Bay1002670, Fibroids, Safety and Efficacy EU,US,Can, Jap: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bay1002670, Fibroids, Safety and Efficacy EU,US,Can, Jap (NCT02131662), a randomized phase 2 study. The primary outcome is Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment.

2. Clinical Question

3. Trial Design

This was a phase 2 randomized, parallel-group, double-blind, placebo-controlled, multicenter study of BAY1002670 in subjects with uterine fibroids. The registry describes the masking as quadruple. The planned treatment period in the official title was 3 months, and the primary endpoint timeframe was after the end of the initial bleeding episode until the end of treatment, up to 12 weeks.

There were five posted arms: VPR 4 mg, VPR 2 mg, VPR 1 mg, VPR 0.5 mg, and placebo. The primary outcome denominators were 60, 61, 61, 60, and 58, respectively. The registry reports overall enrollment of 309. The arm descriptions do not provide additional detail about treatment procedures.

The registry lists the study as completed. Its recorded start date is 2014-05-15 and its primary completion date is 2016-05-04. These dates describe the registry record and do not establish when results were analyzed or posted.

The stated aims extended beyond the primary endpoint: the study also aimed to evaluate a population pharmacokinetic/pharmacodynamic relationship and assess the interchangeability of menstrual pictogram and alkaline hematin methods for judging menstrual blood loss. Posted secondary outcomes include change in menstrual blood loss per 28 days assessed by the alkaline hematin method, time to onset of controlled bleeding, and change in the volume of the largest fibroid measured by MRI. The registry lists 13 outcome measures, but only three secondary outcomes are named in the posted results. The detailed protocol and the original design assumptions 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: 748 subjects were screened; 439 subjects were not randomized, the majority was screen failures. Therefore, 309 subjects were randomized.

Overall Study

Reasons for not completing this period:

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: Baseline characteristics is reported for the Full Analysis Set/Safety Analysis Set (including all subjects who took at least 1 dose of study drug)

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Amenorrhea, Defined as no Scheduled or Unscheduled Bleeding/Spotting After the End of the Initial Bleeding Episode Until End of Treatment, measured over After end of the initial bleeding episode until the end of treatment, up to 12 weeks.

The primary endpoint was the percentage of subjects with amenorrhea after the end of the initial bleeding episode and through the end of treatment, up to 12 weeks. Amenorrhea was defined as having no scheduled or unscheduled bleeding or spotting during that interval. The endpoint therefore describes the proportion of participants meeting a specified bleeding-status definition; it is not a measure of menstrual blood loss volume or fibroid size.

A percentage endpoint is useful for comparing the frequency of a defined outcome across randomized groups. The registry states that the dose-response curve was estimated from this endpoint and that four parameters describing the curve were reported as other prespecified endpoints. Those parameter results are not included in the results.

In general, a binary endpoint reduces each participant's experience over the defined period to whether the endpoint was met or not. That makes the group proportions straightforward to interpret, but it does not convey the timing or pattern of bleeding episodes beyond the endpoint definition. The registry also lists secondary measures intended to describe menstrual blood loss, time to controlled bleeding, and fibroid volume. Those measures address different aspects of the study question and should not be treated as interchangeable with the primary endpoint.

7. Results Posted in the Registry

• VPR 4 mg: 60.0% (36/60) versus 1.7% (1/58) on control; risk difference 58.3 percentage points (95% CI 45.4 to 71.1), risk ratio 34.80 (4.93–245.57); unadjusted two-proportion z-test p = <0.001.
• VPR 2 mg: 54.1% (33/61) versus 1.7% (1/58) on control; risk difference 52.4 percentage points (95% CI 39.4 to 65.3), risk ratio 31.38 (4.43–222.02); unadjusted two-proportion z-test p = <0.001.
• VPR 1 mg: 55.7% (34/61) versus 1.7% (1/58) on control; risk difference 54.0 percentage points (95% CI 41.1 to 66.9), risk ratio 32.33 (4.57–228.55); unadjusted two-proportion z-test p = <0.001.
• VPR 0.5 mg: 30.0% (18/60) versus 1.7% (1/58) on control; risk difference 28.3 percentage points (95% CI 16.2 to 40.3), risk ratio 17.40 (2.40–126.16); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the percentage measure?

