Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia (NCT00001521), a randomized phase 3 study. The primary outcome is Adult Height Relative to General Population.

2. Clinical Question

The trial concerned growth in children with CAH, a condition identified in the registry as the reason for studying the treatment strategies. The investigational regimen was designed around several drugs and a reduced hydrocortisone dose, while the comparator used conventional hydrocortisone and fludrocortisone therapy. The registry summary describes different planned treatment transitions for boys and girls in the investigational group, with follow-up continuing to adult height. Those transitions are part of the summarized study approach, but they do not change the primary comparison reported for the outcome population.

The primary endpoint asks about adult height relative to a general-population reference, rather than a short-term change in growth or a laboratory measure. That makes the question inherently long-term: the record gives an average follow-up timeframe of 11 years from randomization for attainment of adult height. The reported primary comparison therefore concerns the recorded outcome among participants included in the modified intention-to-treat population, not necessarily every randomized child. The complete flow of participants between randomization, follow-up, and endpoint analysis is not reported in the registry record.

3. Trial Design

The registry identifies this as a Phase 3, randomized, parallel-group trial with no masking. It reports an enrollment of 66 and a completed status. The comparison assigned children to investigational therapy or standard therapy. As an open trial, participants and study staff were not masked to treatment assignment; the registry does not report whether endpoint assessors were masked.

The registry summary describes the investigation as a long-term study of children with CAH, following participants to adult height. The posted primary outcome timeframe is attainment of adult height, with an average of 11 years from randomization. Adult height was defined as growth of less than 1.5 cm over 12 months. The record also lists the start date as 1995-06-08 and primary completion date as 2024-04-01. Those dates and the long follow-up timeframe are consistent with an outcome that requires observation through growth, but the registry does not give additional details about visit schedules or follow-up procedures.

The investigational arm description names flutamide and an aromatase inhibitor—testolactone or letrozole—alongside low-dose hydrocortisone. The registry summary also describes fludrocortisone as part of the four-drug combination. The standard arm description names hydrocortisone and fludrocortisone. Exact dosing for the investigational regimen is not fully reported in the registry record because that arm description is incomplete. For standard therapy, the record gives hydrocortisone as approximately 10-15 mg/m²/day orally, not exceeding 25mg/m, but the final unit text is truncated.

The primary endpoint population was modified intention-to-treat and included participants reassigned from investigational to standard therapy due to drug intolerance. The number randomized to each arm, the full participant disposition, and reasons for any other exclusions or missing outcomes are not reported in the registry record. Enrollment should therefore not be treated as the number contributing to the adult-height comparison.

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: 66 participants were consented, two participants withdrew prior to randomization and two were compassionate exemption so were not randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified intention-to-treat population, includes patients who were reassigned from investigational to standard therapy due to drug intolerance.

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 Adult Height Relative to General Population, measured over Followed to attainment of adult height, average of 11 years from date of randomization.

The primary endpoint is adult height expressed in standard deviation score (SDS) units relative to the general population. An SDS expresses a measurement in relation to a reference distribution: values indicate how far the observed height lies from the reference population average, in standard deviation units. The registry states that adult height SDS was based on National Health and Nutrition Examination Survey data from the Centers for Disease Control and Prevention and the National Center for Health Statistics, using the reference at 20 years old.

The endpoint is intended to capture attained stature, rather than growth at a particular visit. Adult height was defined as an incremental growth of less than 1.5 cm over 12 months, and participants were followed to attainment of that endpoint. The reported timeframe is an average of 11 years from randomization. This long-term measure fits the study’s stated interest in growth through final adult height, and it makes the endpoint distinct from the listed secondary measures such as predicted adult height, growth velocity, bone-age measures, and BMI.

The reported endpoint parameter is a mean with standard deviation. The population is modified intention-to-treat, including participants who moved from investigational to standard therapy because of drug intolerance. Thus the result is an average comparison for that defined population, not an individual prediction of adult height. The registry does not report a prespecified clinically important difference in SDS units, so statistical uncertainty should not be confused with a threshold for clinical importance.

7. Results Posted in the Registry

• Investigational Therapy: mean -0.34 versus -0.60 on control; difference 0.26 (95% CI -0.29 to 0.81), standardized effect d = 0.29; z-test p = 0.350.

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.

