Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia (NCT03257462), a non-randomized phase 2 study. The primary outcome is Safety of SPR001 in Patients With CAH.

2. Clinical Question

3. Trial Design

This was a Phase 2, multiple-dose, dose-escalation study of SPR001 in adults with classic CAH. It was multicenter, non-randomized, unmasked, and sequential. The registry lists enrollment of 24 and a completed study. The recorded start date is 2017-07-12, and the primary completion date is 2019-03-02.

The study had three cohorts. Cohort A was described as the first cohort, with 9 patients planned to receive Dose A daily for 2 weeks, followed by Dose B daily for 2 weeks and Dose C daily for 2 weeks. Cohort B was to begin enrollment after Cohort A was fully enrolled. Its starting dose and stepwise dosing paradigm were to be determined after an interim review of Cohort A safety and PK/PD data. Cohort C was to begin after Cohort B was fully enrolled, with its dosing approach determined after review of safety and PK/PD data from Cohort A and Cohort B.

These are sequential decisions, not randomized assignment. The later cohorts’ dosing was to depend on earlier cohort data, so dose and cohort are not independent comparison groups. The registry does not report the specific dose strengths, the final dose-selection decisions for Cohorts B and C, or additional operational details about how the interim reviews were conducted.

The study aimed to evaluate safety, pharmacokinetics, pharmacodynamics, and efficacy. The primary outcome is described as safety over 6 weeks; secondary outcomes include changes in pharmacodynamic markers, maximum plasma concentration (Cmax), and area under the concentration-time curve (AUC). The registry record does not report a randomized comparator or an efficacy outcome result that supports a controlled treatment 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: A total of 24 subjects were enrolled into the study and 24 ICFs were signed. Two subjects were enrolled in more than one cohort: one subject was enrolled in both Cohorts A and C and one subject was enrolled in both in Cohorts A and B. Therefore, the total when adding Cohorts A+B+C = 26; however, 2 subject were the same, thus a total of 24 unique subjects participated and signed the ICFs.

Cohort A

Reasons for not completing this period:

Cohort B

Reasons for not completing this period:

Cohort C

Analysis population for the primary outcome, as defined in the registry: This full analysis set includes all subjects who received at least 1 dose of study drug. The FAS was used to analyze all safety data

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: 24 unique subjects participated in the study; however, two subjects were enrolled in more than one cohort, one subject in Cohorts A and C and one subject in Cohorts A and B. For the subjects enrolled in more than 1 cohort, cohort totals/statistics reflect all baseline values.

6. Primary Endpoint

The registry lists the primary outcome as Safety of SPR001 in Patients With CAH, measured over 6 weeks.

The primary endpoint is titled “Safety of SPR001 in Patients With CAH.” It is expressed as a count of participants. Its description includes the incidence of treatment-emergent adverse events and changes from baseline to end of study in clinical laboratory parameters, physical examination findings, vital signs, and ECG parameters. The stated timeframe is 6 weeks.

A count of participants with an event is a way to describe how many people experienced an event, rather than the number of separate episodes each person experienced. The registry describes the full analysis set as all subjects who received at least 1 dose of study drug and says this set was used to analyze all safety data. The adverse-event figures list participants at risk and participants affected, separated into serious and other adverse-event categories.

General: safety endpoints are used to characterize events and changes observed during exposure to a study intervention. They can include different kinds of information, such as reported adverse events and clinical measurements. Because the endpoint combines several safety domains, an overall count alone cannot describe the type, timing, severity, duration, or clinical course of every event. The registry record does not report further endpoint definitions, threshold criteria for clinically important changes, or detailed rules for attributing events to study drug.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a participant count and describes the safety population as the full analysis set: all subjects who received at least 1 dose of study drug. The record says this set was used to analyze all safety data. The posted adverse-event figures are descriptive, reporting participants at risk and participants affected within each listed cohort or dose group. No statistical analyses are listed in the registry record.

What does a participant count describe?

A participant count records whether people experienced an event, rather than adding together every event episode. This distinction matters because one participant may experience more than one event, while a participant-based count still counts that person as affected. The posted figures distinguish serious adverse events from other adverse events and include the number at risk in each category. The registry does not clarify whether each participant could appear in more than one event category or provide event-level detail for the other adverse events.

General: binary outcomes classify participants into categories, such as affected or not affected during a defined observation period. Their interpretation depends on the outcome definition, the population being counted, and the time period over which events are collected. Here, the stated primary timeframe is 6 weeks, and the safety population includes participants who received at least 1 dose. More detailed rules for event collection and classification are not reported in the registry record.

Why is the study structure important?

