Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1 (NCT02574910), a non-randomized phase 1 study. The primary outcome is Normalization of Serum Androstenedione Level.

2. Clinical Question

3. Trial Design

This was a Phase 1, multicenter study sponsored by the University of Texas Southwestern Medical Center. It was nonrandomized, unmasked, and used a sequential model. The study started on 2017-08-01, had a primary completion date of 2023-06-03, enrolled 4 participants, and is listed as terminated. The reason for termination is not reported in the registry record.

Participants were to receive abiraterone acetate in addition to oral hydrocortisone and fludrocortisone. The first listed dose was 1 mg/kg/d for 7 days. The dose description states that 2 mg/kg/d would be used if the lower dose did not normalize androstenedione; 4 mg/kg/d would follow if normalization did not occur at 2 mg/kg/d. This is a conditional sequence, not evidence that every dose was administered. No participants enrolled at 4 mg/kg/d.

Because allocation was nonrandomized, dose groups should not be read as randomized treatment arms. The registry record also explicitly identifies the arms as not being a like-for-like control comparison. Differences across dose levels could reflect the sequence and the small number enrolled, as well as dose, so an independent comparative effect cannot be established from this design.

The primary endpoint timeframe was 7 days. Listed secondary outcomes include 17-hydroxyprogestoerone levels, the area under the plasma concentration versus time curve (AUC) of abiraterone, and peak plasma concentration (Cmax). Six outcome measures are recorded, but numerical results for these secondary measures are not reported in the registry record. The record does not describe a separate control treatment, masking procedures, or a detailed statistical analysis plan.

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: No subjects enrolled at 4 mg/kg/d

5. Baseline Characteristics

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

Population: 4 mg dose level not reached

6. Primary Endpoint

The registry lists the primary outcome as Normalization of Serum Androstenedione Level, measured over 7 days.

The primary endpoint is titled normalization of serum androstenedione level and is expressed as a count of participants. It concerns whether androstenedione reached age-appropriate levels following 7 days of treatment. The original endpoint sought the dose that achieved normalization in 7/8 subjects. The registry record states that insufficient enrollment prevented evaluation of that primary endpoint as originally specified; it instead describes the number of participants at each dose level who normalized androstenedione.

Androstenedione is relevant to the study’s stated aim because the registry record describes elevated circulating androgens in congenital adrenal hyperplasia and the effort to reduce androgen precursor levels. The endpoint therefore measures a short-term biochemical response, not skeletal maturation, linear growth, adult height, or the longer-term balance of benefits and harms. A laboratory value becoming age-appropriate over the treatment period would not, by itself, establish a lasting change in those broader outcomes.

The registry record does not report numerical normalization counts, estimates of uncertainty, or the distribution of androstenedione values. No participants enrolled at 4 mg/kg/d, so the record cannot provide an observed normalization count at that dose. The outcome description is therefore informative about the intended measure and the departure from the original endpoint, but the posted results do not permit a numerical assessment of the biochemical response.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

General statistical explanation: a count endpoint records how many participants meet a specified outcome definition. For this study, the primary outcome definition concerns androstenedione reaching age-appropriate levels after 7 days. A count is most interpretable alongside the number assessed at that dose and a clear definition of the assessment. The registry record describes the intended count-based reporting, but numerical normalization counts are not reported in the registry record. The number enrolled overall is 4; that total should not be substituted for a dose-specific endpoint denominator.

The count is a direct description of observed participants, not an estimate of the size of a continuous change in androstenedione. It does not show how far a value moved, how close values were to the age-appropriate range, or whether a change persisted after the treatment period. Those questions would require additional outcome information, which is not reported in the registry record.

Why does the design matter for interpreting dose levels?

General statistical explanation: random allocation helps make treatment groups comparable in expectation, while nonrandom allocation can leave differences between groups entangled with treatment. Here, allocation was nonrandomized and the model was sequential. The dose descriptions indicate that escalation depended on whether normalization occurred at the preceding dose. Thus, participants reaching a later dose may have been selected because of their earlier response. Such groups are not equivalent to independent groups formed by random assignment.

The registry record lists 1 mg/kg/d and 2 mg/kg/d groups with adverse-event data, and no participants at 4 mg/kg/d. The adverse-event counts do not establish the primary endpoint denominators. The endpoint-specific group sizes and participant-level sequence are not reported in the registry record. Without that information and the numerical response counts, an adjusted or comparative dose analysis cannot be reconstructed.

What can uncertainty estimates add?

General statistical explanation: a confidence interval describes a range of values compatible with the observed data under a stated statistical model and assumptions. For a participant count or an event proportion, an interval can communicate how uncertain an estimate is, particularly when the number observed is small. It does not correct a biased design, remove selection effects from sequential dosing, or replace missing results. Confidence intervals for the primary endpoint are not reported in the registry record, and the numerical endpoint results needed to assess them are also not reported.

