Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Participants With Peripheral Arterial Occlusive Disease Fontaine Stage IIB: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Participants With Peripheral Arterial Occlusive Disease Fontaine Stage IIB (NCT03469349), a randomized phase 3 study. The primary outcome is Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12.

2. Clinical Question

The registry record describes a trial of Actovegin in participants with peripheral arterial occlusive disease (PAD), Fontaine Stage IIB. The primary question was whether the percent change from baseline in initial claudication distance (ICD) at Week 12 differed between participants assigned to Actovegin and those assigned to placebo. ICD is the treadmill distance walked before claudication pain begins, or the pain-free walking distance as defined in the record.

The registry record reports an estimated positive difference in the primary outcome, with an interval estimate that excludes zero in the sponsor's MMRM analysis. This describes the posted statistical result; it does not by itself establish the clinical importance of the difference. A threshold for a clinically meaningful ICD change is not reported in the registry record.

3. Trial Design

This was a Phase 3, randomized, parallel-group, double-blind, placebo-controlled study sponsored by Takeda. The registry record identifies the condition as peripheral arterial diseases and describes the intended population as participants with PAD Fontaine Stage IIB. Enrollment was 366. The study status is completed; the start date is 2018-05-01 and the primary completion date is 2019-05-28.

Participants were assigned to Actovegin or matching placebo. The Actovegin group received 1200 mg intravenously once daily for up to 2 weeks, followed by 200 mg tablets orally three times daily for up to 10 weeks, stated as 1200 mg per day. The placebo group received matching intravenous and tablet formulations on the corresponding schedule. The registry record describes the study as international and multicenter, but the number of sites and countries is not reported in the registry record.

The primary outcome was percent change from baseline in ICD at Week 12, measured using a treadmill test. The primary-analysis population was the full analysis set (FAS), defined as randomized participants who received at least one dose and had at least one valid post-baseline value for the primary endpoint. The registry record reports 180 participants in the placebo primary-outcome group and 177 in the Actovegin group. Safety counts use separate at-risk totals, so those denominators should not be treated as the primary-outcome analysis counts.

Other registered outcomes include changes in ICD and absolute claudication distance at additional time points, rest pain, revascularization procedures, and SF-36 scores. The record lists six outcome measures and 13 analyses. Details of the randomization procedure, allocation concealment, specific masking procedures, site-level enrollment, and the trial's original sample-size justification 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: Participants with peripheral arterial occlusive disease (PAD) Fontaine stage IIB were enrolled in this study to receive either actovegin or placebo in a 1:1 ratio.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The full analysis set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and had at least 1 valid post-baseline value for assessment of primary endpoint. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

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 set included all participants who were randomized and received at least 1 dose of double-blind study medication.

6. Primary Endpoint

The registry lists the primary outcome as Percent Change From Baseline in Initial Claudication Distance (ICD) at Week 12, measured over Baseline up to Week 12.

The primary endpoint was percent change from baseline in initial claudication distance (ICD) at Week 12. ICD is the distance walked before claudication pain starts, or the pain-free walking distance, assessed by treadmill testing. The registry describes a fixed-load test at 3.0 kilometer per hour (km/h) with a 10 percent (%) grade.

ICD is used as a measure of walking performance in the context of claudication. A change from baseline expresses how the measured walking distance changed relative to each participant's baseline value. The reported group summaries are least-squares means for percent change, with standard errors. The reported between-group estimate is a least-square mean difference, so it compares adjusted group means rather than simply subtracting raw participant-level values.

The posted outcome is a percentage-change measure, not an absolute distance change. Its interpretation therefore concerns the relative change in the ICD measure over the specified period, under the treadmill assessment conditions. The registry record identifies the Week 12 assessment as the primary endpoint, while additional ICD assessments and other functional or clinical outcomes are listed as secondary outcomes. A clinically important threshold for interpreting the size of a percent change is not reported in the registry record.

