison, but they are not interchangeable measures and do not establish the same claim as the pVO2 endpoint.

The primary endpoint concerns change in exercise capacity at Week 24. A health-status score, a functional-class category, and a measured gradient capture different features of the trial question. Their results can add context, but agreement across outcomes does not make them equivalent, and a result on one measure does not prove a result on another. The registry also lists gradient and Week 12 functional-class outcomes; numerical results for those outcomes are not reported in the registry record.

Secondary results generally carry less weight than a prespecified primary result when many outcomes or timepoints are examined. General statistical explanation: testing many hypotheses can increase the chance that at least one result appears statistically notable even if there are no true effects across the full set. Multiplicity methods can address this issue, but the registry record does not report whether a correction or hierarchical testing plan was used. The posted secondary p-values should therefore be interpreted cautiously and alongside their confidence intervals, methods, and place in the overall analysis plan.

The secondary outcomes are useful for describing the breadth of measurements collected, not as a reason to overstate what the primary comparison alone establishes. The full protocol and statistical analysis plan, including prespecification and any control of multiplicity, are not reported in the registry record.

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

• Change From Baseline in KCCQ-CSS at Week 24
• Change From Baseline in KCCQ-CSS at Week 12
• Proportion of Participants With ≥1 Class Improvement in New York Heart Association (NYHA) Functional Class From Baseline to Week 24
• Proportion of Participants With ≥1 Class Improvement in NYHA Functional Class From Baseline to Week 12
• Change From Baseline in Valsalva Left Ventricular Outflow Tract Gradient (LVOT-G) at Week 24
• Change From Baseline in Valsalva LVOT-G at Week 12
• Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 24
• Proportion of Participants With Valsalva LVOT G <30 mmHg at Week 12

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous, and the registry reports least-squares mean changes with standard errors. A continuous outcome can take a range of values, so the analysis summarizes the group-level average and compares those averages. The least-squares means are model-based estimates rather than simply a label for the raw average. The record identifies ANCOVA for the sponsor’s primary comparison, but the covariates and other model specifications are not reported in the registry record.

What does ANCOVA contribute?

General statistical explanation: analysis of covariance (ANCOVA) compares outcomes between groups while accounting for selected covariates in a statistical model. Depending on the prespecified model, covariates may include baseline values or other design variables. Adjustment can improve precision or account for differences associated with those variables. Which covariates were used in this trial, and how the model was specified, are not reported in the registry record. The posted result should therefore be read as the sponsor’s stated ANCOVA comparison, without inferring unreported model details.

The registry lists the comparison parameter as a mean difference in final values, while the primary outcome itself is described as change from baseline. The reported comparison is 1.74 mL/kg/min. The record does not provide enough detail to resolve every distinction between the model’s outcome coding, baseline handling, and displayed change summaries. Those details are ordinarily clarified in the analysis plan or full report, neither of which is reported.

What does the standard error describe?

General statistical explanation: a standard error describes the uncertainty in an estimated quantity, such as a group mean, due to sampling variability under a statistical model. It is not the same as the spread of individual participant measurements. The posted group summaries give standard errors of 0.25 for both arms. The registry does not report the underlying participant-level distribution, so these summaries alone cannot show the full range of individual responses.

A confidence interval combines an estimate with an indication of uncertainty. The sponsor reports a 95% confidence interval for the primary difference. In general, a confidence interval is constructed so that a procedure would cover the true parameter at the stated rate over repeated use, if its assumptions hold. It is not a probability statement about the fixed true value after a particular interval has been observed. The interval’s width reflects precision as well as the scale of the estimate.

Why are the recalculated results different in form?

The recalculated results are simple, unadjusted comparisons derived from posted summary statistics. They are not the same as a model that adjusts for covariates or follows the sponsor’s analysis plan. The recalculated primary estimate is 1.74 mL/kg/min, with an interval from 1.047 to 2.433 and p < 0.001. The sponsor reports an ANCOVA estimate of 1.74 mL/kg/min, a 95% interval from 1.04 to 2.44, and p < 0.001. Differences in rounding and analytic method can produce slightly different interval endpoints or displayed p-value thresholds. The record does not flag a discrepancy, and the sponsor’s analysis remains the primary interpretation of the trial analysis.

A p-value is calculated under a null hypothesis, commonly that there is no difference between groups, and under the assumptions of the test. It describes how unusual data at least as discrepant as those observed would be if that null and model were correct. It is not a measure of effect size, clinical value, or the probability that a result occurred “by chance.” Here, the sponsor’s p-value is reported as less than < 0.001; the unadjusted recalculation reports less than 0.001. Both are threshold statements rather than exact p-values.

