A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) (NCT03442764), a randomized phase 2 study. The primary outcome is Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE).

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, parallel-group, placebo-controlled study described as multicenter, double-blind, and exploratory. The masking field lists quadruple masking. The registry record lists the study as completed, with an enrollment of 59. The brief summary describes 60 participants; the reason for this difference is not reported in the registry record.

The study concerned adults with symptomatic non-obstructive hypertrophic cardiomyopathy and preserved left ventricular ejection fraction. Participants assigned to active treatment were placed in Group 1, with a base target trough concentration, or Group 2, with a higher target trough concentration. A third group received placebo. The brief summary describes a 16-week course of mavacamten, with doses titrated to reach one of two target concentrations. The precise target concentrations, treatment schedule details, and allocation ratio are not reported in the registry record.

The registry record lists a study start date of 2018-03-30 and a primary completion date of 2020-01-07. The primary outcome was the percentage of all treated participants who experienced at least one TEAE, assessed from the first dose through 8 weeks following the last dose, with a stated timeframe of up to 24 weeks. The posted results include this outcome for both active-treatment groups and placebo. No secondary outcomes are posted in the registry record.

The record identifies MyoKardia, Inc. as the sponsor. The description of the study as exploratory helps frame the posted results: the primary endpoint concerns adverse events, and the record does not report an efficacy endpoint among the posted outcomes. Details of the study's original sample-size justification and planned statistical analysis 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.

Before assignment: 59 participants were randomized and 58 entered the treatment period.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All treated 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 Percentage of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE), measured over From first dose to 8 weeks following last dose (Up to 24 weeks).

The primary endpoint is the percentage of participants who experienced at least one treatment-emergent adverse event (TEAE). It is reported for all treated participants. The timeframe begins with the first dose and extends through 8 weeks following the last dose; the registry record states that this is up to 24 weeks.

This endpoint describes whether a participant had any qualifying TEAE during the stated observation period. It does not report how many events each participant had, how long events lasted, or their severity. Those details cannot be inferred from an outcome expressed as the percentage with at least one event. The posted percentages are 88.9 for Group 1, 90.5 for Group 2, and 68.4 for placebo.

In general, an adverse-event endpoint is used to describe the occurrence of unwanted events during a study, including events that may not be judged related to treatment. A measure of participants with at least one event offers a straightforward summary of how many people experienced any event, but it treats a participant with one event the same as a participant with multiple events. The registry record's endpoint description does not establish that an event was caused by the assigned treatment. The posted outcome should therefore be read as an event-occurrence measure over the specified period, not as a causal determination about individual events.

7. Results Posted in the Registry

• Group 1: 88.9% (16/18) versus 68.4% (13/19) on control; risk difference 20.5 percentage points (95% CI -5.0 to 45.9), risk ratio 1.30 (0.92–1.84); unadjusted two-proportion z-test p = 0.131.
• Group 2: 90.5% (19/21) versus 68.4% (13/19) on control; risk difference 22.1 percentage points (95% CI -2.3 to 46.4), risk ratio 1.32 (0.95–1.85); unadjusted two-proportion z-test p = 0.082.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary result is a binary outcome at the participant level: each treated participant either experienced at least one TEAE during the specified timeframe or did not. The registry record reports the outcome as a percentage of participants. The posted values are 88.9 for Group 1, 90.5 for Group 2, and 68.4 for placebo. These percentages summarize the occurrence of any event; they do not convey event counts per participant or event severity.

What does a risk difference describe?

In general, a risk difference subtracts the event proportion in one group from the event proportion in another. A value of zero represents no difference between the proportions, while a positive value means the event proportion is higher in the first group named in the comparison. Here, the registry comparisons define the active-treatment groups against placebo. The posted estimates are 0.205 for Group 1 and 0.221 for Group 2. These are proportions on the risk-difference scale, not adjusted estimates from a regression model. They describe the observed group contrast and do not, by themselves, establish causation.

What do relative measures add?

In general, a risk ratio compares event proportions by division, while an odds ratio compares the odds of the event between groups. Each measure answers a different question from the risk difference. The registry record includes relative estimates and intervals, but the risk difference provides a direct description of the absolute group contrast in the endpoint's proportion scale. Relative measures can be more difficult to interpret when event proportions are common, as they are in these posted groups. Regardless of the measure, an estimate is not a substitute for its uncertainty interval or the design context.

