A Phase 2 Study of Intravenous or Subcutaneous Dosing of Sotatercept (ACE-011) in Patients With End-Stage Kidney Disease on Hemodialysis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2 Study of Intravenous or Subcutaneous Dosing of Sotatercept (ACE-011) in Patients With End-Stage Kidney Disease on Hemodialysis (NCT01999582), a randomized phase 2 study. The primary outcome is Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 Days).

2. Clinical Question

3. Trial Design

This was a phase 2, multicenter study with randomized allocation and no masking, according to the registry. Its listed enrollment was 50, and its status is completed. The recorded start date is 2013-11-30 and primary completion date is 2016-08-31. Celgene is listed as sponsor.

The official title describes staggered dose escalation in Part 1 followed by a parallel-group, active-controlled study of selected doses and regimens in Part 2. The registry’s design model, however, is listed as single group. The primary endpoint results are presented for six dose and route groups, all receiving sotatercept. The record does not explain how randomization operated across the study parts, how participants were allocated to the listed groups, or whether the described Part 2 comparison was completed as planned.

The dose descriptions distinguish intravenous and subcutaneous administration, with different starting doses and dose levels. The titrated groups are described as dose-adjusted according to titration rules; the rules themselves are not reported in the registry record. The primary endpoint population is a pharmacokinetic population, rather than an enrollment-wide population: it includes treated participants with at least one non-missing plasma concentration for the endpoint.

The registry lists other outcomes, including hemoglobin measures and adverse events, but the primary result is pharmacokinetic. Although the study’s stated aim includes evaluating route, dose, safety, tolerability, efficacy, dosing regimen, and pharmacodynamics, those aims should not be treated as evidence that each question has a posted comparative analysis. The registry lists zero analyses, and the available primary endpoint results are descriptive group summaries.

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: Pharmacokinetic population-all treated participants with at least one non-missing plasma concentration data for this 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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 Days), measured over Doses 1-2: predose and postdose at 5 min (IV only) 4 hours, 3, and 7 days after each dose; Doses 3-7: predose, and postdose at 5 min after IV injection after each dose; Final dose: predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14 days after dose.

The primary endpoint is the area under the serum concentration-time curve over a 14-day dosing interval, abbreviated AUC14d and measured in day*ng/mL. It represents drug exposure accumulated across the interval, based on plasma concentration measurements taken at specified times around dosing. The registry describes sampling before and after doses, with the timing varying by dose and administration route.

Pharmacokinetic measures are used to characterize how much drug is present in the body over time. An area-under-the-curve measure can capture both the magnitude and duration of observed concentrations during an interval, making it useful for describing exposure across dose regimens and routes. That general role does not make AUC14d a direct measure of hemoglobin response, clinical benefit, or safety.

The registry reports the endpoint as a mean with standard deviation for each dose group. Its pharmacokinetic population includes treated participants with at least one non-missing plasma concentration measurement for this endpoint, analyzed according to the group to which they were randomized. The posted summaries therefore describe exposure among participants with qualifying pharmacokinetic data. They do not, by themselves, establish that one route or dose has greater exposure in the broader study population, or that any observed exposure difference produces a clinical effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous measurement summarized using a mean and standard deviation. The registry gives group-level values for AUC14d, a measure of plasma drug exposure over a 14-day dosing interval. It identifies the pharmacokinetic population and states that participants were analyzed according to their randomized treatment group.

What does a group mean describe?

In general, a mean is the arithmetic average of the measured values in a group. It provides a central summary, but it does not show the full distribution of observations. Two groups can have different means while also having substantial overlap in individual values. For that reason, a mean alone does not establish that groups differ reliably or that the difference is important for a clinical outcome.

The posted mean is paired with a standard deviation. In general, the standard deviation describes how dispersed the observations are around the mean. A larger standard deviation indicates greater spread in the measured values within that group. It is not a measure of uncertainty in the mean in the same way as a confidence interval. The registry does not post confidence intervals for these summaries, so the precision of each group mean and the uncertainty in any between-group contrast cannot be assessed from confidence limits.