Why can over-dispersion matter?

General statistical explanation: for count or binary outcomes, over-dispersion means that observed variability exceeds what a chosen model expects. If a model underestimates variability, standard errors can be too small and confidence intervals too narrow. That concern is not the central form of the primary pVO2 analysis, which is continuous. For binary secondary outcomes, appropriate methods and their assumptions matter; the registry lists Cochran-Mantel-Haenszel analyses for the functional-class outcome. It does not report enough detail to assess all variance assumptions, stratification factors, or model diagnostics.

For binary outcomes, the registry’s reported rate differences and odds ratios are not interchangeable. A rate difference describes an absolute difference between proportions, while an odds ratio compares odds. General statistical explanation: odds are a transformation of probability, and an odds ratio should not be read as a risk ratio. The registry reports both measures for the Week 24 functional-class result, using a Cochran-Mantel-Haenszel method. The specific strata and adjustment details are not reported in the registry record.

Finally, statistical significance and precision are related but distinct. A small p-value alone does not show whether an estimate is precise enough for a particular practical interpretation. The estimate and its confidence interval provide the scale and uncertainty of the comparison. Neither establishes effects beyond the measured population, outcome, and timeframe.

11. Confidence Intervals and Precision

For the primary comparison, the sponsor reports a mean difference of 1.74 mL/kg/min and a 95% confidence interval from 1.04 to 2.44. The interval gives a range of values compatible with the reported analysis and its assumptions. Its endpoints are on the same measurement scale as the estimated difference. The interval does not describe the range of individual participant outcomes, and it should not be interpreted as a probability distribution for the true effect.

The unadjusted recalculation from the posted summaries gives a 95% interval from 1.047 to 2.433. That interval is close to the sponsor’s interval, though the recalculated endpoints retain different rounding. The recalculation uses summary statistics and does not reproduce the sponsor’s ANCOVA model. For interpreting the trial, the sponsor’s reported analysis is the main result; the simpler calculation is a check on the posted group summaries, not a competing primary analysis.

Precision depends on factors such as the amount of information in the data, variability, and the analysis model. General statistical explanation: narrower intervals indicate greater precision under the relevant method, while wider intervals indicate more uncertainty about the size of the estimated difference. A confidence interval can still exclude zero while leaving uncertainty about the exact magnitude. Here, the sponsor’s interval is above zero, but it spans a range of possible positive differences rather than identifying one exact value.

The registry reports standard errors of 0.25 for each group’s least-squares mean. These are uncertainties of estimated group means, not standard deviations of individual participant values. The posted record does not provide participant-level data or a full distribution, so the uncertainty of individual responses cannot be inferred from those standard errors.

The interval also depends on analysis choices and assumptions. The registry identifies ANCOVA but does not report the specific covariates, missing-data handling, or all model details. The stated confidence level should therefore be understood in the context of the sponsor’s reported model, not as a guarantee that all sources of uncertainty have been captured.

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 sample-size table and curve are planning illustrations based on the observed effect, not the trial’s original design calculation. For these continuous and binary comparisons, the displayed sample sizes are participants per arm, not total events. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column indicates the number of participants per arm in the planning calculation for an 80% chance of detecting the specified effect under the listed assumptions, if that effect and the model assumptions were correct. The 90% power column uses a higher target chance of detection. These are design-planning quantities, not guarantees about what a future study will find. They are not observed power: observed power is not a useful substitute for examining the estimate and its confidence interval after a trial has been completed.

The table varies the target effect by showing planning for 100%, 75%, and 50% of the observed effect. The participant requirements rise as the assumed effect becomes smaller. This general pattern occurs because a smaller difference is harder to distinguish from random variation at a given significance level and power target. The listed figures should be read as conditional illustrations, not as a recommendation for a new study or a claim about the sample size used in this trial.

Each table row corresponds to a particular endpoint and a stated fraction of its observed comparison. The curve visualizes how the planning requirement changes with the target effect. Neither display reconstructs the protocol’s original assumptions, which are not reported in the registry record.

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 = 1.740; pooled standard deviation σ = 2.969.
2. n = 2 × (1.96 + 0.842)² × 2.969² / 1.740² = 45.7, rounded up to 46 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 <- 1.74                      # observed difference in means
sigma <- 2.96866071294303                     # 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(5186818)
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 = 46 (80% power), 62 (90% power)
 75% of observed effect: n per arm = 82 (80% power), 109 (90% power)
 50% of observed effect: n per arm = 183 (80% power), 245 (90% power)
power.t.test: 46.7 
Simulated power at n = 46 per arm: 0.789 (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. Analyses Reported by the Sponsor

The sponsor’s primary analysis is an ANCOVA comparison of final values. It reports a mean difference of 1.74 mL/kg/min, a 95% confidence interval from 1.04 to 2.44, and p < 0.001. This is the trial’s reported inferential result for the primary endpoint and should take precedence over a simplified calculation based on summary statistics.