The primary result estimates a difference between randomized groups; it does not establish that every participant experienced a change of that size. Nor does a group mean alone describe the full spread of individual outcomes. The standard errors and confidence interval help convey uncertainty in the estimated group-level difference, while the posted endpoint definition clarifies what was measured and when.

7. Results Posted in the Registry

• Actovegin 1200 mg: mean 51.17 versus 21.99 on control; difference 29.18 (95% CI 3.58 to 54.78), standardized effect d = 0.24; z-test p = 0.025.

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.

Percentage of Participants With Revascularization Procedures at Week 24

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Actovegin 1200 mg: 1.1% (2/180) versus 0.0% (0/182) on control; risk difference 1.1 percentage points (95% CI -0.4 to 2.6); unadjusted two-proportion z-test p = 0.154.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Actovegin 1200 mg and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes broaden the trial's assessment beyond the primary Week 12 ICD endpoint. They include ICD percent change at Weeks 2 and 24; absolute claudication distance at Weeks 2, 12, and 24; rest pain at Weeks 12 and 24; revascularization procedures at Week 24; and SF-36 changes at Weeks 12 and 24. The registry lists five secondary outcomes, but detailed numerical results are not reported in the registry record for every one of them. It is therefore not possible to describe a complete direction or consistency pattern across all secondary outcomes.

For revascularization procedures at Week 24, the posted group values are 0.0% for placebo and 1.1% for Actovegin. The unadjusted risk-difference estimate is 0.011, with a confidence interval from -0.004 to 0.026 and p = 0.154. The registry also reports a logistic-regression p-value of 0.942 and labels that analysis non-inferiority. These are distinct results from distinct analyses; the record does not report a non-inferiority margin or the full model specification.

The primary outcome and the secondary outcomes address related but non-identical questions. The primary result concerns percent change in ICD at Week 12. Secondary measures concern other time points, walking-distance definitions, symptoms, a procedure, and health-related quality of life. A result on one measure cannot automatically be generalized to the others. The available secondary information does not establish that every outcome supports the same interpretation as the primary result.

Secondary analyses also raise multiplicity concerns: testing many outcomes or time points increases the chance of obtaining at least one apparently notable result even if there are no real differences. Unadjusted secondary results therefore generally carry less confirmatory weight than a prespecified primary analysis unless the testing strategy accounts for multiplicity. The registry record does not report whether or how multiplicity was controlled across the full set of secondary analyses. The results should be interpreted as additional evidence requiring context, rather than as independent confirmation of the primary finding.

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

• Percent Change From Baseline in ICD at Weeks 2 and 24
• Absolute Change From Baseline in Absolute Claudication Distance (ACD) at Weeks 2, 12 and 24
• Percentage of Participants With Rest Pain at Weeks 12 and 24
• Percentage of Participants With Revascularization Procedures at Week 24
• Change From Baseline in 36-Item Short Form Survey (SF-36) at Weeks 12 and 24

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it records percent change in ICD rather than a yes-or-no event. The registry reports group least-squares means and standard errors, and identifies the sponsor's primary method as MMRM, with the parameter described as a least-square mean difference. These methods answer related but distinct questions: group summaries describe estimated mean outcome levels, while the between-group estimate quantifies the modeled contrast.

What does MMRM contribute?

In general, a mixed model for repeated measures (MMRM) is used when outcomes are measured repeatedly and the analysis models the pattern of observations over time. It can estimate group contrasts while accounting for the correlation among repeated measurements from the same participant. Its results depend on the model specification, including the chosen covariates, time terms, covariance structure, and missing-data assumptions. Those specific details are not reported in the registry record, so they cannot be evaluated from the posted summary alone. The reported MMRM estimate should therefore be read as the sponsor's model-based result, not as a direct subtraction of the two displayed group means.