Why is a between-group model important?

A comparative analysis would estimate a contrast between groups and quantify its uncertainty, using a method appropriate to the endpoint and study design. The posted record has no such analysis for this continuous endpoint. It indicates that values are missing or not estimable for a two-arm comparison. No inferential p-value or confidence interval for a route or dose contrast is reported. The six group summaries should therefore not be turned into a claim about comparative effects.

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the statistical method. Its width reflects uncertainty in the estimated quantity. A confidence interval for a group mean would address uncertainty about that mean; a confidence interval for a between-group difference would address uncertainty about the contrast. Neither type is included in the reported primary endpoint results.

How should variation be considered?

The standard deviations vary among the reported groups, as do the endpoint population counts. This matters because group means based on different amounts of data can have different precision. In general, variation may also be affected by differences among participants, dose exposure, and measurement patterns. The record does not provide enough detail to separate those sources of variation or to assess whether the endpoint values follow a particular distribution.

For a continuous endpoint, common methods may rely on assumptions about the distribution of residuals or the relationship between variability and the mean. General alternatives can be useful when those assumptions are unsuitable, but the registry does not report a specific comparative model or diagnostics. No method should be attributed to this analysis beyond the descriptive mean and standard deviation that are posted.

What does the endpoint population imply?

The stated pharmacokinetic population includes treated participants with at least one non-missing concentration measurement for the endpoint. This rule means the primary endpoint summaries are not necessarily based on every enrolled participant. The record specifies that the analyses use this population and that participants are analyzed according to their randomized group. The number of participants represented in each group is reported alongside its endpoint summary.

In general, missing concentration measurements can reduce the amount of information available and may affect interpretation if their absence is related to participant characteristics, treatment, or measured exposure. The registry does not report how missing measurements were handled beyond defining the population, whether values were imputed, or whether sensitivity analyses were performed. It is therefore not possible to determine from the record whether missingness could have influenced the summaries.

What can the posted results support?

They support a descriptive account of the observed AUC14d values within each listed group. They do not support a formal test of route or dose differences, because no such analysis is reported. Nor do they establish an exposure-response relationship with hemoglobin outcomes or adverse events. Those questions require analyses linking the relevant measures and accounting for the study design.

General planning calculations based on an observed effect, when available, are not evidence that a study had a particular probability of detecting an effect. A planning illustration is a design aid under stated assumptions; it is not observed power and does not replace a reported analysis. The registry does not report the trial’s sample-size justification, detailed statistical analysis plan, or planned interim analyses. The rationale for the enrollment target and any prespecified approach to statistical testing are therefore not reported in the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) In", "Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) ", "Group 2: Sotatercept 0.2 mg/kg IV Injection", "Group 2: Sotatercept 0.26 mg/kg SC Injection", "Group 3: Sotatercept 0.1 - 0.4 mg/kg IV Injection", "Group 3: Sotatercept 0.4 - 0.5 mg/kg SC Injection")
n   <- c(4, 3, 7, 6, 7, 5)
m   <- c(15204.31, 11269.14, 28647.03, 10327.98, 15886.83, 21982.9)
sp  <- c(7096.55, 1839.92, 10332.19, 8065.12, 4212.12, 5125.4)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) In  4  15204.310  7096.550  3912.115  26496.505
CARM  Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC)   3  11269.140  1839.920  6698.525  15839.755
CARM  Group 2: Sotatercept 0.2 mg/kg IV Injection  7  28647.030  10332.190  19091.348  38202.712
CARM  Group 2: Sotatercept 0.26 mg/kg SC Injection  6  10327.980  8065.120  1864.156  18791.804
CARM  Group 3: Sotatercept 0.1 - 0.4 mg/kg IV Injection  7  15886.830  4212.120  11991.269  19782.391
CARM  Group 3: Sotatercept 0.4 - 0.5 mg/kg SC Injection  5  21982.900  5125.400  15618.875  28346.925

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures and identifies four secondary outcomes, including hemoglobin summaries and adverse events. It does not report how statistical testing across multiple outcomes, dose groups, routes, or time points was controlled. A multiplicity plan is not reported in the registry record. Because no comparative p-values are posted for the primary endpoint, there is no reported primary-endpoint significance result to interpret in relation to multiple testing.