The recalculated, unadjusted comparison gives an estimated difference of 1.74 mL/kg/min, a 95% interval from 1.047 to 2.433, and p < 0.001. The point estimates are the same as displayed, while the interval endpoints and p-value threshold differ slightly. This is expected to be possible when a summary-statistic calculation is compared with a model-based analysis and when results are rounded differently. The recalculation does not reproduce ANCOVA or any unreported covariate adjustment.

The record does not flag a discrepancy between the recalculation and sponsor result. The recalculated estimate is best treated as a transparent, unadjusted check on the posted summaries. The sponsor’s method and reported result remain the appropriate basis for describing the trial analysis. Details needed to compare the methods fully, including model covariates and handling of missing measurements, are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes and analyses, including a primary pVO2 outcome and secondary measures assessed across more than one timepoint. When many hypotheses are tested, the chance of at least one apparently unusual result can increase. General statistical explanation: multiplicity procedures, such as an adjustment or a prespecified sequence for testing outcomes, can help control that risk. Whether such procedures were used for this trial is not reported in the registry record.

The posted primary analysis has a reported p-value of less than < 0.001. Secondary results also have reported p-values, but the registry record does not state whether those values are adjusted for multiple comparisons. They should not be assumed to represent multiplicity-adjusted evidence. The original protocol and full statistical analysis plan, which could clarify endpoint hierarchy and testing procedures, are not reported in the registry record.

The primary population is described as the Full Analysis Set, consisting of all randomized participants. The record does not provide a detailed account of exclusions, adherence requirements, or the exact analysis population used for every secondary endpoint. Although the primary arm summaries include 142 participants assigned to aficamten and 140 assigned to placebo, the number contributing a measured Week 24 value is not separately.

Missing-data handling is also not reported in the registry record. The posted material does not specify whether missing values were imputed, whether a particular likelihood-based method was used, what assumptions were made about missingness, or what sensitivity analyses were conducted. Missing data can affect both the estimated comparison and its uncertainty, particularly if the probability of a measurement being absent is related to participant characteristics or outcomes. Without these details, the analysis cannot be fully assessed from the registry summary alone.

The record identifies ANCOVA for the primary comparison and mixed models for the posted KCCQ-CSS analyses. It does not report the full model specifications, diagnostic checks, or all analysis-plan decisions. These omissions limit independent evaluation of how the statistical results were obtained, without changing the fact that the registry reports a primary result.

16. 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: hypertrophic cardiomyopathy (2.1%), acute coronary syndrome (0.7%), acute myocardial infarction (0.7%), atrial fibrillation (0.7%), cardiac failure congestive (0.7%).

The registry reports serious adverse events for 8 of 142 participants in the aficamten group and 13 of 140 participants in the placebo group. It reports other adverse events for 44 of 142 participants and 46 of 140 participants, respectively. No deaths are listed in either group. These are descriptive counts in the posted record; they do not, by themselves, establish whether an event was caused by the study treatment.

The serious-event terms listed among the top reported terms include hypertrophic cardiomyopathy at 2.1%, and acute coronary syndrome, acute myocardial infarction, atrial fibrillation, cardiac failure congestive, and sinoatrial block at 0.7% each. The registry summary does not provide enough detail to determine the full context, timing, severity criteria, overlap between event categories, or investigator assessment of relatedness. The listed percentages should be read as registry descriptions, not as comparative treatment effects.

Safety counts require context, including how events were defined, how long participants were observed, and whether the analysis was based on participants or event episodes. Further details about event collection and attribution are not reported in the registry record. These figures describe what the posted safety summary reports; they do not provide medical advice or establish an individual risk.

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

The posted primary result describes a difference between randomized groups in change from baseline in pVO2 at Week 24. The sponsor reports a mean difference of 1.74 mL/kg/min, with a 95% confidence interval from 1.04 to 2.44 and p < 0.001. The interval and p-value summarize statistical uncertainty under the reported analysis; they do not say that every participant had the same response or that the exact difference is known.

The endpoint is a measure of exercise capacity assessed by cardiopulmonary exercise testing. A higher pVO2 is described in the registry as indicating better cardiorespiratory fitness. The statistical result does not, on its own, determine the importance of the measured difference for a particular person, how it relates to symptoms or daily functioning, or whether it predicts other outcomes. Those interpretations require clinical context and evidence beyond the single estimate.