The FAS definition is also relevant to interpretation. It includes participants who were randomized, received at least one dose, and had at least one valid post-baseline primary-endpoint value. This definition is narrower than simply including every randomized participant. The record's stated primary-outcome group counts are 180 for placebo and 177 for Actovegin. The number randomized to each group, the reasons that some participants were not evaluable for this endpoint, and the specific handling of missing measurements in the MMRM are not reported in the registry record.

What do the standard error and confidence interval describe?

A standard error describes the estimated uncertainty of a statistic, such as a group mean. It is not the standard deviation of individual participant outcomes. The reported standard errors are 9.286 for placebo and 9.187 for Actovegin. A confidence interval gives a range of values compatible with the data and the analysis procedure at a stated confidence level, subject to the method's assumptions. For the reported MMRM contrast, the 95% confidence interval is 9.35 to 49.02. The interval expresses uncertainty about the estimated group difference; it does not describe the spread of participant responses.

The registry also permits a simple unadjusted recalculation from the posted summary statistics. That calculation uses the displayed means and standard errors to estimate a difference and its uncertainty without reproducing the sponsor's full MMRM. It yields 29.18, with a confidence interval from 3.578 to 54.78 and p = 0.025. This is a useful check on the scale and direction of the reported contrast, but it cannot recover adjustments or modeling choices that are not contained in the summaries. The record does not flag a discrepancy between the sponsor result and the recalculation.

How should the p-values be read?

A p-value measures how incompatible the observed data, or more extreme data, are with a specified null hypothesis under the statistical model. It is not the probability that the null hypothesis is true, nor the probability that the observed result occurred by chance in an everyday sense. The sponsor reports p = 0.004 for the MMRM superiority analysis. The unadjusted recalculation reports p = 0.025. These values belong to different analyses and should not be substituted for one another. Neither p-value measures the clinical value of a difference.

The word superiority describes the type of contrast reported by the sponsor: the analysis tests whether the outcome differs in the direction specified by its superiority framework. The registry reports the result as a superiority analysis, but the complete hypothesis-testing plan and any adjustments to the significance threshold are not reported in the registry record.

How do binary outcomes differ?

The Week 24 revascularization outcome is binary: participants either had or did not have a procedure by that time point. The registry reports a logistic regression analysis and identifies its type as non-inferiority. A simple difference in proportions is a different estimand from a model-based logistic analysis. The posted group proportions and the recalculated risk difference describe an unadjusted contrast, while the registry's reported p-value comes from logistic regression. The non-inferiority margin and fuller model details are not reported in the registry record, so the p-value alone is insufficient to establish how that analysis was specified or interpreted.

For binary outcomes with few events, estimates can be imprecise and sensitive to the method used. A confidence interval helps show the range of plausible risk differences, while a p-value alone does not show the size or precision of the contrast. The Week 24 risk-difference interval spans values on both sides of zero, which signals uncertainty around the unadjusted contrast. No additional conclusions should be drawn from that one secondary result without considering its analysis plan and the larger set of outcomes.

In general, over-dispersion occurs when observed variation is greater than assumed by a statistical model; if ignored, standard errors may be too small and tests may be too optimistic. The registry record does not report an over-dispersion assessment or model details for these analyses. This is a general statistical consideration, not a finding about this trial.

11. Confidence Intervals and Precision

The sponsor's primary MMRM estimate is a least-square mean difference of 29.19, with a 95% confidence interval from 9.35 to 49.02. The interval lies above zero, and its width conveys that the estimate is not known with perfect precision. Values across the interval are compatible with the data under the fitted analysis and its assumptions. The interval does not mean that 95% of participants had outcomes within those limits, or that the true value has a 95% probability of lying in the interval.

The unadjusted recalculation gives a mean difference of 29.18 and a confidence interval from 3.578 to 54.78. This interval is wider than the sponsor's reported interval. Its endpoints remain positive, but it conveys substantial uncertainty about the size of the unadjusted contrast. Because the recalculation and MMRM may not embody identical modeling choices, their intervals should be understood as results from separate analyses, not as competing estimates from an identical procedure.