Number of Participants With Onset of Early Central Puberty

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Investigational Therapy: 75.0% (12/16) versus 37.5% (9/24) on control; risk difference 37.5 percentage points (95% CI 8.8 to 66.2), risk ratio 2.00 (1.11–3.60); unadjusted two-proportion z-test p = 0.020.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Investigational Therapy than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Participants With Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) > 2.5

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Investigational Therapy: 44.4% (8/18) versus 46.2% (12/26) on control; risk difference -1.7 percentage points (95% CI -31.6 to 28.2), risk ratio 0.96 (0.50–1.87); unadjusted two-proportion z-test p = 0.911.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Investigational Therapy and the control. The interval gives the range of effects that remain compatible with the data.

Anterior Posterior Spine Bone Mineral Density (BMD) at Final Visit

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Investigational Therapy: mean -0.19 versus -0.25 on control; difference 0.06 (95% CI -0.61 to 0.73), standardized effect d = 0.06; z-test p = 0.861.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Investigational Therapy and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover several different aspects of growth, development, metabolism, and bone health. They include predicted adult height and its change, bone-age progression, BMI, growth velocity, hydrocortisone dose, onset of early central puberty, insulin resistance, and spine bone mineral density. These outcomes provide context for the long-term adult-height endpoint, but they do not measure the same construct. A short-term or intermediate measure cannot automatically be taken as evidence that attained adult height differs.

The available secondary summaries do not form a uniformly consistent pattern that would independently settle the primary question. The direction and apparent magnitude of the point estimates vary by outcome, and the degree of uncertainty differs. In particular, the outcomes relating to early puberty, insulin resistance, and bone mineral density address distinct questions from adult height. Their findings should be considered alongside, not in place of, the primary result.

The registry lists 20 posted secondary outcomes, but no reported analyses for the listed secondary comparisons. The displayed unadjusted comparisons are therefore descriptive recalculations rather than a record of a reported, prespecified inferential analysis. The registry does not state which secondary outcomes were confirmatory, whether they were ranked in a hierarchy, or whether a multiplicity adjustment was planned.

When many outcomes are considered, chance alone can produce some apparently unusual results. Without a stated analysis hierarchy or multiplicity procedure, unadjusted secondary p-values carry less weight than a clearly prespecified primary analysis. This does not make secondary outcomes irrelevant; it means their role is better viewed as exploratory or contextual unless the registry record documents stronger confirmatory status. The secondary evidence does not resolve the uncertainty in the primary adult-height comparison.

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

• Adult Height Relative to Mid-parental Height
• Predicted Adult Height
• Predicted Adult Height Change
• Number of Years Bone Age Remained Unchanged
• Change in Body Mass Index (BMI)
• Body Mass Index (BMI)
• Average Annual Growth Velocity
• Dose of Oral Hydrocortisone

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each participant has an adult-height SDS value, and the registry reports a mean and standard deviation for each treatment group. A mean difference compares the group averages on the same scale. In this comparison, the estimated mean difference is 0.26 SDS units, calculated as investigational therapy minus standard therapy. The calculation is an unadjusted recalculation from the posted group summary statistics, not a reported adjusted model. The registry record does not describe covariates or an adjustment strategy for the primary result.

What does a mean difference represent?

A mean difference retains the endpoint’s original units, which in this case are SDS units. It describes the separation between the two group averages, not the difference for every child and not a change from baseline. A positive value indicates a higher reported average in the investigational arm under the stated subtraction order. The group standard deviations describe variation among participants within each arm; they are not standard errors of the group means and do not directly express uncertainty in the treatment comparison.

A standardized effect size can express the mean difference relative to pooled variability. The recalculated standardized effect size is 0.287. This can help describe the magnitude on a scale that accounts for observed variability, but it is not a separate clinical endpoint and does not replace interpretation in SDS units. Standardized effects also depend on variability in the studied population, so they should not be treated as universally transferable measures.

How should the interval and p-value be understood?

The 95% confidence interval for the mean difference runs from -0.285 to 0.805 SDS units. In general, a confidence interval describes a range of values compatible with the data and the statistical method, under its assumptions. A wider interval means the estimate is less precise. For this comparison, the interval includes zero, which represents no average difference on the endpoint scale. The unadjusted p-value is 0.35. In general, a p-value measures how unusual data at least as inconsistent with a null hypothesis would be under that hypothesis and the test assumptions; it is not a measure of effect size, clinical importance, or the probability that the null hypothesis is true.

The record identifies the endpoint parameter as a mean with standard deviation, but it does not report the trial’s own statistical analysis plan or the exact model used by the investigators. The displayed mean difference and interval are simple, unadjusted recalculations from posted summary statistics. No discrepancy is flagged in the registry-derived comparison, but that does not supply details of an original investigator analysis that are absent from the record.

