Menopur Mixed Protocol: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Menopur Mixed Protocol (NCT01417195), a randomized phase 4 study. The primary outcome is Fertilization Rate.

2. Clinical Question

The clinical question is therefore about a comparison of fertilization rates under two stimulation regimens in an ART setting. It is not a comparison of pregnancy or live birth outcomes: those are not identified as the primary outcome in the registry record. The question also has a practical component, since the study aimed to assess mixing and storage of the combined drugs and recorded participant and assessor comprehension questionnaires.

3. Trial Design

This was a completed, phase 4, multicenter, randomized, open-label, parallel-group study. The registry lists 122 participants enrolled. One group received Menopur and Bravelle mixed in the same syringe; the other received Menopur alone. Masking was listed as none, so the study was open-label. The registry record does not report the randomization sequence method, allocation concealment, or the number or location of participating centers.

The primary outcome was fertilization rate, reported as a mean and standard deviation for the intent-to-treat population. Its timeframe was approximately day 13, measured 16-20 hours after insemination by IVF insemination or ICSI. The registry record does not report how many participants contributed outcome data or how missing outcome values were handled.

The combination group received an initial daily dose of 225 IU of gonadotropins mixed in one syringe and administered subcutaneously for 5 days. The initial dose proportions were selected at the investigator's judgment. The combination-arm description includes one option of 150 IU of Menopur and 75 IU of Bravelle, followed by a second option whose wording is incomplete in the registry record. Later dose adjustment details for this group are not reported in the registry record.

The Menopur-alone group received an initial daily dose of 225 IU subcutaneously for 5 days. Dosing adjustments were allowed as of day 6, with daily doses between 150-450 IU and treatment not continuing beyond day 20. The registry lists the study start as 2011-07 and primary completion as 2012-01; its status is completed.

Secondary outcomes included subject comprehension questionnaires on Day 1 and Day 6, assessor questionnaires on Day 1 and Day 6, and participants with treatment-emergent adverse events, including ovarian hyperstimulation syndrome. The registry record does not report the full operational details for these assessments.

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: A total of 122 subjects (60 Menopur/Bravelle, 62 Menopur) entered pituitary down-regulation and were randomized in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent to treat population

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Fertilization Rate, measured over approximately day 13 (16-20 hours post insemination by in vitro fertilization (IVF) insemination or intracytoplasmic sperm injection (ICSI)).

The primary endpoint was fertilization rate, expressed as a percentage of oocytes retrieved. For each participant, the registry defined it as the number of 2 pronuclei (2PN) oocytes divided by the total number of oocytes retrieved, multiplied by 100. The endpoint was assessed approximately day 13, at 16-20 hours after insemination by IVF insemination or ICSI.

As a general statistical concept, a participant-level rate can summarize the proportion of retrieved oocytes that were fertilized for each participant. Comparing the average of those individual rates describes the typical participant's rate as represented by the group mean; it is not necessarily the same as combining all oocytes across participants and calculating one overall proportion. The registry record reports a mean and standard deviation, but does not report details such as the distribution of oocyte counts per participant or a separate analysis weighted by those counts.

Fertilization rate is used in this study as an intermediate laboratory outcome relevant to ART. It directly addresses the stated comparison of the two regimens at fertilization, but it does not by itself describe later outcomes such as pregnancy or live birth. Those outcomes are not identified as the primary endpoint in the registry record. The registry also reports participant comprehension and safety outcomes, which address different aspects of the treatment procedures rather than the primary fertilization-rate comparison.

7. Results Posted in the Registry

• Menopur Alone: mean 59.56 versus 63.14 on control; difference -3.58 (95% CI -11.39 to 4.23), standardized effect d = -0.16; z-test p = 0.369.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents the primary endpoint as a continuous measure summarized by a mean and standard deviation. The reported group summaries are the mean participant-level fertilization rates and the spread of those rates among participants. An unadjusted comparison recalculated from these summaries uses the difference between the two group means. It does not incorporate covariates, stratification variables, or other adjustments unless those are explicitly included in the calculation. The registry record does not report the method used for the sponsor's own analysis.