How should confidence intervals be read?

In general, a confidence interval represents a range of effect estimates compatible with the observed data under the statistical procedure used. It indicates precision: a narrow interval gives a more constrained range than a broad interval. It does not assign a probability that the true value lies within the particular calculated interval. The Group 1 risk-difference interval runs from -0.050 to 0.459, and the Group 2 interval runs from -0.023 to 0.464. Both include zero, so each interval includes no difference as well as differences in the positive direction. The registry record does not identify the method used to calculate these intervals.

What do the p-values tell readers?

In general, a p-value describes how incompatible the observed data are with a specified null model, assuming that model and the calculation's assumptions hold. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The posted unadjusted p-values are 0.131 for Group 1 and 0.082 for Group 2. They are not adjusted for multiplicity in the posted results. The record does not report whether any other analysis was prespecified or what statistical procedure the sponsor used for these comparisons.

For both comparisons, the sample sizes are limited: the posted outcome groups include 18.0 participants in Group 1, 21.0 in Group 2, and 19.0 in placebo. With a binary outcome, the precision of a group proportion and its contrast depends in part on how many participants contribute outcome information and how frequent the event is. The posted estimates should therefore be read alongside their intervals rather than as exact descriptions of an underlying effect.

The primary population is specified as all treated participants. That is useful context, but it does not explain how the analysis handled participants with incomplete follow-up or missing outcome status. Such handling is not reported in the registry record. The record also does not report any adjusted analysis, stratification factors, or model assumptions for the primary comparison. No secondary analyses are posted. These absences limit assessment of how the results might change under alternative analysis choices.

In general, randomized assignment helps make treatment groups comparable at the start of a study, but it does not remove uncertainty in a small study or make every observed difference attributable to treatment. Interpretation also depends on the endpoint definition, follow-up, missing data, and analysis methods. In this study, the primary result is an event-occurrence summary over a defined period, with unadjusted comparisons and confidence intervals that cover both zero and positive risk differences. The statistical evidence should be understood within those limits.

10. Confidence Intervals and Precision

The risk-difference estimates are accompanied by confidence intervals that are wide relative to the point estimates. For Group 1 versus placebo, the estimate is 0.205 and the interval extends from -0.050 to 0.459. For Group 2 versus placebo, the estimate is 0.221 and the interval extends from -0.023 to 0.464. Each interval includes zero, as well as positive values, so the observed data do not specify a single narrow range of plausible differences.

In general, a confidence interval communicates uncertainty around an estimate. The point estimate is the center of the reported comparison, while the interval shows how much uncertainty remains under the calculation used. A confidence interval is not a guarantee that the true effect is inside its limits, nor does it tell readers the probability that a particular effect is correct. The interval's interpretation depends on the statistical method, which is not reported in the registry record.

The event percentages are high in all three groups, and the posted outcome is whether each participant had at least one event, not how many events occurred. The group sizes contributing to this outcome are 18.0, 21.0, and 19.0. With this amount of information, the comparisons leave substantial uncertainty about the size and direction of the underlying difference. The unadjusted p-values, 0.131 and 0.082, are consistent with that caution: neither comparison gives a precise estimate of a group difference. The results should be read as estimates with considerable uncertainty, not as exact or definitive measurements.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed risk difference for each active-treatment group versus placebo, not the original trial's sample-size justification. The original design assumptions are not reported in the registry record.

The planning illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It uses an effect to detect that is the stated fraction of the observed effect. The 80% power column means the illustrated number of participants per arm intended to give an 80% chance of detecting the specified effect if that effect and the calculation assumptions hold. The 90% power column uses a higher chance of detection and therefore requires more participants per arm for the same effect size. These are planning illustrations, not observed power.

For Group 1 versus placebo, planning for 100% of the observed effect gives 62 participants per arm for 80% power and 83 for 90% power. Planning for 75% of the observed effect gives 120 participants per arm for 80% power and 161 for 90% power. Planning for 50% of the observed effect gives 291 participants per arm for 80% power and 389 for 90% power.

For Group 2 versus placebo, planning for 100% of the observed effect gives 52 participants per arm for 80% power and 69 for 90% power. Planning for 75% of the observed effect gives 102 participants per arm for 80% power and 136 for 90% power. Planning for 50% of the observed effect gives 248 participants per arm for 80% power and 331 for 90% power.