The standard errors for the group least-squares means are 9.286 for placebo and 9.187 for Actovegin. A standard error reflects uncertainty in an estimated mean, not participant-to-participant variability. The registry's comparison record also includes a pooled standard deviation of 123.4, marked as approximate. That quantity is used in the simple effect-size and planning calculations, and its approximate status matters: it is inferred from the posted summary information rather than a direct variance estimate from participant-level data.

Precision depends on the amount and variability of information available and on the model used. The posted confidence intervals are the most direct way to judge uncertainty in the estimates. Statistical significance does not eliminate uncertainty, and the positive point estimate does not establish that the difference meets a clinically important threshold. Such a threshold is not reported in the registry record.

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 figures are planning illustrations based on the observed effect, not the trial's original design calculation. The registry's stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrated effect to detect is 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.

All figures for this continuous primary outcome are participants per arm, not total participants and not total events. The planning rows consider detecting 100%, 75%, and 50% of the observed effect. For the full observed effect, the illustration gives 281 participants per arm for 80% power and 376 participants per arm for 90% power. For planning at 75% of the observed effect, it gives 500 participants per arm for 80% power and 669 participants per arm for 90% power. For planning at 50% of the observed effect, it gives 1,124 participants per arm for 80% power and 1,504 participants per arm for 90% power.

In plain language, the 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the assumed effect if that effect were real and the planning assumptions held. The 90% power column makes the corresponding illustration for a 90% chance. Detecting a smaller effect generally requires more participants, which is reflected by the increasing planning figures as the assumed fraction becomes smaller. These figures are not observed power.

The illustrations should not be read as a retrospective verdict on whether the completed trial was adequately designed. They reuse an effect estimated from the trial itself, and the observed estimate is uncertain. A planning exercise based on that estimate does not replace the original design rationale, which is not reported in the registry record. Any curve associated with the planning display should be read in the same context: it illustrates assumptions about a hypothetical future design rather than reporting an observed trial outcome.

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 = 29.180; pooled standard deviation σ = 123.421.
2. n = 2 × (1.96 + 0.842)² × 123.421² / 29.180² = 280.8, rounded up to 281 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 <- 29.18                      # observed difference in means
sigma <- 123.420533975441                     # 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(3469349)
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 = 281 (80% power), 376 (90% power)
 75% of observed effect: n per arm = 500 (80% power), 669 (90% power)
 50% of observed effect: n per arm = 1,124 (80% power), 1,504 (90% power)
power.t.test: 281.8 
Simulated power at n = 281 per arm: 0.801 (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 own primary analysis is the MMRM result: a least-square mean difference of 29.19, with a 95% confidence interval from 9.35 to 49.02 and p = 0.004. This is the registry-reported analysis and should take precedence over a simple recalculation when describing the trial's primary result. The registry record does not flag a discrepancy between the sponsor analysis and the recalculation.

The unadjusted recalculation uses the posted group means and standard errors. It estimates a difference of 29.18, with a confidence interval from 3.578 to 54.78 and p = 0.025. The close point estimates indicate that the summary-statistic calculation reproduces a similar central contrast, but the uncertainty estimates and p-values are not identical. The recalculation is not a refit of the MMRM and cannot reproduce any model adjustments or assumptions that are not encoded in the posted summaries.

Both analyses estimate a positive group difference. Their confidence intervals exclude zero, but the model-based and unadjusted results must remain distinguished because they arise from different procedures. The registry does not report enough model specification to independently reproduce the MMRM from participant-level data. The sponsor result is therefore the primary inferential result, while the recalculation serves as a transparent, simple check based on the posted summary statistics.

15. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint, five secondary outcomes, six outcome measures, and 13 analyses. Testing several outcomes and time points creates a multiplicity issue: the more statistical comparisons made, the greater the opportunity for a nominally notable result to arise by chance. A prespecified testing hierarchy, family-wise error control, or another multiplicity procedure can help define how such results should be interpreted. Whether any such procedure was planned or applied is not reported in the registry record.