For the primary pharmacokinetic endpoint, the analysis population is defined as treated participants with at least one non-missing plasma concentration measurement. Participants are analyzed according to their randomized group. The record does not describe a broader intention-to-treat population for this endpoint or explain how participants without qualifying measurements were handled beyond exclusion from the defined pharmacokinetic population.

Missing-data methods, including imputation or sensitivity analyses, are not reported in the registry record. The concentration-sampling schedule is described, but the record does not state how incomplete sampling profiles were incorporated into AUC calculations or whether any particular approach was used when measurements were unavailable. Detailed analysis specifications, including model assumptions and prespecified contrasts, are also not reported.

The registry lists zero analyses, while providing descriptive endpoint values. That distinction matters: posted group means and standard deviations are not substitutes for inferential analyses. No basis is given for claims about statistical significance, adjustment for multiplicity, or robustness to missing data.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure (16.7%), mitral valve incompetence (16.7%), supraventricular tachycardia (16.7%), gastrointestinal angiodysplasia haemorrhagic (16.7%), device related infection (16.7%).

The registry reports serious adverse events and other adverse events by dose group. In the intravenous 0.1 mg/kg group, serious adverse events affected 3 of 7 participants at risk, and other adverse events affected 7 of 7. In the subcutaneous 0.13 mg/kg group, the corresponding counts are 0 of 7 and 3 of 7. In the intravenous 0.2 mg/kg group, they are 3 of 9 and 9 of 9; in the subcutaneous 0.26 mg/kg group, 1 of 9 and 6 of 9.

For the titrated intravenous 0.1 - 0.4 mg/kg group, serious adverse events affected 3 of 12 participants at risk and other adverse events affected 9 of 12. For the titrated subcutaneous 0.4 - 0.5 mg/kg group, the counts are 3 of 6 and 6 of 6. The registry reports one death in that last group and zero deaths in each other group.

These are counts within groups, not comparative risk estimates. The registry lists serious-event terms including cardiac failure, mitral valve incompetence, supraventricular tachycardia, gastrointestinal angiodysplasia haemorrhagic, and device related infection, each at 16.7%, and atrial fibrillation at 14.3%. The record does not provide enough context in these summaries to attribute those term percentages to a particular group or to infer comparative safety. Differences in group size and the descriptive nature of the reporting limit cross-group interpretation.

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

The results establish that the registry reports group-specific mean AUC14d values and standard deviations for intravenous and subcutaneous sotatercept dose groups. They also show that the endpoint population counts differ across groups. These summaries describe the pharmacokinetic observations recorded for participants who met the stated endpoint-population definition.

They do not establish that one route or dose produces greater exposure than another. The study has multiple dose levels and titrated groups, and the registry provides no comparative estimate with a confidence interval or p-value. A numerical difference between two group means is not, by itself, a statistically tested treatment effect. The record specifically indicates that values are missing or not estimable for a two-arm comparison of this continuous endpoint.

The summaries also do not show whether the observed exposure levels correspond to changes in hemoglobin, whether hemoglobin was maintained, or whether one regimen had a more favorable safety profile. Although those topics appear among the study aims and secondary outcomes, the primary endpoint data are pharmacokinetic. The serious adverse event counts are descriptive and do not provide adjusted comparisons across groups.

Randomized allocation is listed, but the record does not report enough detail about allocation procedures or analysis to establish how the randomization supports any particular contrast. The registry’s single-group model designation and its six sotatercept dose-group summaries should be considered alongside the official title’s description of study parts. The record does not resolve how those design descriptions relate to the posted endpoint results.