This was a non-randomized, sequential study. Cohort A received an escalating dose sequence, while starting doses and stepwise dosing for Cohorts B and C were to be selected after review of safety and PK/PD data from earlier cohorts. This design can support staged evaluation of dose exposure and safety. It does not create randomized, exchangeable groups for a direct comparison between doses or cohorts.

General: random allocation is used in many comparative trials to reduce systematic differences between treatment groups at the time of assignment. In a sequential dose-escalation study, cohort order and dose decisions may instead be linked to earlier observations. This means that factors associated with enrollment time, dose selection, or cohort progression could also relate to observed outcomes. The registry does not report an analysis that adjusts for such factors, and the posted counts should not be interpreted as adjusted treatment effects.

What can be inferred from zero serious-event counts?

The posted value of zero affected participants in a group means that no serious adverse event was recorded for that group in the registry figures. It does not establish that the underlying probability of such an event is zero. General: when an event is uncommon, a study can observe no cases even though the event remains possible in the broader population. The amount of information depends on the number of people observed, the follow-up period, and how completely events were collected. The registry does not provide confidence intervals or other uncertainty estimates for the serious-event counts.

The listed death count is 0 in every group. This is a separate descriptive count from the serious-event count. The registry does not provide additional narrative detail about deaths or serious-event terms, and the list of top serious terms is empty.

What is not available for statistical assessment?

The registry lists no analyses. It does not report hypothesis tests, confidence intervals, adjusted estimates, interim-analysis results, or a statistical analysis plan. Although the cohort descriptions refer to interim review of safety and PK/PD data for later dose selection, the methods and findings of those reviews are not reported in the registry record. A sample-size justification is also not reported in the registry record.

General: a formal comparison requires a defined estimand, an analysis method, and an account of uncertainty. When estimates and uncertainty measures are absent, readers can describe the observed counts but cannot determine the precision of a difference or whether an apparent contrast is compatible with chance variation under a specified model. No comparative effect estimate is posted for these safety groups.

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("Cohort A", "Cohort B", "Cohort C")
n      <- c(10, 9, 7)
events <- c(6, 5, 4)
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  Cohort A  10  6  60.0  26.2  87.8  31.3  83.2  30.8  83.3
ARM  Cohort B  9  5  55.6  21.2  86.3  26.7  81.1  26.2  81.3
ARM  Cohort C  7  4  57.1  18.4  90.1  25.0  84.2  24.5  84.3

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a hierarchy for testing outcomes, or a procedure for controlling multiplicity. It lists the safety outcome as primary and lists pharmacodynamic marker changes, maximum plasma concentration (Cmax), and area under the concentration-time curve (AUC) as secondary outcomes. It also records multiple safety domains within the primary outcome description. How these outcomes or domains were prioritized for analysis is not reported in the registry record.

General: multiplicity arises when several hypotheses or outcomes are examined. Without an analysis plan, the chance of a misleading positive finding across many tests can be difficult to assess. No multiplicity-adjusted analyses or decision rules are reported in the registry record, so none should be inferred from the listed outcomes.

Missing-data methods are not reported in the registry record. The record does not describe how missing visits, unavailable laboratory or ECG measurements, withdrawal, or incomplete adverse-event follow-up were handled. It also does not report the extent or pattern of missing data for the primary or secondary outcomes. The safety population is described as all subjects who received at least 1 dose, but additional details about inclusion of individual outcome observations are not stated.

The analysis populations for the secondary outcomes are not reported in the registry record. The record does not specify whether those outcomes used the same full analysis set, a pharmacokinetic population, or another population. It also does not report how the analysis handled the sequential design or dose-selection reviews. These omissions constrain assessment of the study’s statistical procedures; they do not establish that a particular method 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 registry reports zero participants with serious adverse events in each of the five listed groups: Cohort A - Dose A, Cohort A - Dose B, Cohort A - Dose C, Cohort B, and Cohort C. The corresponding numbers at risk are 10, 10, 10, 9, and 7. Deaths are listed as 0 for each group. The registry’s list of top serious-event terms is empty.

These are participant counts, not rates adjusted for follow-up time, and the record does not report confidence intervals or a formal comparison. The groups arose in a non-randomized, sequential study, so the counts should not be read as a controlled comparison of doses or cohorts.

The other adverse-event category lists 6, 3, 3, 5, and 4 participants affected across those same groups, with the listed numbers at risk of 10, 10, 9, 9, and 7. The registry does not give details on the event terms, severity, timing, duration, or attribution for these events. Zero observed serious events is a description of the posted results, not proof that serious events cannot occur.

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

The results describe safety observations among participants who received SPR001 in a Phase 2 study of adults with classic CAH. The registry posts participant counts for serious and other adverse events across three Cohort A dose groups and Cohorts B and C. It reports zero participants with serious adverse events and zero deaths in each group, alongside nonzero counts in the other adverse-event category.