The primary endpoint is identified, and the sponsor reports a superiority analysis for it. However, the full statistical analysis plan, the prespecified significance threshold for the primary analysis, and any relationship between primary and secondary testing are not reported in the registry record. The stated sample-size illustration uses a two-sided significance level of 0.05, but this planning assumption does not establish the original trial's analysis plan or confirm how multiplicity was handled.

Missing data also affect interpretation. The FAS definition requires at least one valid post-baseline primary-endpoint value, so participants without such a value are not included in that stated primary analysis population. The record does not report the number or reasons for missing primary-endpoint observations, the completeness of follow-up by arm, or the specific MMRM missing-data assumptions and sensitivity analyses. It is not possible to assess from the posted summary how sensitive the primary result is to alternative assumptions about missing outcomes.

The record also does not report whether any interim analyses were conducted, whether they affected the analysis plan, or whether adjustment was made for interim looks. These details should not be inferred from the final reported p-value. The number of randomized participants by arm and the reasons for differences between enrollment, analysis, and safety denominators are likewise not reported in the registry record. These gaps limit assessment of the full analysis pathway, but they do not change what the registry explicitly reports: a primary MMRM estimate and additional analyses whose multiplicity and missing-data handling are not fully documented.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gangrene (1.1%), extremity necrosis (0.5%), thrombophlebitis superficial (0.5%), angina unstable (0.5%), pneumonia (0.5%).

The safety record gives at-risk denominators of 182 for placebo and 184 for Actovegin. Serious adverse events affected 3 participants in the placebo group and 9 in the Actovegin group. Other adverse events affected 20 participants in the placebo group and 23 in the Actovegin group. No deaths are reported in either group. These are counts of participants affected, as indicated by the registry fields, and should not be read as counts of all event episodes.

The registry lists serious-event terms including gangrene at 1.1%, extremity necrosis at 0.5%, superficial thrombophlebitis at 0.5%, unstable angina at 0.5%, pneumonia at 0.5%, and arterial bypass thrombosis at 0.5%. The listed terms are not accompanied by arm-specific counts in the record, so they cannot be attributed to a particular group from these figures alone.

Adverse-event counts describe events recorded during the study; they do not by themselves establish that a study drug caused an event. Comparisons should account for the at-risk denominators, follow-up, event definitions, and uncertainty. The safety denominators differ from the primary-outcome analysis counts because the populations and outcome availability are not the same. The posted counts are descriptive and are not a complete assessment of comparative safety.

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

The posted primary analysis estimates a positive difference in percent change from baseline in ICD at Week 12 between the Actovegin and placebo groups. The sponsor's MMRM estimate is 29.19, with a 95% confidence interval from 9.35 to 49.02 and p = 0.004. The simple unadjusted recalculation is similar in its point estimate but has a different interval and p-value. The model-based result is the registry-reported primary analysis.

These findings describe a group-level statistical comparison in the registry-defined FAS, under the study's treadmill measurement protocol and at the primary time point. They do not mean that each participant experienced the estimated average difference, nor do they explain how outcomes varied among individual participants. The registry record does not report a threshold for a clinically meaningful change in ICD, so statistical evidence of a difference cannot by itself determine the practical or clinical importance of the estimate.

The result also does not answer every question about the treatment. The primary endpoint does not substitute for secondary outcomes such as symptoms, revascularization, absolute claudication distance, or SF-36. Detailed numerical results are not reported in the registry record for all secondary outcomes. The record's reported serious adverse events and other adverse events are descriptive counts and do not alone establish causation or provide a complete comparative safety assessment.

Interpretation is bounded by the available analysis details. The MMRM specification, missing-data handling, multiplicity strategy, and original sample-size justification are not reported in the registry record. Those omissions limit independent assessment of some assumptions and the strength of conclusions across multiple outcomes. The results should therefore be read as the posted estimates for this randomized comparison, with their stated uncertainty, rather than as a universal claim about outcomes in other settings or populations.