How do binary outcomes differ?

Some secondary endpoints are counts of participants meeting an outcome definition. For those outcomes, the recalculated comparison uses a risk difference: the proportion with the outcome in one group minus the proportion in the other group. A risk difference is expressed as an absolute difference in proportions. Its confidence interval describes uncertainty in that contrast. The unadjusted p-value for a binary comparison is also conditional on the test and assumptions used; no adjustment for multiple secondary outcomes is reported.

Other secondary measures, such as anterior-posterior spine bone mineral density, are continuous and are reported as means with standard deviations. Their mean differences are interpreted on their own measurement scales. Different endpoints answer different questions, so an estimate for bone mineral density, insulin resistance, or early central puberty should not be treated as a substitute for the primary adult-height result.

What does over-dispersion mean in general?

For count or binary data, the observed variability can sometimes exceed what a simple statistical model expects. This is called over-dispersion. When present, ignoring it can make standard errors too small and uncertainty appear narrower than warranted. The posted outcome comparisons do not report a model-based over-dispersion assessment, and it is not possible to infer such an assessment from the summary counts alone. This general point is relevant when judging how much modeling detail is available, not a claim that over-dispersion occurred in this trial.

The record lists 21 outcome measures, including the primary endpoint and secondary outcomes, and 20 posted secondary outcomes. It lists no reported secondary analyses. This matters because testing multiple outcomes creates more opportunities for apparently notable findings, even when each individual test uses a conventional threshold. Whether the investigators specified a hierarchy, correction, or restricted set of confirmatory analyses is not reported in the registry record.

The trial is randomized, which supports comparison of assigned groups, but the open-label design means treatment knowledge was not masked. The registry does not describe allocation concealment, endpoint-assessor masking, handling of missing data, or any adjustment for the long-term follow-up structure. These are not details that can be reconstructed from group means and standard deviations. They remain relevant uncertainties when evaluating whether the simple summary-statistic comparison fully captures the original study analysis.

11. Confidence Intervals and Precision

The estimated primary mean difference is 0.26 SDS units, and its 95% confidence interval extends from -0.285 to 0.805. This interval is wide enough to include no average difference as well as differences in either direction. It indicates that the point estimate alone should not be read as a precise estimate of the underlying contrast. The data are compatible with a range of possible effects under the assumptions of the recalculation.

Precision depends in part on the amount of information in the endpoint comparison and the amount of variation in the outcome. The reported group sizes are 18 and 27, and the reported standard deviations are 0.93 and 0.89. Those summaries describe a relatively limited endpoint sample, but the registry does not report the full analysis population flow or why some enrolled participants are not represented in the endpoint counts. The effect of unavailable outcomes on precision or bias cannot be determined from the record.

The confidence interval is not a prediction interval for individual children, and it does not mean that a stated proportion of individual outcomes will fall within its limits. It concerns uncertainty in the estimated group mean difference under the method used. Nor does an interval containing zero prove that the groups are equivalent: equivalence would require a prespecified margin and a design and analysis suited to that question. Such a margin is not reported in the registry record.

The unadjusted p-value of 0.35 is consistent with considerable uncertainty, but the interval is more informative about the range of effect sizes compatible with the posted summaries. Because the primary comparison is recalculated from summary statistics and the investigator’s analysis details are not reported, its precision should be interpreted as applying to this simple unadjusted comparison.

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 planning illustration gives participants per arm for the continuous primary endpoint. Its 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 original trial’s sample-size justification and design assumptions are not reported in the registry record, so these planning figures are not a reconstruction of the trial’s original plan.

The 80% power column describes the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the assumed effect under the stated assumptions, if that effect and model were correct. The 90% power column uses a higher target chance of detecting the same assumed effect, and therefore gives a larger planning count. These are planning illustrations, not observed power.

The rows consider planning for 100%, 75%, and 50% of the observed effect. The reported counts rise as the assumed effect becomes smaller: for the primary endpoint, the listed participants per arm for 80% power are 191, 339, and 763 respectively, while the corresponding 90% power figures are 256, 454, and 1,021. This pattern reflects a general feature of study planning: smaller effects are harder to distinguish from random variation and generally require more participants to detect with the same target power.

These figures use the observed effect as their starting point, so they should not be interpreted as a recommendation for a future study without considering its scientific aims, endpoint, design, and assumptions. The illustration also assumes equal allocation and a normal approximation. The trial’s own power target, significance threshold, anticipated effect, allowance for attrition, and justification are not reported in the registry record.

