Efficacy and Tolerability of Human FSH Versus Recombinant FSH (Follitropin Alpha) in ICSI.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Tolerability of Human FSH Versus Recombinant FSH (Follitropin Alpha) in ICSI. (NCT00335725), a randomized phase 3 study. The primary outcome is Total Number of Oocytes Retrieved.

2. Clinical Question

This is a comparison of two FSH preparations within an ICSI setting, not a comparison of ICSI with another fertility procedure. The primary question concerns the number of oocytes retrieved, a continuous outcome recorded as a mean and standard deviation for each group. The registry also names clinical pregnancy rate as a secondary outcome, but a result for that outcome is not reported in the registry record. The clinical question is therefore narrower than a comparison of all possible outcomes relating to treatment, pregnancy, or tolerability. The record describes the study as prospective, randomized, controlled, and multicentric, and identifies it as phase 3. It does not report the allocation procedure in more detail or explain which people, if any, were masked. The outcome comparison can describe the posted group averages and their uncertainty; by itself, it does not establish what accounts for any difference or answer questions about outcomes that were not reported.

3. Trial Design

The registry describes a prospective, randomized, controlled, multicentric phase 3 study with a parallel-group model and single masking. It lists infertility as the condition and ICSI as the treatment setting. The study title frames the comparison as urinary FSH (Fostimon) versus recombinant FSH (Gonal-F), and the brief summary specifies subcutaneous administration. The registry does not report who was masked, how randomization was carried out, or whether any additional procedures were used to maintain masking.

Enrollment was 151. The posted outcome record gives 73 participants for Fostimon and 72 for Gonal-F for the primary outcome. These are the group counts recorded for that outcome; further details about participant flow, exclusions, or missing measurements are not reported in the registry record. The primary outcome population is described as patients who started stimulation with FSH.

The study began in 2003-03, had primary completion in 2005-12, and is listed as completed. The primary outcome was total number of oocytes retrieved, assessed 10 days after stimulation start. Clinical pregnancy rate is listed as a secondary outcome. Results for that secondary outcome are not reported in the registry record. The record names IBSA Institut Biochimique SA as sponsor. It does not report the trial’s original sample-size assumptions, detailed statistical analysis plan, or any interim analysis procedures.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: patients who started the stimulation with FSH

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 Total Number of Oocytes Retrieved, measured over 10 days after stimulation start.

The primary endpoint is the total number of oocytes retrieved, measured 10 days after stimulation start. The outcome description specifies patients who started stimulation with FSH as the population. The registry reports the endpoint as a mean with a standard deviation in each group, which treats the count as a continuous measure for this comparison. The posted mean was 10.9 oocytes in the Fostimon group and 12.0 oocytes in the Gonal-F group; the corresponding standard deviations were 4.9 and 5.6.

Oocyte retrieval is used as a direct measure of the number of oocytes obtained during the stimulation and ICSI treatment process. Comparing group means gives a concise description of the average outcome in each randomized group. The spread around each mean matters too: individual participants’ counts can vary, and the standard deviation describes that variability within a group. A mean comparison does not show the full distribution of counts, nor does it give a result for every participant. It also does not stand in for the secondary outcome of clinical pregnancy rate. The registry record does not report a result for that secondary outcome or further details about how the endpoint was measured beyond its description and timeframe.

7. Results Posted in the Registry

• Gonal-f: mean 12.00 versus 10.90 on control; difference 1.10 (95% CI -0.61 to 2.81), standardized effect d = 0.21; z-test p = 0.208.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous in the registry’s statistical classification and is summarized with a mean and standard deviation. A mean describes the average observed number of oocytes in a group. A standard deviation describes how dispersed individual observations are around that group average. It is not the uncertainty in the mean difference; that uncertainty is represented by the interval for the comparison.

What does the mean difference describe?

The comparison is expressed as a mean difference for Gonal-F relative to Fostimon. The estimate is 1.1 oocytes, with group means of 12.0 for Gonal-F and 10.9 for Fostimon. A mean difference retains the measurement scale of the outcome, so it can be read in oocytes rather than as a standardized unit. Its direction depends on the order of the groups in the comparison. Here, the posted estimate is positive and the Gonal-F mean is higher.