The pattern is important: smaller effects need more participants to detect under the same assumptions. These figures should not be interpreted as evidence that the trial was designed with these targets, or as a measure of the trial's achieved power. They are conditional planning calculations based on the observed effects, which themselves are uncertain.

12. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.684; treatment proportion p₁ = 0.889; average p̄ = 0.787.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5795 = 1.1357.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5611 = 0.4722.
4. n = (1.1357 + 0.4722)² / (0.2047)² = 61.7, rounded up to 62 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
p0 <- 0.684210526315789                          # control proportion
p1 <- 0.888888888888889                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3442764)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 62 (80% power), 83 (90% power)
 75% of observed effect: n per arm = 120 (80% power), 161 (90% power)
 50% of observed effect: n per arm = 291 (80% power), 389 (90% power)
power.prop.test: 61.7 
Simulated power at n = 62 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record posts one primary outcome and no secondary outcomes. It includes comparisons of each active-treatment group with placebo for the primary outcome. No multiplicity adjustment is reported. When multiple comparisons are made, the chance of at least one apparently noteworthy result can increase; in general, a multiplicity procedure is used to account for that issue. The posted p-values are unadjusted, so readers should not assume they control for multiple comparisons.

The analysis population for the primary endpoint is described as all treated participants. The record does not state how participants were handled if they stopped treatment early, missed visits, or had incomplete adverse-event follow-up. Missing-data methods, censoring rules, and sensitivity analyses are not reported in the registry record. The primary timeframe is described as from first dose through 8 weeks following last dose, up to 24 weeks, but the record does not provide further detail on how follow-up differences were addressed.

The study is described as randomized, double-blind, and quadruple-masked, with a parallel design. Those design characteristics do not supply the missing analysis details. The statistical plan, prespecified contrasts, model choice, covariate adjustment, and handling of any deviations from assigned treatment are not reported in the registry record. Nor does the record say whether any interim analyses were planned or conducted.

These omissions do not invalidate the posted summaries, but they limit the ability to assess whether the reported comparisons match a prespecified analysis or how robust they are to alternative assumptions. The results are best read as the registry's posted outcome percentages and unadjusted group contrasts, with the stated population and timeframe, while recognizing that details about multiplicity and incomplete data are not reported.

14. 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: atrial fibrillation (9.5%), arthritis (5.6%), mental status changes (5.6%), renal failure (5.6%), angina pectoris (5.3%).

The serious adverse event figures describe counts of participants affected in each listed group. The record lists serious adverse events for 2 participants in Group 1 Mavacamten, 2 in Group 2 Mavacamten, 4 in the combined MAVA treatment group, and 4 in placebo. The number at risk is also listed for each group: 18, 21, 39, and 19, respectively. No deaths are listed in any group.

These serious adverse event counts are separate from the primary endpoint, which is the percentage with at least one TEAE. A serious adverse event is not interchangeable with any adverse event, and the serious-event counts do not describe the total number of all events. The record also lists serious-event terms and percentages, including Atrial fibrillation at 9.5%, Arthritis at 5.6%, Mental status changes at 5.6%, Renal Failure at 5.6%, Angina pectoris at 5.3%, and Atrial Flutter at 5.3%.

The registry record does not provide enough detail in these summaries to determine whether participants experienced more than one serious event or whether listed terms overlap. These figures describe what is posted, without establishing that an event was caused by treatment.

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

The results show that the percentage of participants with at least one TEAE was higher in each mavacamten group than in placebo during the stated observation period. The reported percentages are 88.9 for Group 1, 90.5 for Group 2, and 68.4 for placebo. The risk-difference estimates are positive for both comparisons, but their confidence intervals include zero and extend across a broad range of possible differences.

This means the posted data do not determine the size of the difference precisely. They are compatible with no difference as well as with a range of positive differences. The unadjusted p-values do not provide strong evidence against a no-difference explanation using the conventional 0.05 reference in the planning assumptions. Neither the interval nor the p-value proves that the groups are identical, and neither establishes that the observed difference was caused by treatment.

The endpoint records whether a participant experienced at least one TEAE. It does not summarize the number, duration, or severity of all events for each person. The registry record's description also does not say that events counted in the primary endpoint were judged related to study treatment. The serious adverse event counts provide a separate safety summary and should not be substituted for the primary outcome.

