Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) (NCT02927080), a randomized phase 2 study. The primary outcome is Safety and Tolerability (Incidence of Adverse Events).

2. Clinical Question

3. Trial Design

This was a Phase 2 randomized, double-blind, placebo-controlled study with a parallel-group model. The registry record describes two parts: Part 1 was open-label dose escalation, and Part 2 was randomized and placebo controlled. The listed masking designation is quadruple. The study is marked terminated in the registry record.

Part 1 included six ACE-083 cohorts. Doses and injection sites varied: participants received unilateral TA or BB treatment at 150 mg or 200 mg, and bilateral TA treatment at 200 mg or BB treatment at 240 mg. These cohorts were not placebo controlled, so their safety counts describe treatment experience without a concurrent randomized placebo comparison.

Part 2 assigned participants to ACE-083 240 mg or placebo in the TA or BB. Treatment was bilateral and scheduled once every 3 weeks for up to 9 doses. The arm descriptions also state that participants were rolled over into an open-label portion afterward, receiving ACE-083 240 mg in the corresponding muscle for up to 8 doses. The registry record lists the Part 2 primary safety timeframe through Day 190; the Part 1 timeframe is through Day 106.

The registry record gives a start of 2016-11 and a primary completion date of 2019-09-17. It does not report the rationale for the enrollment target, details of randomization implementation, or the planned statistical analysis in the information summarized for this study.

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.

Only the first 6 of 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety set population is all participants that received at least one dose of ACE-083 or placebo during the study.

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: The Safety population was used for the results posting for both parts of the study. The Safety Set consists of all patients who received at least one dose of the study drug (including placebo).

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Safety and Tolerability (Incidence of Adverse Events), measured over From initiation of treatment to Day 106 for Part 1 and Day 190 for Part 2.

The primary endpoint counts participants who had at least one treatment-emergent adverse event during the applicable study-part timeframe. It is a participant-level count: a person with multiple events is counted as a participant with an event, rather than contributing one count for every event. The registry defines the safety set as all participants who received at least one dose of ACE-083 or placebo.

This endpoint is used to describe the frequency of participants experiencing adverse events during treatment. It is relevant to safety and tolerability, but it does not convey the number of events per participant, their duration, severity, relationship to treatment, or clinical consequences. Those details are not reported in the primary endpoint definition.

The registry lists the Part 1 observation period as initiation of treatment to Day 106 and the Part 2 period as initiation of treatment to Day 190. These different timeframes matter when reading counts across study parts: a count from an open-label dose-escalation cohort is not directly interchangeable with a count from a randomized Part 2 arm. The endpoint also does not establish whether an observed difference is caused by treatment. Group sizes are limited, and the primary outcome is reported as counts rather than as a prespecified adjusted treatment effect in the information available.

7. Results Posted in the Registry

• ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg: 100.0% (14/14) versus 80.0% (12/15) on control; risk difference 20.0 percentage points (95% CI -0.2 to 40.2), risk ratio 1.25 (0.97–1.61); unadjusted two-proportion z-test p = 0.077.
• Placebo (Part 2, DB-PC) Biceps Brachii (BB): 86.7% (13/15) versus 80.0% (12/15) on control; risk difference 6.7 percentage points (95% CI -19.9 to 33.2), risk ratio 1.08 (0.79–1.49); unadjusted two-proportion z-test p = 0.624.
• ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg: 100.0% (14/14) versus 80.0% (12/15) on control; risk difference 20.0 percentage points (95% CI -0.2 to 40.2), risk ratio 1.25 (0.97–1.61); unadjusted two-proportion z-test p = 0.077.

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.

Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)

• 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:
  • ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg: mean -3.05 versus -0.32 on control; difference -2.73 (95% CI -5.27 to -0.19), standardized effect d = -0.81; z-test p = 0.035.
  • Placebo (Part 2, DB-PC) Bicpes Brachii (BB): mean 1.03 versus -0.32 on control; difference 1.35 (95% CI -1.21 to 3.91), standardized effect d = 0.39; z-test p = 0.301.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for ACE-083 (Part 2, DB-PC) Tibialis Anterior (TA) 240 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Placebo (Part 2, DB-PC) Bicpes Brachii (BB) and the control. The interval gives the range of effects that remain compatible with the data.

Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled

• 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:
  • ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg: mean 32.58 versus -3.54 on control; difference 36.12 (95% CI 7.79 to 64.45), standardized effect d = 0.98; z-test p = 0.012.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percent Change From Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled

• 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:
  • ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg: mean 1.70 versus -1.19 on control; difference 2.89 (95% CI -0.34 to 6.12), standardized effect d = 0.66; z-test p = 0.079.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between ACE-083 (Part 2, DB-PC) Biceps Brachii (BB) 240 mg and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcome set addresses different aspects of muscle status and function, including muscle fat fraction, strength, upper-limb performance, tibialis anterior function, muscle volume, a patient-reported health index, and serum concentration. These outcomes are related to the study’s broader aims but are not interchangeable. A change in an imaging measure, a strength measure, a functional measure, or a patient-reported measure represents a different dimension of experience and may have a different scale and interpretation.

The reported results do not form a uniform pattern across all outcomes and muscle groups. Some estimates favor ACE-083 relative to placebo under their reported analysis, while other estimates are less conclusive. That variability should be read alongside the small group sizes, different outcome measures, and different analysis approaches. The primary endpoint is the incidence of treatment-emergent adverse events, so secondary changes in muscle measures do not directly answer the primary safety question.

Unadjusted secondary results carry less weight when many outcomes and comparisons are examined because the chance of finding apparently notable results can increase across a collection of tests. The registry lists 19 outcome measures and 11 analyses, and it does not report a multiplicity adjustment. Without a reported plan for controlling the overall error rate or identifying a hierarchy of outcomes, individual p-values among secondary outcomes should be treated as exploratory rather than as stand-alone confirmation.

Secondary outcomes can help describe patterns and motivate further investigation, but they cannot replace a prespecified primary analysis. Interpretation also depends on details that are not reported in the registry record, including the handling of missing measurements and the full model specification. The secondary findings therefore provide context, not a single overall conclusion about benefit or harm.

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

• Percent Change in Total Muscle Volume (TMV) in Muscle in Patients With FSHD Administered ACE-083 During Part 1 (Open-label, Dose-escalation Portion)
• Absolute Change in Fat Fraction (FF) of the Muscle in Patients With FSHD Administered ACE-083 or Placebo During Part 2 (Randomized, Controlled Portion)
• Percent Change From Baseline in Function of Tibialis Anterior, Part 2 (Randomized, Controlled Portion)
• Percent Change From Baseline in Strength of Biceps Brachii, Part 2, Randomized-controlled
• Percent Change From Baseline in Performance of the Upper Limb (PUL) Mid-Level Elbow Dimension, Part 2, Randomized-controlled
• Change From Baseline in Facioscapulohumeral Muscular Dystrophy-health Index (FSHD-HI), Patient-reported Outcome (PRO) Measures Part 2 (Randomized, Controlled Portion)- Total Score
• ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 2, 24-hours After Dose
• ACE-083 Serum Concentration Following Local Intramuscular Administration (200 mg Tibialis Anterior (TA) Bilaterally) Day 85, 6-hours After Dose

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each person is classified according to whether at least one treatment-emergent adverse event occurred during the relevant timeframe. Counts and denominators are therefore central to interpretation. A count such as 14 of 14 communicates that each participant in that arm was recorded as having an event, but it does not tell whether the events were similar in type or seriousness.

The posted primary comparisons are expressed as risk differences. A risk difference subtracts the event risk in a reference group from the event risk in another group. A value above zero indicates a higher observed event risk in the arm being compared, based on the stated ordering; a value below zero indicates a lower observed risk. The risk difference is an absolute contrast, not a relative measure. The registry’s comparison output also gives relative-risk estimates for selected contrasts, but those do not replace the absolute group counts.