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 = 0.260; pooled standard deviation σ = 0.906.
2. n = 2 × (1.96 + 0.842)² × 0.906² / 0.260² = 190.6, rounded up to 191 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 <- 0.26                      # observed difference in means
sigma <- 0.906025052274404                     # 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(1521)
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 = 191 (80% power), 256 (90% power)
 75% of observed effect: n per arm = 339 (80% power), 454 (90% power)
 50% of observed effect: n per arm = 763 (80% power), 1,021 (90% power)
power.t.test: 191.6 
Simulated power at n = 191 per arm: 0.798 (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. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures, including the primary adult-height endpoint and 20 posted secondary outcomes. A plan for controlling multiplicity, prioritizing outcomes, or distinguishing confirmatory from exploratory analyses is not reported in the registry record. The available secondary comparisons therefore should not be interpreted as if each were an isolated, prespecified test with no broader testing context. When several outcomes are examined, the chance of observing an apparently notable result can increase; multiplicity methods or a prespecified hierarchy can address that issue, but no such approach is described.

The registry reports no analyses for the secondary outcomes. It also does not report a full statistical analysis plan, details of the primary model, or whether subgroup analyses were planned. The primary comparison available from the summaries is an unadjusted recalculation. The record does not establish whether the trial investigators used additional analyses or adjustments outside the posted registry results.

The primary population is described as modified intention-to-treat and includes participants reassigned from investigational to standard therapy due to drug intolerance. That description is important because it indicates that treatment reassignment did not automatically exclude those participants from the named population. However, the number reassigned, timing of reassignment, and handling of other protocol deviations are not reported in the registry record.

Missing-data methods are also not reported in the registry record. The overall enrollment is 66, while the primary endpoint summaries include 18 participants in the investigational group and 27 in the standard group. Without a participant flow diagram or further accounting, it is not possible to determine why the endpoint counts are smaller than enrollment, whether outcomes were missing, or how missing values were handled. The possible effect of missing outcome data on the estimated difference cannot be assessed from the posted summaries alone.

The registry identifies randomization and an open-label design, but further details about allocation concealment, analysis populations beyond the modified intention-to-treat description, and assessor masking are not reported in the registry record. These gaps limit evaluation of how closely the available comparison reflects the original analysis strategy.

15. 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: hospitalisation (22.9%), supraventricular tachycardia (3.2%), appendicitis (3.2%), cholecystitis (3.2%), liver function test increased (3.2%).

The registry reports serious adverse events among 3 of 31 participants at risk in the investigational therapy group and 10 of 35 participants at risk in the standard therapy group. It reports no deaths in either group. The record also reports other adverse events among 31 of 31 participants at risk in the investigational group and 31 of 35 at risk in the standard group. These are descriptive counts and should be read with their stated at-risk denominators.

The listed serious adverse-event terms include hospitalisation at 22.9%, supraventricular tachycardia at 3.2%, appendicitis at 3.2%, cholecystitis at 3.2%, increased liver function test at 3.2%, and hypoglycaemic seizure at 2.9%. The registry listing does not give group-specific denominators or clarify in this summary whether the percentages refer to participants, events, or another calculation. They should therefore be understood as the registry’s reported percentages, not reinterpreted as rates for a particular arm.

Adverse-event counts alone do not establish that treatment caused an event or explain its severity, timing, or relationship to study therapy. The registry record does not provide enough detail to assess those factors, so these figures are descriptive safety information rather than a causal comparison.

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

The primary result describes the mean adult-height SDS in the two outcome groups and an unadjusted estimate of their difference. It does not show that every participant in one group had a higher or lower adult height than every participant in the other. Group averages conceal individual variation, and the standard deviations indicate that individual outcomes varied within both groups.

The confidence interval includes zero and spans possible differences on both sides of no average difference. This means the posted summary statistics do not determine the direction or size of a population-level contrast precisely. A p-value of 0.35 does not prove that the treatment approaches are the same, and the point estimate does not establish a benefit. Equivalence or non-inferiority would require a defined margin and an analysis designed for that purpose; such a margin is not reported in the registry record.

The comparison evaluates treatment strategies as used in this long-term trial, not the isolated effect of one drug. The investigational approach involved multiple medicines and reduced-dose hydrocortisone, and the registry summary describes later treatment transitions that differed for boys and girls. The primary result consequently cannot be attributed to any single component of the regimen from these data.