What does a mean difference represent?

A mean difference describes the distance between two group averages on the outcome's scale. Its sign depends on which group is subtracted from which. The recalculated estimate is Menopur alone minus Menopur and Bravelle, while the registry's reported estimate is oriented in the reverse direction. Therefore, opposite signs do not by themselves indicate disagreement about the underlying comparison. The numerical estimate and its confidence interval need to be read alongside the stated group order and endpoint definition.

The unadjusted recalculated mean difference is -3.58, and its 95% confidence interval ranges from -11.39 to 4.233. The interval describes a range of values compatible with the data under the method's assumptions. As a general explanation, a confidence interval is not a guarantee that the true value lies within the particular interval, nor does it assign a probability to each value inside it. Its width conveys precision: a wider interval leaves more uncertainty about the size and direction of the difference. The unadjusted p-value is 0.369. As a general statistical concept, a p-value measures how unusual data at least as inconsistent with a specified null model would be if that model and the test assumptions held. It is not the probability that the null hypothesis is true.

Why can variation matter?

The standard deviations, 21.57 and 22.46, describe the spread in participant-level fertilization rates within each group. A mean difference is interpreted in the context of that variability and the number of observations. A standard error represents uncertainty in an estimated mean or contrast, whereas a standard deviation describes variation among observations. The recalculation gives standard errors of 2.784 and 2.852 for the two group means. These standard errors are not themselves measures of participant-to-participant variability.

As a general concept, over-dispersion occurs when data vary more than a chosen statistical model expects. If present, it can make standard errors too small when the model fails to account for the extra variation, leading to intervals that are too narrow and tests that are too optimistic. Whether over-dispersion is relevant depends on the model and data structure. The registry record does not report a distributional model, diagnostic checks, or a method for assessing over-dispersion. The endpoint is a participant-level percentage derived from counts of oocytes, and the record does not provide participant-level counts or results that would allow readers to assess its distribution.

What does the registry's analysis label tell us?

The posted sponsor analysis is categorized as non-inferiority or equivalence and reports a final-values mean difference of 3.6, with a 95% confidence interval from -4.3 to 11.5. General statistical practice distinguishes these questions from a conventional test for any difference. An equivalence analysis asks whether an interval falls within prespecified bounds around no difference. A non-inferiority analysis asks whether the data rule out a difference worse than a prespecified margin in a particular direction. The margin, direction, analysis method, and decision rule are not reported in the registry record. Since an interval that includes zero does not itself demonstrate equivalence, the classification cannot be fully evaluated from the posted information alone.

The two sets of estimates also differ in reported precision and presentation. The recalculation is a simple unadjusted comparison from posted summary statistics; the sponsor's result is identified as a final-values analysis, but its computational details are not reported. Small differences between estimates or intervals can arise from analysis choices, rounding, or the specific data analyzed. The registry record does not supply enough detail to determine which explanation applies. The discrepancy flag is false, and the sponsor's own analysis takes precedence only when that flag is true; no such precedence condition is indicated for this record.

What are the assumptions behind the recalculation?

A recalculation from group means and standard deviations is necessarily limited to the available summaries. It cannot adjust for participant characteristics, investigate outliers, handle missing observations in a tailored way, or examine how results vary across subgroups. It also does not recreate a participant-level model or the sponsor's analysis. The registry identifies the intent-to-treat population for the endpoint, but does not report whether the posted group counts represent all randomized participants or only those with measured values.

Randomization is important because, in expectation, it balances measured and unmeasured baseline characteristics across groups. That general principle does not establish that every characteristic was balanced in this particular study. Baseline data and details of randomization implementation are not reported in the registry record. The open-label design is also relevant context, although the primary endpoint is a laboratory rate rather than a self-reported outcome. The registry does not report whether outcome assessment or laboratory procedures were masked.