The confidence interval describes a range of effect estimates compatible with the data under the method used. A wide interval indicates limited precision. When an interval includes zero for a risk difference, it includes the possibility of no difference; it may also include differences in either direction. A p-value assesses compatibility with a specified null hypothesis under statistical assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect.

For continuous secondary outcomes, the registry reports least-squares means and standard errors, and sponsor-reported ANCOVA analyses. ANCOVA compares groups while accounting for covariates in the fitted model. The covariates and full model specification are not reported in the registry record. The sponsor-reported results use mean differences in final values and 90% confidence intervals. These adjusted analyses should be distinguished from the posted recalculations, which are simple unadjusted estimates reconstructed from the posted summary statistics.

The unadjusted continuous comparisons use a pooled standard deviation estimated from the reported standard errors and sample sizes, with an approximation noted in the results. A standardized effect expresses a mean contrast relative to a measure of variability; it can make outcomes measured on different scales easier to compare, but it does not retain the original outcome units. Because the dispersion estimate is approximate and the analysis is unadjusted, these calculations are illustrative rather than a replacement for the sponsor’s ANCOVA analysis.

Planning figures based on observed effects are illustrations of the group sizes that might be needed under stated assumptions. They are not the trial’s original design calculation and are not observed power. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation, a normal approximation, and detection of a stated fraction of the observed effect. Such projections depend strongly on the observed effect, which can be unstable in small studies. They should be read as conditional planning examples, not as evidence that the trial had or lacked adequate power.

General statistical context: small samples make estimates sensitive to the outcomes of individual participants. Binary outcomes can also have limited information when event counts are close to the group size, and confidence intervals can remain broad even when the observed counts differ. For continuous measures, variation among participants affects the uncertainty of the estimated mean contrast. These principles help explain why point estimates and p-values should be considered alongside intervals, sample sizes, outcome definitions, and the analysis method.

How do the randomized and open-label parts differ?

Randomization in Part 2 supports comparisons between assigned groups by reducing systematic differences at allocation, on average. The open-label Part 1 cohorts do not provide the same concurrent placebo contrast. Their counts describe the observed experience in those cohorts and should not be interpreted as randomized treatment effects. The registry does not report enough detail to assess whether all later open-label observations were included in the primary outcome summaries.

What is not available about the statistical plan?

The registry record does not report a complete prespecified analysis plan for the outcomes described. In particular, it does not report the planned handling of missing data, the covariates in the ANCOVA models, or whether interim analyses were conducted. Those omissions limit assessment of how closely the posted analyses follow an original plan.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimated effect. The primary safety risk-difference intervals are broad relative to their point estimates. For the TA ACE-083 comparison against TA placebo, the interval runs from -0.002 to 0.402; for the listed BB ACE-083 comparison against the same reference, it is also -0.002 to 0.402. Both include zero and extend to a substantial positive risk difference. The estimates therefore leave considerable uncertainty about the size and direction of a possible contrast.

The reported secondary ANCOVA analyses give 90% confidence intervals. For TA fat fraction, the interval runs from -4.86 to -0.59. For BB fat fraction, the reported interval runs from -3.49 to 0.99. The BB strength interval runs from 11.78 to 60.46, while the PUL mid-level elbow result runs from 0.09 to 5.69. These ranges convey uncertainty around the reported adjusted mean differences; their interpretation also depends on the outcome scale and analysis model.

A confidence interval is not a range containing a fixed proportion of individual participant outcomes, nor does it guarantee that the true effect lies within its bounds. It describes uncertainty in an estimate under the analysis assumptions. Narrower intervals generally indicate greater precision, but precision does not by itself establish that an effect is important or unbiased.

Group sizes for the randomized comparisons are modest, so individual observations can materially affect estimates. The registry record does not report the amount or handling of missing outcome data. That makes it difficult to assess whether uncertainty from missing observations is reflected in the reported intervals. The recalculated intervals are unadjusted; the sponsor-reported ANCOVA intervals are based on a different analysis and should be interpreted as such.

12. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes, groups, or comparisons are tested. Even if each test is evaluated using a conventional threshold, considering many tests increases the possibility that some results will appear notable by chance. This is especially relevant for a trial with numerous secondary outcomes and more than one muscle group or treatment comparison.

The registry record lists 19 outcome measures and 11 analyses. It does not report whether the sponsor adjusted for multiple comparisons, used a prespecified hierarchy, or treated particular secondary outcomes as confirmatory. The reported secondary p-values should therefore be read as individual analyses rather than as a family of results with a documented multiplicity strategy. The record also does not report interim analyses or stopping rules, so their role cannot be assessed.

Missing-data methods are also not reported in the registry record. The reported denominators differ across some outcomes and arms, but the reason for each difference, the amount of missingness, and the assumptions used for analysis are not stated in the information available. Missing outcomes can affect both the estimate and its uncertainty, particularly if the probability of missingness is related to health status or treatment experience.

The primary safety population is defined as participants receiving at least one dose. This is a safety-set definition, not necessarily the population used for every secondary analysis. The registry record does not provide a complete accounting of analysis populations for all outcomes, nor does it state the handling of participants who discontinued or rolled over to open-label treatment. These gaps limit evaluation of potential selection and follow-up effects.

These limitations do not invalidate the posted results, but they narrow what can be concluded from them. A fuller assessment would require the prespecified statistical analysis plan, analysis-population definitions, missing-data procedures, and any multiplicity strategy; these are not reported in the registry record.

13. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lung abscess (7.1%), sepsis (7.1%), pneumonia (7.1%), diverticulitis (6.7%), invasive ductal breast carcinoma (3.7%).

Serious adverse events are distinct from the primary endpoint, which counts participants with at least one treatment-emergent adverse event of any type as defined in the registry. The serious-event counts are reported separately by study group. No serious adverse events were recorded in the listed Part 1 cohorts. In Part 2, the serious-event counts were 0 of 15 for TA placebo, 1 of 14 for TA ACE-083, 1 of 15 for BB placebo, and 1 of 14 for BB ACE-083. The open-label groups are also listed separately, with 1 of 27 for TA and 0 of 26 for BB.

These counts are sparse and should be read as descriptive observations, not as reliable estimates of comparative risk. A count of zero in a group does not establish that the underlying risk is zero. Nor does a similar count across groups establish equivalence. The record lists lung abscess, sepsis, pneumonia, diverticulitis, and invasive ductal breast carcinoma among the top serious-event terms, with percentages as posted. The denominators and method behind those percentages are not reported in the registry record, so the percentages cannot be interpreted as group-specific risks from this information alone.

The serious-event summary does not establish whether an event was caused by treatment. Causality, timing, severity beyond the serious classification, and participant-level overlap among event terms are not reported in the registry record. The open-label observations should not be combined conceptually with the randomized comparison as if they were concurrent controlled evidence.

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

The results describe what was recorded among participants in this Phase 2 study. They show that treatment-emergent adverse events were reported for most participants in the listed Part 1 and Part 2 groups, and that the randomized primary-outcome estimates are uncertain. The posted confidence intervals include values compatible with no risk difference for the listed comparisons. This does not establish that the groups had the same risk; it indicates that the data do not precisely distinguish among a range of possible differences.

The trial’s primary endpoint is a safety count, not a direct measure of strength, muscle volume, function, or quality of life. The secondary outcomes address some of these domains, but they are varied and their analyses are not all equivalent. The registry record does not report a multiplicity strategy, complete analysis details, or missing-data methods. Individual secondary findings therefore require caution, particularly when considered apart from the overall set of outcomes.

These results do not establish whether ACE-083 improves or worsens FSHD, whether an observed muscle-measure change is meaningful to participants, or whether an adverse event was caused by the intervention. They also do not establish that an absence of a statistically notable contrast means the treatments are equivalent. Such conclusions would require evidence and analyses beyond the posted summaries.