The primary endpoint is binary at the participant level: the endpoint is met when a participant has no scheduled or unscheduled bleeding or spotting after the initial bleeding episode through the end of treatment. The group percentage is the proportion meeting that definition. In general, binary outcomes are often compared by contrasting group proportions. The posted results give the percentage in each group and the number of participants included in each primary-outcome denominator.

The recorded counts were 36 of 60 in VPR 4 mg, 33 of 61 in VPR 2 mg, 34 of 61 in VPR 1 mg, 18 of 60 in VPR 0.5 mg, and 1 of 58 in placebo. Those counts correspond to the posted percentages of 60.0%, 54.1%, 55.7%, 30.0%, and 1.7%, respectively. The registry does not describe whether the denominator represents all randomized participants, participants with evaluable outcome data, or a defined analysis population.

What is a risk difference?

The comparison metric used for the recalculation is the risk difference, which subtracts one group's outcome proportion from the other group's proportion. It expresses an absolute contrast in percentage points. It does not express a relative change, and it should not be confused with a risk ratio or odds ratio. The registry also contains recalculated relative measures, but the sponsor's posted analyses are reported as percentage differences. For the sponsor's comparisons with placebo, the reported point estimates are 58.28, 52.37, 54.01, and 28.28 percentage points for VPR 4 mg, 2 mg, 1 mg, and 0.5 mg, respectively.

What do the confidence intervals and p-values describe?

A confidence interval gives a range of values compatible with the observed data under the method's assumptions. Wider intervals indicate less precision, while narrower intervals indicate greater precision. The sponsor reported 95% confidence intervals for each percentage difference. The intervals are 44.55 to 70.94 for VPR 4 mg, 38.8 to 65.42 for VPR 2 mg, 40.41 to 66.95 for VPR 1 mg, and 15.92 to 41.5 for VPR 0.5 mg. The registry does not name the estimation method used for these intervals.

The recalculated p-values are unadjusted and are reported as p < 0.001 for each dose-versus-placebo comparison. In general, a p-value evaluates the data under a null hypothesis and a specified statistical model. It is not the probability that the null hypothesis is true, nor does it communicate the magnitude or practical importance of an effect. A p-value also does not account for multiple comparisons unless an adjustment is explicitly part of the analysis. Whether an adjustment was part of the sponsor's analysis is not reported in the registry record.

Why distinguish the sponsor analysis from recalculation?

The posted sponsor results use the label “Percentage difference” and include point estimates and 95% confidence intervals. The additional comparisons are simple unadjusted recalculations from the posted group summaries. Their point estimates correspond to the sponsor's reported differences, while the confidence-interval endpoints are not identical. The registry does not identify the sponsor's analysis method, so the difference in intervals cannot be explained from the record. The registry does not flag a discrepancy. The sponsor's reported analysis remains the trial's posted analysis, and the recalculations provide a supplementary summary based on the available group statistics.

What is not specified?

The registry record does not report the statistical model for the sponsor's primary comparison, the method used to construct its confidence intervals, the handling of missing primary-outcome data, or the exact analysis population. It also does not report whether the dose-response analysis adjusted for covariates, how dose was represented in the model, or the estimates for the four curve parameters. These details matter for reproducing the primary analysis and assessing its assumptions. They should not be inferred from the fact that the study was randomized, masked, or described as estimating a dose-response curve.

In general, randomization supports comparison of assigned groups by reducing systematic differences at the time of allocation, while masking can limit some forms of bias in treatment delivery and outcome assessment. Those design features do not by themselves resolve incomplete outcome data, departures from assigned treatment, or multiplicity. How those issues were addressed in this trial is not reported in the registry record.