18. Why This Trial Matters Statistically

This trial illustrates why the estimated effect, its uncertainty, and the analysis method all matter. The primary outcome is a continuous walking measure, and the sponsor reports both a model-based group contrast and a confidence interval. The interval communicates more than the p-value alone: it gives a range of effect sizes compatible with the analysis, while still leaving uncertainty about the exact magnitude.

The trial also shows the difference between a sponsor analysis and a simple recalculation. The MMRM estimate and the recalculated estimate have closely aligned point estimates, but their intervals and p-values differ. A summary-statistic check can make the scale of a result more transparent, yet it cannot reproduce a model that uses information or assumptions not present in the summary. Keeping these analyses distinct avoids treating an approximate recalculation as though it were the primary model.

The endpoint is measured under a specified treadmill protocol and the primary analysis uses a defined FAS. These choices determine what the estimate represents. At the same time, the registry does not report several details needed for a full audit of the analysis plan, including the full MMRM specification, missing-data methods, multiplicity handling, or original sample-size rationale. This makes the distinction between reported findings and unreported methods especially important.

Finally, the planning illustrations show how sample-size requirements depend on the assumed effect size and desired power. They are not evidence about the completed trial's power or a substitute for its original planning rationale. Taken together, these points make the trial useful for understanding how endpoint definition, model-based inference, uncertainty, secondary analyses, and transparency of the statistical plan shape interpretation.

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 provide the full MMRM specification, including covariates, time structure, covariance assumptions, or other model details. It also does not report participant-level data, so the sponsor's model cannot be independently refitted from the posted summary statistics. The simple recalculation is explicitly unadjusted and should not be treated as a replacement for the reported MMRM.

Details of missing primary-endpoint observations, reasons for missingness, follow-up completeness, and sensitivity analyses are not reported in the registry record. Although the FAS definition is stated, the record does not fully explain the flow from enrollment to the primary and safety analysis populations. The registry does not report the original sample-size justification, interim-analysis details, or whether interim analyses occurred.

Multiplicity procedures are not reported despite the listed range of outcomes, time points, and analyses. Detailed results are also not reported for all secondary outcomes, limiting assessment of whether findings are consistent across different measures. For the Week 24 revascularization outcome, the record includes a logistic-regression p-value labeled as non-inferiority but does not report the non-inferiority margin or complete model details.

The primary endpoint is a treadmill-based measure, and the registry record does not report a clinically meaningful threshold for its percent change. The posted group means and standard errors do not describe the full distribution of individual responses. Safety counts are descriptive; the serious-event terms are not provided with arm-specific detail, and the record does not establish causality. These limitations leave important aspects of clinical interpretation and statistical robustness unresolved.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in Participants With Peripheral Arterial Occlusive Disease Fontaine Stage IIB — NCT03469349.
• Registry record last updated 2020-10-28; status last verified 2020-10.
• Results first posted 2020-10-28.
• 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, randomized, double-blind, parallel-group, placebo-controlled Phase 3 study of Actovegin in participants with PAD Fontaine Stage IIB. Enrollment was 366. Treatment consisted of intravenous Actovegin followed by oral tablets, compared with matching placebo formulations.

The primary endpoint was percent change from baseline in ICD at Week 12, assessed by treadmill testing. The sponsor's MMRM analysis reported a least-square mean difference of 29.19, with a 95% confidence interval from 9.35 to 49.02 and p = 0.004. A simple unadjusted recalculation gave a difference of 29.18, with a confidence interval from 3.578 to 54.78 and p = 0.025.

Secondary outcomes and safety findings are also listed, but detailed results are not reported in the registry record for every outcome. The original sample-size rationale, full statistical analysis plan, multiplicity handling, and several model and missing-data details are not reported in the registry record.