The registry marks the study as terminated, but the reason for termination is not reported in the registry record. The status alone does not explain why the study ended or imply a particular safety or efficacy finding. The posted information supports descriptive interpretation of the reported groups and estimates, while leaving important questions about causality, precision, and analysis conduct unresolved.

15. Why This Trial Matters Statistically

This trial illustrates why endpoint definition matters. The primary endpoint counts participants with at least one treatment-emergent adverse event, while serious adverse events are recorded separately and secondary outcomes assess muscle and functional measures. These outcomes answer different questions. Treating them as interchangeable could blur the distinction between overall event experience, seriousness, and potential changes in disease-related measures.

It also highlights the difference between a point estimate and precision. A risk-difference estimate can appear sizeable while its confidence interval remains broad. Conversely, a p-value alone does not show how large or important a contrast may be. Reading counts, estimates, intervals, and group sizes together gives a more complete account of what the study can resolve.

The study’s two-part structure adds another statistical lesson. Open-label dose-escalation cohorts contribute safety experience, whereas randomized placebo-controlled groups support comparative interpretation. Those sources of evidence have different strengths and should not be blended into a single treatment contrast. The reported Part 2 comparison references also matter: the listed BB comparisons use TA placebo as the reference, rather than establishing a direct comparison within BB.

Finally, the registry record demonstrates the importance of transparent reporting. Missing details about multiplicity, missing data, model covariates, and the reason for termination limit interpretation, even when numerical outcome summaries are available. Planning illustrations based on observed effects can help frame future study design, but they are not evidence of observed power or of the original design rationale. Clear distinctions among observed results, recalculated estimates, and sponsor-reported analyses are essential for responsible statistical interpretation.

16. 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 study includes an open-label dose-escalation part and a randomized, placebo-controlled part, but the primary safety summaries span arms from both parts. Part 1 cohorts lack a concurrent placebo group and use varying doses and injection sites. Their event counts are useful descriptions of those cohorts, but they do not provide controlled comparisons. Part 2 has separate TA and BB groups, and the listed primary-outcome contrasts use TA placebo as the reference even for BB treatment groups. A direct BB placebo-versus-BB ACE-083 primary contrast is not listed.

The group sizes in the randomized comparisons are modest, and the primary outcome is common in several arms. This limits precision and means that counts can be sensitive to individual observations. The record does not report the reason for study termination, so termination should not be interpreted as evidence for a particular efficacy or safety outcome.

Several details needed to assess the results are not reported in the registry record: the complete statistical analysis plan, missing-data procedures, the covariates used in ANCOVA, multiplicity handling, interim analyses, and reasons for differences in outcome denominators. The serious-event term percentages are listed without denominators or an explanation of their calculation. These omissions restrict independent evaluation of the analyses and their assumptions.

Part 2 participants were described as rolling over into open-label treatment after the controlled portion. The registry summaries do not provide enough information to assess how that transition affected follow-up or the analyses presented. Secondary outcomes cover different measures, with unadjusted recalculations alongside sponsor-reported analyses; those should not be treated as if they were a single common estimand.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) — NCT02927080.
• Registry record last updated 2022-09-26; status last verified 2022-09.
• Results first posted 2021-04-22.
• 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.

20. Record Summary

The registry record describes a Phase 2 randomized, double-blind, placebo-controlled parallel-group study of locally administered ACE-083 in participants with FSHD. It included open-label dose escalation in Part 1 and randomized placebo-controlled treatment in Part 2, with treatment directed to the tibialis anterior or biceps brachii. The registry lists enrollment as 95, a start of 2016-11, primary completion on 2019-09-17, and study status as terminated.

The primary endpoint was the number of participants with at least one treatment-emergent adverse event during the applicable study-part timeframe. Counts were high across the listed groups, while the posted unadjusted randomized comparisons had broad confidence intervals. Secondary outcomes included muscle and functional measures; their reported analyses vary, and no multiplicity strategy is reported in the registry record.

The summaries support descriptive interpretation but leave important uncertainties about precision, missing data, analysis methods, and the reason for termination. The registry record does not report a complete statistical analysis plan.