10. Confidence Intervals and Precision

The sponsor reported 95% confidence intervals for the percentage differences between each active dose group and placebo. The VPR 4 mg estimate was 58.28 percentage points, with an interval from 44.55 to 70.94. For VPR 2 mg, the estimate was 52.37, with an interval from 38.8 to 65.42. For VPR 1 mg, it was 54.01, with an interval from 40.41 to 66.95. For VPR 0.5 mg, it was 28.28, with an interval from 15.92 to 41.5.

Each interval lies above zero, indicating that the sponsor-reported estimates are compatible with a positive absolute difference under the analysis method used. The width of an interval reflects the precision of that estimate: the interval conveys a range of uncertainty rather than a single exact value. The 0.5 mg comparison has a lower point estimate and its interval spans a range of positive differences. The registry does not report a threshold for interpreting the size of these differences, so statistical precision alone cannot establish whether a particular value is important in practice.

The recalculated unadjusted confidence intervals differ slightly from the sponsor's intervals. Because the registry does not state the sponsor's method, the reason for that difference is not reported in the registry record. The registry does not flag a discrepancy, and the sponsor's estimates and intervals remain the posted trial analyses. Neither interval width nor a p-value removes uncertainty about the result's applicability beyond this study population and treatment period.

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 illustrations based on the observed group effect, not the trial's original design calculations. The registry record does not report the trial's own sample-size justification or design assumptions. The planning calculations assume a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They consider detecting the stated fraction of the observed effect.

For each dose-versus-placebo comparison, the entries are participants per arm, not a total across both groups. The columns for 80% and 90% power describe the number of participants per arm estimated to give those respective probabilities of detecting the specified effect under the planning assumptions, if the assumptions and target effect hold. They are not counts from the trial. The illustrations use three effect targets: 100%, 75%, and 50% of the observed effect.

For example, for the VPR 4 mg comparison, planning to detect 50% of the observed effect gives 25 participants per arm for 80% power and 32 participants per arm for 90% power. For VPR 0.5 mg, the corresponding illustration gives 62 participants per arm for 80% power and 83 participants per arm for 90% power. The estimates differ between comparisons because the observed group effects differ. In general, a smaller effect is harder to detect and therefore requires more participants under otherwise unchanged planning assumptions.

These figures are not observed power. They are prospective planning illustrations calculated from observed effects; they do not report the probability that the completed trial's findings are true or the probability that a future study will reproduce them. The dose-response curve is intended to represent the relationship between dose and the endpoint, but the registry does not provide its parameter estimates in the results. The planning figures should not be read as evidence about the exact curve shape.

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 = 0.017; treatment proportion p₁ = 0.600; average p̄ = 0.309.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6533 = 1.2804.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5069 = 0.4266.
4. n = (1.2804 + 0.4266)² / (0.5828)² = 8.6, rounded up to 9 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 <- 0.0172413793103448                          # control proportion
p1 <- 0.6                          # 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(2131662)
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 = 9 (80% power), 11 (90% power)
 75% of observed effect: n per arm = 14 (80% power), 18 (90% power)
 50% of observed effect: n per arm = 25 (80% power), 32 (90% power)
power.prop.test: 8.6 
Simulated power at n = 9 per arm: 0.870 (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. Analyses Reported by the Sponsor

The registry's own analyses report a percentage difference for each active dose versus placebo, along with a 95% confidence interval. The reported differences are 58.28 for VPR 4 mg, 52.37 for VPR 2 mg, 54.01 for VPR 1 mg, and 28.28 for VPR 0.5 mg. The corresponding intervals are also reported in the registry. The sponsor analysis method and p-values are not reported in the registry record.

The recalculated comparisons use the posted group counts and percentages to make simple, unadjusted comparisons. Their point estimates correspond to the sponsor's reported percentage differences, but their confidence-interval endpoints differ slightly from the sponsor's. The registry does not identify the reason for this difference or flag a discrepancy. Accordingly, the sponsor's posted analysis is the trial's formal reported analysis; the recalculation is supplementary and should not be presented as a replacement for the sponsor result.

The recalculated p-values are unadjusted and are reported as p < 0.001 for each dose comparison. They should not be interpreted as the sponsor's p-values: those are not reported in the registry record. The record also does not explain whether the sponsor adjusted for multiple comparisons or used a prespecified testing procedure.