These observations can help readers understand what was recorded within the study groups. They do not establish comparative safety across doses or cohorts, because allocation was non-randomized and sequential. The later cohorts’ starting doses and dosing steps were to depend on review of earlier safety and PK/PD data. Group differences could therefore reflect factors other than dose, and the registry does not report a statistical analysis that separates those possibilities.

The counts also do not establish the absence of risk. General: an event not observed in a study may still occur in a larger or different population, and an observed count does not by itself describe the precision of an underlying event probability. The registry does not provide uncertainty intervals, detailed event descriptions, or results for the laboratory, examination, vital-sign, and ECG components named in the primary outcome.

The study was intended to assess pharmacokinetics, pharmacodynamics, and efficacy as well as safety. The listed secondary outcomes include pharmacodynamic marker changes, Cmax, and AUC. Results for those outcomes, and efficacy results, are not reported in the registry record. The posted safety counts therefore cannot answer all of the study’s stated objectives.

These data should be interpreted as descriptive registry results from a small, staged study with no randomized control group. They do not provide a controlled estimate of benefit or harm, and they do not support a conclusion about how SPR001 compares with another treatment or with no treatment.

14. Why This Trial Matters Statistically

This study is statistically notable for its sequential dose-escalation structure. Cohort A was described as moving through Dose A, Dose B, and Dose C, while subsequent cohort dosing was to depend on interim review of earlier safety and PK/PD data. Such a design makes dose progression part of the study’s decision process rather than a simple randomized assignment. The registry record does not report the results or methods of those reviews.

The design context is essential when reading the safety counts. Cohort and dose groups are not randomized control groups, so apparent variation across them is descriptive. The registry’s non-randomized allocation and sequential model mean that a direct numerical contrast would not, on its own, isolate a dose effect. No inferential analyses are listed in the registry record.

The study also illustrates the distinction between a stated endpoint and the detail available to interpret it. The primary safety outcome includes adverse events and changes in several clinical measurement domains. The registry posts adverse-event counts, but does not report group-level results for the other listed safety components. It also lists PK and PD outcomes without reporting their results in the registry record.

General: early-phase studies often focus on characterizing exposure and safety while informing later study decisions. Descriptive data can be informative for that purpose, but precision and generalizability depend on the amount and quality of observed data and on the design. Here, the counts are accompanied by no posted confidence intervals or formal comparisons, which limits assessment of uncertainty.

The statistical lesson is to distinguish what the record reports from what a reader might wish to conclude. Counts describe recorded events within study groups; they are not randomized estimates of comparative risk. The staged design and the limited posted analyses are central to an accurate reading of these results.

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.

The registry lists enrollment of 24, while its adverse-event figures give different numbers at risk across cohort and dose groups. The Cohort A description says the first cohort includes 9 patients, whereas the posted at-risk counts for its Dose A, Dose B, and Dose C groups are 10, 10, and 9. The registry record does not explain this difference, so the relationship between the cohort description and the safety denominators is not clear from the record.

The study is non-randomized, unmasked, and sequential. It has no randomized control group, and later cohort dose selection was to follow review of earlier safety and PK/PD data. These features limit direct comparison across groups and can make observed group differences difficult to interpret causally.

The registry provides participant counts but no inferential analyses, confidence intervals, or adjusted estimates. It does not report detailed information about adverse-event terms, severity, timing, duration, relatedness, or missing observations. Although the primary outcome includes laboratory, examination, vital-sign, and ECG changes, results for those components are not reported in the registry record.

The record does not report the specific dose strengths, the final dosing decisions for Cohorts B and C, a sample-size justification, a statistical analysis plan, or results of the interim reviews. Results for the listed pharmacodynamic and pharmacokinetic secondary outcomes are also not reported in the registry record. These gaps limit assessment of outcome definitions, precision, dose-response patterns, and the full set of study objectives.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia — NCT03257462.
• Registry record last updated 2025-10-22; status last verified 2025-10.
• Results first posted 2025-10-22.
• 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

NCT03257462 is a completed Phase 2, multicenter study of SPR001 in adults with classic CAH. It was non-randomized, unmasked, and sequential, with enrollment of 24. The recorded start date was 2017-07-12, and the primary completion date was 2019-03-02.

The primary outcome was safety over 6 weeks, including treatment-emergent adverse events and changes in clinical measurements. The posted adverse-event figures list zero participants with serious adverse events and zero deaths in each group, alongside participants affected by other adverse events. No statistical analyses are listed. The registry also lists pharmacodynamic and pharmacokinetic secondary outcomes, but their results are not reported in the registry record.