The estimate is a summary of the observed group averages, not a guarantee that an individual participant would have more oocytes with one preparation than another. It also does not describe how many participants had values above or below either mean. Those details would require participant-level distributions, which are not reported in the registry record.

What does the interval add?

A confidence interval is a range of values compatible with the observed data and the statistical procedure used to calculate it. It expresses uncertainty about the estimated mean difference; it is not a range containing a specified proportion of individual participants’ results. The reported interval for this comparison spans zero. Zero represents no difference in the group means on the outcome scale. Because the interval reaches values on both sides of zero, the data are compatible with different directions of the mean difference as well as with no mean difference. The registry record does not state the confidence level for the reported interval, so no confidence percentage is assigned.

How should the p-value be read?

The unadjusted p-value is 0.208. A p-value describes how unusual the observed data, or data more extreme, would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. The record does not report a threshold for statistical significance or whether the p-value was adjusted for multiple comparisons. It should therefore be considered alongside the estimate and interval, rather than as a stand-alone verdict.

What is standard deviation useful for?

The standard deviations are 4.9 for Fostimon and 5.6 for Gonal-F. In general, standard deviation gives a sense of how much observations vary around the mean. Greater variation can make a group average less precisely estimated when the number of observations is limited. The standard deviation is distinct from a standard error, which describes uncertainty in an estimate such as a group mean. The registry lists standard errors in its calculation details, but those values are not needed to interpret the group-level result.

Why might count data require care?

Oocyte counts are non-negative whole-number counts at the participant level. A mean-based comparison can be a useful summary, but count outcomes can have distributions that are skewed or more variable than a simple model expects. In general, over-dispersion means that variability is greater than a model’s assumed level; if present and not accounted for, it can affect standard errors and uncertainty estimates. The registry record does not report a distributional assessment, an over-dispersion assessment, or a model specification for the primary comparison. It is therefore not possible to assess from the record whether the analysis addressed those features of count data.

The record reports a pooled standard deviation and a standardized effect calculation as part of its planning illustrations. In general, a standardized effect expresses a difference relative to a measure of variability, which can help compare effects measured on different scales. It is less directly interpretable in clinical units than the mean difference. The registry does not report that this standardized quantity was the primary trial analysis.

Finally, the registry lists zero posted analyses. That entry describes what is available in the registry record; it does not establish that investigators conducted no analyses. The detailed statistical plan, including the model used for the primary outcome and any adjusted analyses, is not reported in the registry record. The posted means, mean difference, interval, and unadjusted p-value should be interpreted within those limits.

10. Confidence Intervals and Precision

The estimated mean difference was 1.1 oocytes for Gonal-F compared with Fostimon. The interval reported for this estimate extends below zero and above zero. That span is important: it indicates that the observed data do not pin down the direction of the underlying mean difference with precision. The interval includes values compatible with a lower mean in Gonal-F, no difference, and a higher mean in Gonal-F, without establishing which is most plausible.

Precision is about how narrowly an estimate is determined by the data and statistical procedure. It is separate from the size of the point estimate. A point estimate can be positive while its interval covers zero, as it does for this comparison. The unadjusted p-value of 0.208 is consistent with the same general reading: the result does not sharply distinguish the group averages in this dataset. Neither the interval nor the p-value says that the treatments are equivalent.

The group standard deviations were 4.9 and 5.6, indicating that observations varied around the group means. The interval’s width reflects uncertainty in the comparison, which depends on the observed variability and the amount of information available, as well as on the analysis method. The registry record does not state the interval’s confidence level or provide a detailed statistical model, so precision should be described using the reported interval’s relation to zero rather than a confidence percentage or model-specific interpretation.

The estimate also has a practical scale: it is measured in oocytes. However, the registry record does not report a threshold for a meaningful difference, so statistical precision cannot by itself determine the importance of the estimated difference. A more precise estimate would still need to be interpreted in light of the clinical question and other outcomes, including the secondary outcome whose result is not reported in the registry record.

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 participants per arm, not total events. They are illustrative calculations based on the observed mean difference, not the trial’s original design assumptions. The stated 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 trial’s own original sample-size assumptions are not reported in the registry record.