14. Multiplicity, Missing Data and Analysis Populations

The primary outcome is reported for four active dose groups, each compared with placebo. The registry's posted results include four sponsor-reported percentage differences and confidence intervals, and the recalculated comparisons report p < 0.001 for each dose. When several comparisons are assessed, the chance of at least one false-positive result can differ from the chance associated with a single comparison. In general, a prespecified testing strategy or multiplicity adjustment can address that issue.

Whether this trial used an adjustment, a testing hierarchy, or another approach to multiplicity is not reported in the registry record. The sponsor analysis method is not named, and the reported sponsor analyses do not include p-values. The posted recalculated p-values are unadjusted, so they do not account for the set of dose comparisons. The record also says the study estimated a dose-response curve and that four parameters characterizing it were reported in other prespecified endpoints; the results for those parameters are not included in the posted information.

Handling of missing data for the primary endpoint is not reported in the registry record. The primary outcome denominators vary by arm, and the record does not explain the difference between those denominators and overall enrollment, or whether any participants were excluded from the outcome analysis. The analysis population, imputation method, and sensitivity analyses for missing outcomes are not reported in the registry record.

Although the study is described as randomized and quadruple-masked, the registry record does not specify whether the primary analysis followed randomized assignment, was restricted to participants with observed outcomes, or used another analysis population. It also does not report how treatment discontinuation, protocol deviations, or incomplete follow-up were handled. These omissions limit assessment of the robustness of the reported comparisons and make it impossible to reproduce the sponsor analysis from the registry record alone.

15. Safety Results

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

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: uterine leiomyoma (1.7%), pulmonary embolism (1.7%), anaemia (1.7%), alanine aminotransferase increased (1.7%), aspartate aminotransferase increased (1.7%).

The registry reports participants affected by at least one serious adverse event and participants affected by other adverse events, by arm. Serious adverse events were reported for 2 of 60 participants in VPR 4 mg, 4 of 61 in VPR 2 mg, 3 of 61 in VPR 1 mg, 2 of 60 in VPR 0.5 mg, and 2 of 58 in placebo. The “other adverse events” counts were 31 of 60, 30 of 61, 31 of 61, 32 of 60, and 32 of 58, respectively.

These are group-level counts during the trial record's reported safety collection; the registry does not provide further detail on event timing, severity grading beyond the serious-event category, relatedness to treatment, or how recurrent events were counted. The listed serious-event terms include uterine leiomyoma, pulmonary embolism, anaemia, alanine aminotransferase increased, aspartate aminotransferase increased, and breast cancer, each reported as 1.7%. The registry does not provide an arm-by-arm allocation of those terms in the information.

Deaths are not reported in the registry record. These counts describe posted safety observations and do not, by themselves, establish a causal relationship between an event and treatment. Differences in counts should be interpreted with the group denominators and the limited detail available.

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

The primary endpoint results show that the posted percentage of participants meeting the amenorrhea definition was 60.0% for VPR 4 mg, 54.1% for VPR 2 mg, 55.7% for VPR 1 mg, 30.0% for VPR 0.5 mg, and 1.7% for placebo. The sponsor-reported absolute differences versus placebo were positive for all four dose groups, with 95% confidence intervals above zero. These are descriptions of the registered trial outcome and its analysis, not a complete account of every outcome the study intended to assess.

The endpoint captures whether participants met a specific bleeding-status definition during a specified period. It does not report the volume of menstrual blood loss, the timing or number of bleeding episodes outside that definition, or change in fibroid volume. The registry lists secondary outcomes for menstrual blood loss, time to controlled bleeding, and largest fibroid volume, but their results are not reported in the information.

The observed results do not establish an orderly dose-response pattern across all four doses. The registry states that a dose-response curve was estimated, but its curve parameters are not reported in the registry record. The group percentages should therefore be read as observed results at the listed doses rather than as a full characterization of the relationship between dose and outcome.