Likewise, a p-value would address a specified statistical hypothesis under a specified analysis. It would not measure the probability that a treatment is effective, and it would not resolve the nonrandomized design or the lack of endpoint counts. No p-values or inferential analyses are reported in the registry record; the analysis count is listed as 0.

What do the planning assumptions mean?

General statistical explanation: sample-size planning asks how many participants might be needed for a future study under chosen assumptions about the effect to detect, the significance level, allocation, and statistical method. The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as stated fractions of the observed effect. These assumptions describe the illustration, not the trial’s own design. The registry record does not report a trial-specific sample-size justification.

Planning estimates are not observed power. They are conditional calculations, and their usefulness depends on the reliability of the effect estimate and the suitability of the assumptions. In a study with 4 participants overall and no participants at the 4 mg/kg/d dose, an observed effect may be highly uncertain; numerical planning estimates are not reported in the registry record. The assumptions should not be read as evidence that the study enrolled enough participants to answer its original endpoint.

Why are methods and analysis details important?

General statistical explanation: an analysis plan ordinarily clarifies which participants are included, how missing outcome assessments are handled, how repeated or multiple endpoints are addressed, and which statistical procedures are used. Those choices affect what an estimate means and how uncertainty should be reported. The registry record does not report a detailed statistical analysis plan, an analysis population for the primary endpoint, missing-data procedures, or an approach to multiplicity. Since the main outcome counts and inferential results are absent, readers cannot verify the statistical treatment of the primary outcome from the registry information alone.

The record lists six outcome measures and describes several secondary outcome types, including a hormone level and pharmacokinetic measures. Multiple outcomes can create multiple opportunities to identify an apparently notable result. General methods may address this through prespecified prioritization or adjustment, but the registry record does not report how multiplicity was handled. It also does not report interim analyses or a protocol for dose escalation beyond the conditional descriptions of the dose sequence. No such procedures should be inferred from the study’s Phase 1 label or sequential model.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Abiraterone acetate 1 mg/kg/d", "Abiraterone acetate 2 mg/kg/d")
n      <- c(2, 2)
events <- c(0, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Abiraterone acetate 1 mg/kg/d  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Abiraterone acetate 2 mg/kg/d  2  1  50.0  1.3  98.7  9.5  90.5  9.4  90.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures, including the primary normalization endpoint and secondary outcomes concerning 17-hydroxyprogestoerone levels, AUC of abiraterone, and Cmax. Numerical results for the secondary outcomes are not reported in the registry record. The record does not describe a multiplicity adjustment, a hierarchy for interpreting secondary outcomes, or a strategy for controlling the chance of false-positive findings across outcomes. It is therefore not possible to determine whether multiplicity was considered in the statistical analysis.

Analysis populations are not described. The record does not state which participants were included in each primary or secondary analysis, whether every enrolled participant contributed outcome data, or how exclusions were handled. The primary endpoint description notes insufficient enrollment for the original 7/8 target, but does not report the number assessed for normalization at each dose. The at-risk counts in the adverse-event record should not be treated as endpoint-analysis denominators.

Missing-data methods are also not reported in the registry record. There is no description of how unavailable laboratory assessments, incomplete treatment, or other missing observations were handled. No imputation approach or sensitivity analysis is reported. Since the primary numerical results are absent, the effect of missing data on the endpoint cannot be assessed.

The registry record lists 0 analyses and does not report a detailed statistical analysis plan, interim analyses, or specific inferential procedures. These omissions limit reproducibility and make it difficult to connect the stated endpoint to a formal statistical conclusion. Absence of reported methods does not establish that a procedure was or was not used outside the registry record.

12. 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 non-serious adverse event terms

The serious adverse-event figures are participant counts. In the abiraterone acetate 1 mg/kg/d group, 2 participants were at risk and 0 participants had a serious adverse event. In the 2 mg/kg/d group, 2 participants were at risk and 0 had a serious adverse event. At 4 mg/kg/d, 0 participants were at risk and 0 had a serious adverse event. The record lists 0 deaths.

For other adverse events, 2 participants were at risk and 2 had an event in the 1 mg/kg/d group; 2 were at risk and 1 had an event in the 2 mg/kg/d group. At 4 mg/kg/d, 0 participants were at risk and 0 had an event. These counts indicate how many participants were recorded as having an event, not the total number of separate event episodes or the severity of every event.

No serious adverse-event terms are listed. The small numbers and lack of exposure at 4 mg/kg/d mean the record offers limited information about uncommon events or events at that dose. Zero recorded serious events in these groups is not proof that serious events cannot occur. The registry record does not provide event descriptions or additional safety analyses in the information reported.

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

The registry record establishes that this was a small, terminated Phase 1 study of abiraterone acetate as adjunctive therapy in pre-pubescent children with classic 21-hydroxylase deficiency. It describes a short-term biochemical objective: identify a dose that normalizes serum androstenedione to age-appropriate levels after 7 days. It also explains that insufficient enrollment prevented evaluation of the original endpoint, which sought normalization in 7/8 subjects, and that the reporting approach was changed to counts normalized at each dose.