Statistical significance, precision, and clinical meaning are separate considerations. A p-value addresses compatibility with a statistical null model, a confidence interval displays uncertainty about an estimated contrast, and clinical interpretation requires context about meaningful differences. The registry record does not report a threshold for a clinically important difference in fertilization rate. Accordingly, neither a p-value nor the non-inferiority or equivalence label alone resolves the clinical meaning of the estimate.

10. Confidence Intervals and Precision

The recalculated mean difference is -3.58 for Menopur alone minus the combination group, with a 95% confidence interval from -11.39 to 4.233. The interval includes zero and extends across negative and positive values. This means that the posted estimate is not precise enough to determine the direction of the difference from the interval alone. It also leaves uncertainty about the magnitude of any difference in either direction.

The registry's own final-values analysis reports a mean difference of 3.6, with a 95% confidence interval from -4.3 to 11.5. That interval also includes zero. Its direction is opposite to the recalculation's stated contrast, so interpretation requires attention to which group is subtracted from which. The record does not report the sponsor's analysis method or explain the interval's computation.

As a general explanation, a confidence interval is a measure of statistical uncertainty around an estimate, conditional on the method and its assumptions. Greater precision is generally reflected in a narrower interval. A confidence interval does not show the range of individual participant outcomes, and it does not establish that every value within it is equally plausible. The group standard deviations describe participant-level spread; they are distinct from the confidence intervals around the group contrast.

The registry record does not report a threshold for a clinically important difference, nor does it report the margin required to assess non-inferiority or equivalence. Without such context, the interval can be described statistically but cannot be used to determine whether the range of differences would be important for a clinical decision. The posted information also does not permit a detailed assessment of how missing endpoint data or analysis choices might affect precision.

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 sample-size figures are planning illustrations based on the observed effect, not the trial's original design assumptions. The trial's own sample-size justification and design assumptions are not reported in the registry record. The figures are participants per arm, not total events: this is a continuous endpoint, and the planning method assumes equal allocation between two arms.

The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. The row for 100% of the observed effect gives 595 participants per arm for 80% power and 796 participants per arm for 90% power. Planning for 75% of the observed effect gives 1,057 participants per arm for 80% power and 1,415 participants per arm for 90% power. Planning for 50% of the observed effect gives 2,377 participants per arm for 80% power and 3,182 participants per arm for 90% power.

In plain language, the 80% power column gives the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions. The 90% column gives the corresponding number for a design with a 90% chance. These are prospective planning quantities, not a measure of the probability that the observed study result is correct. This is not observed power.

Smaller effects are harder to distinguish from random variation, so the illustration requires more participants per arm when the target effect is reduced from 100% to 75% or 50% of the observed effect. The figures rely on the observed contrast as their starting point; they should not be read as a sample-size recommendation without considering the intended question, outcome assumptions, and design details, which are not reported in the registry record.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -3.580; pooled standard deviation σ = 22.025.
2. n = 2 × (1.96 + 0.842)² × 22.025² / -3.580² = 594.2, rounded up to 595 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 <- -3.58                      # observed difference in means
sigma <- 22.0254665957008                     # 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(1417195)
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 = 595 (80% power), 796 (90% power)
 75% of observed effect: n per arm = 1,057 (80% power), 1,415 (90% power)
 50% of observed effect: n per arm = 2,377 (80% power), 3,182 (90% power)
power.t.test: 595.1 
Simulated power at n = 595 per arm: 0.799 (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.

13. Analyses Reported by the Sponsor

The registry reports the sponsor's final-values mean difference as 3.6, with a 95% confidence interval from -4.3 to 11.5. It labels the result as a non-inferiority or equivalence analysis. The unadjusted recalculation from the posted group summaries is -3.58, with a 95% confidence interval from -11.39 to 4.233. The estimates use opposite contrast directions: the recalculation is Menopur alone minus the combination group, whereas the sponsor's reported positive estimate is presented in the reverse direction. The signs therefore should not be compared without aligning the group order.

The recalculated result is a simple unadjusted calculation from the posted means and standard deviations. The sponsor result is identified as a final-values analysis, but the registry record does not report its statistical method, adjustment strategy, handling of missing values, or p-value. The registry's analysis label also does not include the non-inferiority or equivalence margin. Those details are necessary to assess how the sponsor reached its interpretation.