These data do not establish a general result for people or settings outside the trial, and the registry record does not report the eligibility details or analysis population needed to characterize broader applicability. The safety counts also require cautious interpretation because event-level details and the handling of recurrent events are not reported. The primary endpoint and posted adverse-event counts do not, on their own, summarize every dimension of treatment effect or risk.

17. Why This Trial Matters Statistically

Statistically, this trial is informative because it reports a binary primary outcome across four doses and a placebo group, alongside sponsor-reported absolute comparisons and confidence intervals. Absolute differences in percentages are directly interpretable as percentage-point contrasts. The posted estimates make it possible to distinguish the observed dose-group results rather than collapsing all active treatment into one group.

The results also illustrate why a dose-response question cannot be answered solely by ordering the observed percentages. The percentages for the 1 mg, 2 mg, and 4 mg groups are relatively close in the posted data, while the 0.5 mg result is lower. The registry states that a dose-response curve was estimated, but does not report its parameter estimates. A formal model and its uncertainty would be needed to describe the shape of that relationship from the registry record.

The confidence intervals add information beyond the point estimates by communicating uncertainty in each contrast. The sponsor's intervals are all above zero, but the registry does not report the method behind them, the analysis population, missing-data handling, or multiplicity strategy. Those omissions matter when interpreting several dose comparisons together and when assessing reproducibility.

Finally, the trial illustrates the difference between trial results and planning illustrations. The sample-size calculations use observed effects as planning inputs and describe participant counts under stated assumptions. They do not report the trial's original design rationale or observed power. Keeping those uses distinct avoids treating a retrospective calculation as evidence that the study was originally planned around the same assumptions.

18. 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.

Several trial-specific details needed for a complete statistical assessment are not reported in the registry record. The study's original sample-size justification and design assumptions are not reported, even though the record provides planning illustrations based on observed effects. The sponsor's statistical method for the percentage-difference analyses, the confidence-interval method, and sponsor p-values are also not reported.

The primary endpoint analysis population and missing-data handling are not reported. The record does not explain the relationship between overall enrollment of 309 and the arm-level primary-outcome denominators, nor does it describe exclusions or incomplete follow-up. The protocol details needed to understand the initial bleeding episode, outcome assessment procedures, adherence, and treatment discontinuation are not reported in the registry record.

Although the stated study aims include dose-response estimation and a population pharmacokinetic/pharmacodynamic relationship, the reported dose-response parameter results and pharmacokinetic/pharmacodynamic results are not included in the information. The registry lists 13 outcome measures, but only three secondary outcomes are named in the posted results. Results for the listed secondary outcomes are not reported.

The record also does not state how multiplicity across doses or endpoints was handled. It does not provide a detailed account of adverse-event ascertainment, relatedness, event recurrence, or arm-level distribution of the listed serious-event terms. These limitations restrict independent reproduction and leave important questions about analysis choices and the completeness of outcome reporting unresolved.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Bay1002670, Fibroids, Safety and Efficacy EU,US,Can, Jap — NCT02131662.
• Registry record last updated 2017-12-08; status last verified 2017-11.
• Results first posted 2017-12-08.
• 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.

22. Record Summary

NCT02131662 is a completed, randomized, parallel-group, quadruple-masked, placebo-controlled phase 2 multicenter study of BAY1002670 in subjects with uterine fibroids. The registry reports overall enrollment of 309 and five groups: VPR 4 mg, VPR 2 mg, VPR 1 mg, VPR 0.5 mg, and placebo.

The primary endpoint was the percentage of participants with amenorrhea after the initial bleeding episode through the end of treatment, up to 12 weeks. Posted group percentages ranged from 1.7% in the placebo group to 60.0% in the VPR 4 mg group. The sponsor reported positive percentage differences versus placebo for each dose, with 95% confidence intervals. Recalculated unadjusted comparisons report p < 0.001 for each dose.

The registry also lists secondary outcomes involving menstrual blood loss, time to controlled bleeding, and fibroid volume. Important details about the sponsor's statistical methods, multiplicity, missing-data handling, analysis population, and the trial's original sample-size assumptions are not reported in the registry record.