However, the registry record does not report those normalization counts. The posted information therefore does not support a numerical estimate of the primary response, an estimate of precision, or a conclusion about which dose reached the biochemical target. No participants enrolled at 4 mg/kg/d, so there is no observed participant response at that dose in the registry record. The adverse-event counts are descriptive and are not a substitute for the missing primary efficacy counts.

The study also does not establish a randomized comparison with standard therapy alone. It was nonrandomized, unmasked, and sequential; the dose descriptions make later dosing conditional on results at earlier doses. The registry record cautions that the arms are not a like-for-like control comparison. Consequently, the results cannot be treated as a controlled estimate of the effect of abiraterone acetate relative to hydrocortisone and fludrocortisone alone.

The short biochemical timeframe should be kept distinct from clinical outcomes such as skeletal maturation, linear growth, or adult height. Those broader outcomes are part of the rationale described in the registry record, but the primary endpoint does not measure them. The record does not establish long-term effects, and it does not provide enough information to characterize the full safety profile. Its contribution is a description of the intended dose-sequencing question and limited participant-level event counts, with substantial limits on outcome interpretation.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it makes the difference between a planned endpoint and an evaluable endpoint explicit. The original primary aim was to identify a dose that normalized androstenedione in 7/8 subjects after 7 days. The registry record says enrollment was insufficient to evaluate that aim and describes a different presentation of the outcome: the number normalized at each dose. The actual counts are not reported in the registry record, so even the revised descriptive endpoint cannot be assessed numerically from the posted results.

The dose sequence also illustrates why design structure matters. A sequential, conditional dose escalation is not equivalent to random allocation across dose groups. Participants reaching a higher dose may do so because normalization was not achieved at a lower dose. Any comparison across those groups would need to account for that structure, but a detailed statistical analysis plan is not reported. No participants enrolled at 4 mg/kg/d, further limiting what can be learned about the full planned sequence.

The study also shows why a small safety count must be read in context. The registry reports no serious adverse events in the groups with participants at risk, but there were only 2 participants at risk in each of the 1 mg/kg/d and 2 mg/kg/d groups, and none at 4 mg/kg/d. These observations describe this enrollment, not the range of risks that might be seen with wider exposure.

More broadly, the record distinguishes statistical description from a conclusive estimate. A short-term laboratory endpoint can address a focused pharmacologic question, while a small nonrandomized study with missing numerical primary results cannot provide a precise comparative conclusion. Transparent reporting of the endpoint’s change in status, enrollment, and absent dose group helps readers recognize those limits rather than mistake a planned objective for a demonstrated result.

15. 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.

Enrollment was 4, and the registry record states that this was insufficient to evaluate the original primary endpoint. No participants enrolled at 4 mg/kg/d, leaving that listed dose without observed participants. The numerical counts for the revised normalization endpoint are not reported in the registry record, nor are dose-specific endpoint denominators or estimates of uncertainty. This prevents assessment of the primary biochemical response.

The nonrandomized, unmasked, sequential design does not support a straightforward causal comparison between dose levels or against standard therapy alone. Dose escalation was described as conditional on normalization at the preceding dose, and the registry record explicitly says the arms are not a like-for-like control comparison. The participant flow through the dose sequence is not reported in the registry record.

The study is listed as terminated, but the reason for termination is not reported. A detailed statistical analysis plan, analysis populations, missing-data procedures, multiplicity approach, interim analyses, and trial-specific sample-size justification are not reported in the registry record. The six outcome measures are noted, but numerical secondary outcome results are not reported.

The primary endpoint assesses a short-term laboratory measure over 7 days. It does not itself evaluate longer-term growth, skeletal maturation, adult height, or sustained outcomes. Safety counts are based on very few participants, with no exposure at 4 mg/kg/d, and the listed serious-event terms are empty. These limitations constrain both efficacy interpretation and safety characterization; they do not identify why the study ended or what would have been observed with different enrollment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1 — NCT02574910.
• Registry record last updated 2025-11-04; status last verified 2025-10.
• Results first posted 2025-11-04.
• 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.

19. Record Summary

NCT02574910, titled “Androgen Reduction in Congenital Adrenal Hyperplasia, Phase 1,” is a Phase 1, multicenter, nonrandomized, unmasked sequential study sponsored by the University of Texas Southwestern Medical Center. It enrolled 4 participants and is listed as terminated. The study evaluated abiraterone acetate added to hydrocortisone and fludrocortisone in pre-pubescent children with classic 21-hydroxylase deficiency.

The primary outcome concerned normalization of serum androstenedione after 7 days. The original target was normalization in 7/8 subjects, but the registry record says enrollment was insufficient to evaluate that endpoint as planned. It describes reporting participant counts by dose instead; those counts are not reported in the registry record. No participants enrolled at 4 mg/kg/d. Serious adverse events were recorded for 0 participants in the 1 mg/kg/d and 2 mg/kg/d groups; each had 2 participants at risk. The reason for termination and detailed analysis methods are not reported in the registry record.