The study was exploratory and Phase 2, with a relatively limited number of participants in each posted outcome group. The posted results address this adverse-event outcome over the stated timeframe; they do not establish effects on outcomes that were not posted, nor do they describe events beyond the follow-up period. No secondary outcomes are posted in the registry record. The findings are therefore a description of the observed groups and uncertain comparisons, not a complete account of all possible benefits and risks.

These results should not be interpreted as medical advice or as a conclusion about whether mavacamten should be used. They summarize the registry record's outcome definitions, percentages, comparisons, and uncertainty, with important analysis details such as missing-data handling and multiplicity not reported.

16. Why This Trial Matters Statistically

This trial illustrates why a statistical interpretation should include more than a comparison of point estimates. The percentages with at least one TEAE are visibly different across the posted groups, and both risk-difference estimates favor a higher observed event percentage in the active-treatment groups. Yet the confidence intervals include zero and remain broad. Looking only at the point estimates would miss the uncertainty around how large the group differences may be.

The endpoint also matters. A participant-level indicator of at least one TEAE is useful for describing how commonly any event occurred, but it does not capture the number or seriousness of events. The registry record separately reports serious adverse events, which answer a different question. Keeping these outcome types distinct prevents a broad adverse-event percentage from being mistaken for a count of serious events or for an assessment of causation.

The study's exploratory Phase 2 design and the absence of posted secondary outcomes are relevant context for the claims the results can support. The results estimate a particular safety outcome during a defined period. They do not, on their own, resolve questions about effects beyond that endpoint or timeframe. The unadjusted comparisons, together with unreported multiplicity and missing-data procedures, also show why transparent reporting of analysis choices is important.

Finally, planning illustrations based on observed effects can help readers understand how estimates relate to potential future study sizes, but they are not evidence of the original design rationale or of achieved power. Because the observed effects are uncertain, planning values derived from them are conditional. The central statistical lesson is to interpret outcome definitions, effect estimates, intervals, and analysis context together rather than treating a single percentage or p-value as a complete conclusion.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary outcome is a broad measure of whether a participant experienced at least one TEAE. It does not show event frequency per participant, severity, duration, or whether the event was considered treatment-related. The registry record specifies the observation period, but does not provide further information about event adjudication or causality.

The posted group sizes are limited, and the risk-difference confidence intervals are broad and include zero for both comparisons. The reported percentages and contrasts therefore have substantial uncertainty. The record lists enrollment as 59, while its brief summary describes 60 participants; the reason for the discrepancy is not reported in the registry record.

The study is described as exploratory, and no secondary outcomes are posted. The registry record does not report its original sample-size justification, full statistical analysis plan, multiplicity handling, missing-data procedures, or the method used to calculate the confidence intervals. As a result, readers cannot assess those analytic choices from the posted information. The comparisons are unadjusted, and no adjustment for other factors is reported.

The outcome's timeframe is limited to first dose through 8 weeks following last dose, stated as up to 24 weeks. The posted results do not characterize events outside that period. The registry summaries also do not establish whether serious adverse event terms overlap or whether an individual participant had multiple serious events. These limitations constrain interpretation to the posted event summaries and comparisons.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) — NCT03442764.
• Registry record last updated 2022-08-09; status last verified 2022-07.
• Results first posted 2022-08-09.
• 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.

21. Record Summary

The registry record describes a completed, randomized, parallel-group, placebo-controlled Phase 2 study of mavacamten in adults with symptomatic non-obstructive hypertrophic cardiomyopathy and preserved left ventricular ejection fraction. It was described as multicenter, exploratory, double-blind, and quadruple-masked. The active-treatment groups had different target trough concentrations, and the comparator was placebo.

The primary outcome was the percentage of all treated participants with at least one TEAE, measured from first dose through 8 weeks after the last dose, up to 24 weeks. The posted percentages were 88.9 for Group 1, 90.5 for Group 2, and 68.4 for placebo. Both unadjusted risk-difference intervals include zero. No secondary outcomes are posted, and multiplicity and missing-data methods are not reported in the registry record.

The registry lists enrollment of 59, while its brief summary describes 60 participants; the reason is not reported. The record lists MyoKardia, Inc. as sponsor and the study status as completed.