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, if that effect is real and the model assumptions apply. The 90% power column gives the corresponding planning target for a design with a 90% chance under those same assumptions. These are design probabilities, not probabilities that the observed result is correct. The figures are not observed power.

The planning entries are 359 participants per arm for 80% power and 481 for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the figures are 638 participants per arm for 80% power and 855 for 90% power. For 50% of the observed effect, they are 1,436 participants per arm for 80% power and 1,922 for 90% power.

The pattern reflects a general planning principle: smaller effects are harder to distinguish from random variation, so they require more participants to achieve the same target power under otherwise unchanged assumptions. These figures are planning illustrations based on the observed effect, not evidence about the power the completed trial actually had. The curve should be read in that same planning context, rather than as another outcome from the trial.

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 = 1.100; pooled standard deviation σ = 5.259.
2. n = 2 × (1.96 + 0.842)² × 5.259² / 1.100² = 358.8, rounded up to 359 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 <- 1.1                      # observed difference in means
sigma <- 5.25921103391951                     # 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(335725)
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 = 359 (80% power), 481 (90% power)
 75% of observed effect: n per arm = 638 (80% power), 855 (90% power)
 50% of observed effect: n per arm = 1,436 (80% power), 1,922 (90% power)
power.t.test: 359.8 
Simulated power at n = 359 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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists total number of oocytes retrieved as the primary outcome and clinical pregnancy rate as a secondary outcome. It does not report a result for the secondary outcome. Although the record identifies two outcome measures, the registry does not give a detailed account of how many hypotheses were tested, which analyses were considered confirmatory, or whether any adjustment was made for multiple comparisons.

Multiplicity arises when several outcomes, comparisons, time points, or analyses are examined. In general, making many statistical tests can increase the chance of at least one apparently unusual result even when there is no underlying effect. Methods for controlling that issue depend on the analysis plan and the questions considered primary. The registry record does not report a multiplicity strategy, so it is not possible to determine whether or how multiplicity was addressed. The posted p-value is identified as unadjusted.

Missing-data handling is also not reported in the registry record. The record does not describe whether primary outcome measurements were missing, how missing values were handled, or whether any sensitivity analyses were conducted. The outcome population is described as patients who started stimulation with FSH, but the record does not provide further definitions of the analysis population or explain how participants were handled after starting stimulation.

The registry entry lists zero analyses, which should be read as the number of analyses posted in the registry record, not as proof that no analyses were performed. A statistical analysis plan, any interim analyses, and details of adjusted or subgroup analyses are not reported in the registry record. These omissions limit assessment of how the posted result relates to the complete set of planned and conducted analyses.

14. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ohss (5.6%), spontaneous abortion (1.4%), ectopic pregnancy (1.4%).

For serious adverse events, the registry reports 2 affected participants among 73 at risk in the Fostimon group and 5 among 72 at risk in the Gonal-F group. For other adverse events, it reports 3 affected participants among 73 at risk in the Fostimon group and 3 among 72 at risk in the Gonal-F group. These are the posted counts and denominators; they should be read as group-specific reported figures, not as a comparison adjusted for differences in participant characteristics or follow-up.

The registry lists OHSS at 5.6%, spontaneous abortion at 1.4%, and ectopic pregnancy at 1.4% among the top serious event terms. The record does not clarify in this summary how those terms map to the group-level affected-participant counts, and the listed terms should not be treated as a complete account of all events. Death counts are not reported in the registry record.

Adverse-event counts are descriptive safety information. The registry record does not provide further details about event definitions, severity grading, relatedness assessments, or the duration of safety follow-up. These figures alone do not establish a causal relationship between a preparation and an event.

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

The primary result is an estimated difference in average oocyte retrieval between the two randomized groups. The observed mean was 10.9 oocytes with Fostimon and 12.0 with Gonal-F, and the reported mean difference was 1.1 oocytes for Gonal-F compared with Fostimon. The interval crosses zero, and the unadjusted p-value is 0.208. These results describe an uncertain difference in group averages rather than a precise separation between the preparations.

The result does not establish that the average outcomes are identical. An interval that includes zero leaves room for a range of possible differences, including differences in either direction. Nor does the point estimate alone demonstrate a meaningful benefit: the registry record does not define what size of difference would matter clinically. The result also does not predict the outcome for an individual patient.