The discrepancy indicator is false, so the special precedence rule for a discrepancy does not apply. The sponsor's analysis remains the registry's reported analysis; the recalculation is best understood as a supplementary summary-based comparison rather than a replacement for the sponsor's method. Because the reported confidence intervals include zero and the relevant analysis details and margins are not reported, the registry information alone does not establish an equivalence or non-inferiority conclusion.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists five secondary outcomes: subject comprehension questionnaires on Day 1 and Day 6, assessor questionnaires on Day 1 and Day 6, and participants with treatment-emergent adverse events, including ovarian hyperstimulation syndrome. It also lists the primary fertilization-rate outcome. The registry record does not report whether all planned secondary outcomes were analyzed or whether additional outcomes were prespecified.

When a study tests several outcomes or makes several comparisons, the chance of obtaining at least one apparently notable result can increase. As a general statistical concept, multiplicity procedures can address this by adjusting inference or by defining a hierarchy of outcomes. The registry record does not report a multiplicity adjustment, a testing hierarchy, or a statistical analysis plan. The number of posted analyses is one, but that count does not establish that only one statistical test was conducted or that multiplicity was not relevant.

The primary outcome is identified for the intent-to-treat population. The registry record does not report the number of participants with observed fertilization-rate data, how missing values were handled, whether participants were excluded from the analysis, or whether sensitivity analyses were performed. It also does not report a detailed analysis population definition beyond the intent-to-treat label. These omissions limit assessment of whether the outcome comparison retained the intended randomized groups and how incomplete data may have affected the result.

Randomization and open-label status are reported, but sequence generation and allocation concealment are not reported in the registry record. The record also does not report a statistical model, covariate adjustments, subgroup analyses, or the sponsor's method for the final-values contrast. For the non-inferiority or equivalence classification, the margin and decision rules are not reported. These missing details matter because interpretation depends not only on the estimate but also on which analyses were planned, how data were handled, and what thresholds were prespecified.

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 2% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures show 0 affected participants among 60 at risk in the Menopur and Bravelle combination group and 0 among 62 at risk in the Menopur-alone group. The registry lists no serious adverse event terms. These figures describe the recorded serious adverse events for the groups; they do not establish that the risk of serious events is zero or that the groups have identical safety profiles.

The registry also reports participants with other treatment-emergent adverse events: 29 of 60 in the combination group and 30 of 62 in the Menopur-alone group. These are counts of participants affected, not event counts or rates. The registry record does not report the event types in this summary, the severity distribution, or the timing of the events. Death counts are not reported in the registry record.

As a general statistical consideration, an absence of observed serious events in a study does not rule out events that could occur in a larger population or over a different period of observation. Safety interpretation also depends on completeness of reporting, definitions, follow-up, and exposure. The registry record does not report those details sufficiently for a fuller comparison. The figures should therefore be read as the recorded counts in this study, not as a general estimate of comparative safety.

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

The posted results describe mean participant-level fertilization rates of 63.14 for the Menopur and Bravelle combination group and 59.56 for the Menopur-alone group. The unadjusted recalculation gives a mean difference of -3.58 when expressed as Menopur alone minus the combination, with a 95% confidence interval from -11.39 to 4.233 and an unadjusted p-value of 0.369. These numbers summarize the observed groups and the uncertainty in the estimated contrast; they do not establish that the groups are identical.

The registry's own analysis reports a mean difference of 3.6, with a 95% confidence interval from -4.3 to 11.5, and labels it as non-inferiority or equivalence. The positive sign reflects the opposite contrast direction from the recalculation. The registry record does not report the margin or decision rule needed to evaluate that label. An interval that includes zero is not, by itself, evidence of equivalence: equivalence depends on whether the interval is contained within prespecified bounds.

The primary endpoint concerns fertilization at an early laboratory stage of ART. It does not answer whether the groups differ in later outcomes such as pregnancy or live birth; those outcomes are not identified as primary in the registry record. The study also aimed to assess mixing and storage, participant comprehension, assessor comprehension, and adverse events, but the available summary does not provide complete detail for each of these questions.