The comparison applies to the trial’s randomized groups and stated treatment period, with the primary outcome assessed at Week 24. It does not establish what would happen beyond that timeframe, in populations not represented by the trial, or under treatment conditions not described in the record. The available registry summary also does not provide all details needed to assess missing data, analysis assumptions, or the handling of multiple outcomes.

The secondary outcomes can provide complementary information, but they measure different constructs. Their results should not be treated as replacements for the primary endpoint, and unadjusted secondary tests may warrant more caution when many outcomes and timepoints are considered. The registry record does not report whether multiplicity was controlled.

Finally, the safety summary is descriptive. Counts of serious and other adverse events do not establish causation, comparative risk, or the likelihood of an event for an individual. Taken together, the posted results describe a statistically distinguishable primary group comparison and a set of additional outcomes and safety counts; they do not answer every question about benefit, harm, or longer-term effects.

18. Why This Trial Matters Statistically

This trial is statistically informative because it uses randomized, double-blind, placebo-controlled groups to compare a continuous functional outcome at a defined assessment time. Randomization supports a between-group comparison by reducing systematic differences in expectation across assigned groups, while masking can reduce some forms of bias in care or assessment. The registry identifies both design features, though details of implementation are not reported in the registry record.

The primary result is presented with an estimated difference, confidence interval, and p-value. That combination is more informative than a p-value alone: the estimate describes the scale of the comparison, the interval conveys uncertainty, and the test addresses compatibility with a null hypothesis under the stated analysis. The sponsor’s result and the close unadjusted recalculation also allow readers to distinguish the trial analysis from a simpler check using posted summaries.

The record also illustrates why analysis details matter. ANCOVA is named for the primary comparison, but the covariates and missing-data methods are not reported. Multiple secondary outcomes and timepoints are listed, while multiplicity handling is not reported. These omissions do not erase the reported result, but they limit how fully an independent reader can evaluate the complete analysis strategy.

Finally, separating the primary endpoint from secondary and safety summaries prevents different kinds of evidence from being conflated. Exercise capacity, health status, functional class, gradients, and adverse events answer related but distinct questions. Statistical interpretation is strongest when each result is read in light of its measure, uncertainty, analysis method, and place in the trial’s stated outcome structure.

19. 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 registry record does not report the original sample-size justification, its design assumptions, or detailed power calculations. The planning illustrations on this page are based on observed effects and specified general assumptions; they cannot reconstruct the trial’s original design rationale.

Important analysis details are not reported in the registry record. These include the covariates in the primary ANCOVA, full model specifications, methods for handling missing measurements, sensitivity analyses, and whether the analysis followed an intention-to-treat approach beyond the description of the Full Analysis Set as all randomized participants. The number with observed primary endpoint measurements is not separately stated in the available summary.

The record lists multiple secondary outcomes and timepoints, but it does not report whether multiplicity was controlled or provide the full analysis plan. Numerical results for some listed outcomes, including listed gradient outcomes, are not reported in the registry record. This limits assessment of the complete pattern and hierarchy of secondary findings.

The posted registry summary also does not provide participant-level data, distributions, or enough safety detail to assess event timing, relatedness, or overlap among terms. The safety counts are descriptive and should not be read as causal comparisons. Details about masking implementation, adherence, and the representativeness of enrolled participants are not reported in the registry record. These limitations constrain interpretation of precision, generalizability, and the full balance of outcomes without changing the numerical results that the registry does report.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM — NCT05186818.
• Registry record last updated 2026-03-03; status last verified 2025-02.
• Results first posted 2026-03-03.
• 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.

23. Record Summary

The registry record describes a completed Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial in adults with symptomatic obstructive hypertrophic cardiomyopathy. It lists 282 participants enrolled and compares aficamten, with dose levels guided by echocardiography, against matching placebo for up to 24 weeks.

The primary endpoint was change from baseline in pVO2 at Week 24. The sponsor’s ANCOVA analysis reports a mean difference of 1.74 mL/kg/min, with a 95% confidence interval from 1.04 to 2.44 and p < 0.001. The primary analysis population is described as all randomized participants. The record also lists health-status, functional-class, and gradient outcomes, as well as descriptive safety counts.

The registry does not report the full statistical analysis plan, original sample-size justification, missing-data methods, or multiplicity procedures. These omissions limit assessment of the full analysis strategy and secondary results. The reported primary comparison should be read within its specified endpoint, population, and timeframe.