The outcome is adult height relative to a general-population reference, not a direct measure of every aspect of health or quality of life. The record lists other outcomes, but their availability and analysis do not remove uncertainty in the primary endpoint. Nor does the adult-height comparison answer all questions about safety: adverse-event summaries require separate interpretation, and the registry does not provide detailed causal assessments in the information reported.

Finally, enrollment, the modified intention-to-treat definition, and the smaller endpoint group counts should be distinguished. The record gives a reason for including participants reassigned due to intolerance, but does not fully explain the endpoint sample. Without that accounting, readers cannot determine how missing or unavailable adult-height outcomes might affect the result. The safest interpretation is therefore descriptive: the observed averages differ by the recalculated amount, with substantial uncertainty and important reporting gaps.

17. Why This Trial Matters Statistically

This trial raises statistical questions that are especially relevant to long-term pediatric research. Adult height is an endpoint that requires extended follow-up, and the record reports an average of 11 years from randomization to attainment. Long follow-up can yield a clinically interpretable endpoint, but it also makes complete participant accounting and transparent outcome handling important. The registry’s modified intention-to-treat definition is useful, yet the endpoint counts are smaller than enrollment and the reasons are not fully documented.

The contrast is also between treatment strategies rather than single components. The investigational approach combined several drugs and a reduced hydrocortisone dose, while the registry summary describes treatment transitions over time. A group-level comparison can address the strategy as studied, but it cannot isolate the contribution of flutamide, the aromatase inhibitor, hydrocortisone dose, or fludrocortisone.

The open-label randomized design and the long horizon make clear reporting of allocation, follow-up, and analysis methods valuable. The registry identifies randomization but does not report important statistical details such as the original sample-size justification, missing-data methods, or multiplicity plan. These omissions constrain what can be inferred from the posted outcome summaries.

Finally, the primary confidence interval illustrates why effect estimates and their precision matter together. The point estimate is not enough to characterize the evidence: the interval includes zero and a range of differences in either direction. Statistical interpretation should therefore distinguish the observed estimate from the uncertainty around it, and from any clinical threshold that the record does not specify.

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 gives limited detail about the trial’s original statistical plan. The sample-size justification, intended power, primary analysis model, covariate adjustments, and interim analyses are not reported in the registry record. The planning illustration based on the observed effect is not evidence of the original design rationale.

The primary endpoint summaries include fewer participants than the reported enrollment, but the full participant flow is not described. The record names a modified intention-to-treat population and explains that participants reassigned because of drug intolerance were included. It does not report how many participants were reassigned, why other enrolled participants are absent from the endpoint summaries, or how missing outcomes were addressed.

The trial was open-label, and the registry does not state whether adult-height assessment was conducted by masked assessors. It also does not report allocation concealment details. These omissions do not negate the randomized design, but they leave aspects of implementation and outcome assessment unclear.

The investigational arm description is incomplete, and the standard therapy dosing text is truncated. The registry summary describes a multi-drug treatment strategy with later transitions that differ by sex, so the primary estimate cannot isolate an individual drug effect. The registry record also does not report a clinically important difference threshold for adult-height SDS, a multiplicity strategy, or a hierarchy for secondary outcomes. These limits support a cautious, descriptive reading of the posted comparisons rather than a definitive claim about clinical importance.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Three Drug Combination Therapy Versus Conventional Treatment of Children With Congenital Adrenal Hyperplasia — NCT00001521.
• Registry record last updated 2025-06-12; status last verified 2024-05-08.
• Results first posted 2025-06-12.
• 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 identifies a completed, randomized, open-label, parallel-group Phase 3 trial of investigational combination therapy versus conventional treatment in children with congenital adrenal hyperplasia. Enrollment was 66. The primary outcome was adult height relative to the general population, expressed in SDS units, with follow-up to attainment of adult height and an average timeframe of 11 years from randomization.

The primary endpoint summaries report mean SDS values of -0.34 for investigational therapy and -0.6 for standard therapy. The unadjusted recalculated mean difference is 0.26, with a 95% confidence interval from -0.285 to 0.805 and an unadjusted p-value of 0.35. The record defines the primary population as modified intention-to-treat, including participants reassigned because of drug intolerance.

The registry also posts secondary outcomes and adverse-event summaries. It does not report the original sample-size justification, missing-data methods, multiplicity plan, or full analysis plan. Those omissions, alongside the uncertainty in the primary interval and incomplete endpoint accounting, limit the conclusions that can be drawn from the posted record.