The endpoint is the number of oocytes retrieved after stimulation, not a pregnancy or live-birth outcome. Clinical pregnancy rate is named as a secondary outcome, but its result is not reported in the registry record. The primary result therefore cannot be used to draw conclusions about that secondary outcome. It also cannot settle broader questions about tolerability, because the adverse-event summary does not provide detailed definitions, follow-up, or event-level context.

Randomization and the parallel-group design are relevant features of the comparison, but important design and analysis details are absent from the registry record. The record does not describe the masking procedure, detailed eligibility criteria, missing-data methods, or the statistical model. The most defensible reading is consequently limited to the posted group summaries and their uncertainty for this primary endpoint. No medical recommendation follows from these statistics alone.

16. Why This Trial Matters Statistically

This trial illustrates why an estimated difference, its uncertainty, and the outcome being measured should be considered together. The group means differ, and the posted estimate is expressed in the clinical unit of oocytes. At the same time, the reported interval crosses zero and the unadjusted p-value is 0.208. Looking only at the positive point estimate would miss the uncertainty; looking only at the p-value would discard the direction and scale of the estimate.

The endpoint also highlights the distinction between an intermediate treatment outcome and a broader clinical outcome. The registry’s primary measure is oocyte retrieval, while clinical pregnancy rate is listed as secondary. Since the secondary result is not reported in the registry record, the available primary comparison cannot answer the pregnancy-outcome question. Keeping the endpoint clear prevents a statistical result for one measure from being overstated as evidence about another.

The planning illustrations offer a separate statistical lesson. Their required participant counts rise as the target effect becomes smaller, under the stated assumptions. That relationship is useful for understanding how effect size influences study planning, but the calculations are not evidence about the original design or the completed trial’s observed power. The record does not report the original sample-size justification.

Finally, the record’s limited reporting demonstrates why registry results should be interpreted with attention to missing methods and outcomes. The randomized design is documented, but details of masking, missing-data handling, multiplicity, and the full analysis plan are not. Statistical interpretation depends not only on the numerical estimate but also on how the outcome was defined and analyzed.

17. 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 gives limited detail about the conduct and analysis of the trial. It identifies the study as randomized, single-masked, prospective, multicentric, and parallel-group, but does not say who was masked, how allocation was generated or concealed, or how masking was maintained. Those details are not reported in the registry record.

The primary outcome is described for patients who started stimulation with FSH. Further participant-flow information, eligibility criteria, baseline characteristics, and details about missing outcome measurements are not reported. The record does not explain whether all randomized participants contributed to the posted outcome comparison or how any missing data were handled.

The registry reports a mean-based result for a count outcome but does not give a detailed model specification or a description of checks on the outcome distribution. It does not report the confidence level for the interval, a multiplicity strategy, subgroup analyses, or interim analyses. The trial’s original sample-size assumptions and justification are also not reported in the registry record.

Clinical pregnancy rate is listed as a secondary outcome, but its result is not reported in the registry record. Safety information is brief: event definitions, relatedness, severity, follow-up duration, and the relationship between the listed serious event terms and the group counts are not detailed. These limitations restrict conclusions to the reported primary outcome summaries and the limited adverse-event figures, rather than a comprehensive assessment of all outcomes or methods.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Tolerability of Human FSH Versus Recombinant FSH (Follitropin Alpha) in ICSI. — NCT00335725.
• Registry record last updated 2015-03-27; status last verified 2015-03.
• Results first posted 2015-03-27.
• 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.

21. Record Summary

NCT00335725 is a completed phase 3 randomized, controlled study comparing Fostimon, a highly purified urinary FSH preparation, with Gonal-F, a recombinant FSH preparation, in patients undergoing ICSI. The registry describes a prospective, multicentric, parallel-group study with single masking. Enrollment was 151, and the record names IBSA Institut Biochimique SA as sponsor.

The primary outcome was total number of oocytes retrieved 10 days after stimulation start. The posted means were 10.9 for Fostimon and 12.0 for Gonal-F, with a reported mean difference of 1.1 and an unadjusted p-value of 0.208. The reported interval crosses zero. Clinical pregnancy rate is listed as a secondary outcome, but its result is not reported in the registry record. The study began in 2003-03 and had primary completion in 2005-12.