The results apply to the participants and procedures represented in this completed randomized, open-label study. The registry lists 122 participants enrolled, and the primary outcome population is identified as intent to treat. Participant characteristics, missing-data handling, and full analysis methods are not reported in the registry record. Thus, the estimate should be interpreted with its stated uncertainty and the limitations of the available reporting. It does not establish a treatment recommendation or demonstrate that one regimen is preferable.

17. Why This Trial Matters Statistically

This study illustrates how a clinical comparison can have a clear endpoint and randomized design while still leaving important statistical questions unanswered in the registry record. The endpoint is explicitly defined as a participant-level fertilization rate, and the groups are reported with means, standard deviations, and sample sizes. That allows readers to understand the scale of the outcome and the broad degree of variability represented by the summaries.

It also illustrates why contrast direction matters. The sponsor's reported mean difference is 3.6, while the unadjusted recalculation is -3.58 because it expresses the comparison in the reverse order. A sign is meaningful only together with the specified group order. Confidence intervals add information beyond the point estimate by showing how much uncertainty remains, while a p-value alone cannot show the likely range of effect sizes or prove equality.

The non-inferiority or equivalence label makes the missing analysis details especially relevant. A margin and a prespecified decision rule are central to those designs, but the registry record does not report them. The label cannot be evaluated from a point estimate alone, and an interval that includes zero does not automatically demonstrate equivalence.

Finally, the planning illustration shows how sample-size requirements depend on the target effect and desired power under stated assumptions. Its figures are not the original design rationale and are not observed power. Together, these points demonstrate the value of reporting the statistical plan, missing-data methods, analysis populations, and clinically meaningful thresholds alongside the outcome estimates.

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.

The registry record provides limited information for judging how representative the enrolled participants were. It identifies infertility and ART but does not report detailed eligibility criteria, baseline characteristics, or the number and location of centers. The open-label design is recorded, while masking of outcome assessment and laboratory procedures is not reported in the registry record.

The combination-arm description is incomplete for one of the investigator-selected dose options. It also does not report later dose-adjustment details for that arm. The Menopur-alone arm description gives initial dosing and later dose limits, but details about adherence and actual treatment exposure are not reported. These gaps limit a detailed comparison of how the protocols were implemented.

For the primary endpoint, the registry identifies the intent-to-treat population and gives group summaries, but does not report the number with measured outcomes, the handling of missing data, participant-level distributions, or a complete statistical analysis method. The sponsor's analysis is labeled non-inferiority or equivalence, but the margin, decision rule, and method are not reported. The registry record does not report a clinically important difference threshold for fertilization rate.

The posted safety summary gives counts of participants with serious and other treatment-emergent adverse events, but it does not provide full event descriptions, exposure-adjusted summaries, or detail on completeness of follow-up. The record also does not report a multiplicity strategy for the listed secondary outcomes. These limitations do not invalidate the reported figures, but they constrain how comprehensively the outcome, safety, and analysis results can be evaluated.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Menopur Mixed Protocol — NCT01417195.
• Registry record last updated 2014-05-16; status last verified 2014-05.
• Results first posted 2014-04-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

The registry describes a completed, phase 4, multicenter, randomized, open-label, parallel-group study of Menopur and Bravelle mixed in one syringe versus Menopur alone in participants undergoing ART for infertility. Enrollment was 122. The primary outcome was mean fertilization rate, defined from each participant's fertilized 2PN oocytes and total oocytes retrieved, and assessed approximately day 13.

The combination group had a reported mean of 63.14 and standard deviation of 21.57 among 60 participants; the Menopur-alone group had a mean of 59.56 and standard deviation of 22.46 among 62 participants. The recalculated unadjusted contrast and the registry's reported final-values analysis are presented in opposite directions. The registry labels its analysis as non-inferiority or equivalence, but the margin and method are not reported. The record also lists comprehension and safety outcomes, with no serious adverse events recorded in either group in the posted safety summary.