Accordingly, the most defensible interpretation is descriptive: the posted results characterize observed drug exposure within the listed groups. They do not quantify a causal route or dose effect, prove clinical efficacy, or establish the absence or presence of a safety difference. Further conclusions would require comparative analyses and relevant clinical outcome results that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates the distinction between pharmacokinetic description and clinical-effect estimation. AUC14d summarizes drug exposure over time, while hemoglobin outcomes and adverse events address different questions. Keeping those endpoints separate prevents an exposure summary from being mistaken for evidence about clinical response or safety.

The six dose and route groups also show why study labels and result structure need to be read together. The registry identifies randomized allocation and an official title describing dose escalation followed by a parallel active-controlled part, yet its model is listed as single group and the primary results are presented as six sotatercept groups. The record does not provide the details needed to reconcile these descriptions or define a formal comparative estimand.

The reported means and standard deviations are informative as descriptive pharmacokinetic summaries, but they do not answer whether group differences exceed what might arise from sampling variation. That question requires a specified contrast and an uncertainty estimate. In the absence of a reported comparative analysis, readers should avoid treating apparent differences in the group means as tested effects.

The endpoint populations are also smaller than the registry’s overall enrollment and differ among groups. This emphasizes that the population used for a particular endpoint can differ from the population enrolled in a trial. Clear reporting of population definitions, missing-data handling, and inferential methods is needed to understand how strongly results support a conclusion.

Finally, the safety counts reinforce the value of distinguishing descriptive event reporting from comparative safety analysis. Counts identify what was recorded within groups, but without an appropriate analysis they do not establish that the groups differ. These features make the record useful for understanding the scope and limits of registry results, not for drawing conclusions beyond the analyses posted.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint results are descriptive. No confidence intervals, p-values, or formal between-group estimates are reported, and values are missing or not estimable for a two-arm comparison of the continuous endpoint. This limits assessment of uncertainty around route or dose contrasts.

Endpoint population counts vary across groups and are based on treated participants with at least one non-missing plasma concentration measurement. Missing-data handling beyond that population definition is not reported in the registry record. It is therefore unclear how incomplete concentration profiles were treated or whether missingness could affect the group summaries.

The groups do not constitute a straightforward comparison of the same dose administered by different routes: the dose levels differ, and the titrated groups include ranges. The record does not report the titration rules, allocation details, or a prespecified comparative analysis. It also lists a single-group model while the official title describes a later parallel-group active-controlled study, leaving the relationship between those design descriptions unclear.

The registry lists multiple outcomes, but a multiplicity approach is not reported. The detailed statistical plan, sample-size justification, interim analyses, and sensitivity analyses are not reported in the registry record. Safety summaries are also descriptive; the record does not provide adjusted comparisons or enough information to interpret the listed serious-event term percentages by group. These limitations restrict conclusions to the reported group summaries and event counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 2 Study of Intravenous or Subcutaneous Dosing of Sotatercept (ACE-011) in Patients With End-Stage Kidney Disease on Hemodialysis — NCT01999582.
• Registry record last updated 2024-06-24; status last verified 2024-01.
• Results first posted 2024-06-24.
• 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

The registry record describes a completed phase 2, multicenter, randomized, open-label study of intravenous and subcutaneous sotatercept in participants with end-stage kidney disease receiving hemodialysis. Listed enrollment is 50. The primary endpoint is mean AUC14d, a pharmacokinetic measure reported in day*ng/mL.

Results are posted for six dose and route groups, with group means, standard deviations, and endpoint population counts. The pharmacokinetic population includes treated participants with at least one non-missing concentration measurement for the endpoint. No comparative analysis is reported for the continuous primary endpoint; the record notes that values are missing or not estimable for a two-arm comparison.

The registry also lists hemoglobin outcomes and adverse events. Serious adverse events, other adverse events, and deaths are reported by group, but the posted summaries do not provide comparative safety estimates. Statistical planning details, missing-data methods, multiplicity procedures, and the relationship between the stated study parts and the single-group model designation are not reported in the registry record.