Treatment of Cushing's Disease With R-roscovitine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment of Cushing's Disease With R-roscovitine (NCT02160730), a na phase 2 study. The primary outcome is Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks.

2. Clinical Question

3. Trial Design

This is a Phase 2, single-group study of R-roscovitine in Cushing disease. The registry records enrollment of 4 participants and lists the study status as terminated. The start date is 2014-05, and the primary completion date is 2018-10. The reason for termination is not reported in the registry record.

The intervention was R-roscovitine 400 mg by mouth twice daily for 4 days every week for a total of 4 weeks. The listed outcomes include measurements at baseline and 4 weeks, including 24-hour urinary free cortisol, plasma ACTH, fasting glucose, and HbA1c, along with clinical signs, symptoms, tumor size, and adverse events. The record does not report results for these outcomes apart from the adverse-event counts described separately.

Allocation is marked NA, masking is none, and the study model is single-group. There is no randomized comparison or concurrent control group. The registry’s own caution notes that the arms are not a like-for-like control comparison. This design can describe outcomes among participants who received the intervention, but it does not provide a controlled estimate of how those outcomes compare with an alternative treatment or with no intervention.

The registry record does not describe a statistical analysis plan, a sample-size justification, interim analyses, or an analysis population. It lists 11 outcome measures and 0 analyses. Those entries do not establish why the study enrolled 4 participants or how outcomes were to be analyzed. The posted record also does not explain why the study was terminated.

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: Patients on medical treatment for CD must complete washout periods before screening assessments are performed: Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks; somatostatin receptor ligand (SRL; pasireotide): short-acting, 2 weeks; long active, 4 weeks; progesterone receptor antagonist (mifepristone): 2 weeks; dopamine agonists (cabergoline): 4 weeks; CYP3A4 strong inducers or inhibitors: varies between drugs, minimum 5-6 x the drug half-life.

Overall Study

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 Number of Participants With a Normalized 24 Hour Urinary Free Cortisol After 4 Weeks, measured over Baseline, 4 weeks.

The primary endpoint is the number of participants with a normalized 24-hour urinary free cortisol result after 4 weeks. The registry defines a normalized result as a urine free cortisol level within the normal range for the laboratory value. This makes the endpoint a participant count based on a binary classification: each participant either meets the stated normal-range criterion or does not. The registry gives the timeframe as baseline and 4 weeks.

Urinary free cortisol is used in this study because the investigators’ stated hypothesis concerns suppressing pituitary corticotroph tumor ACTH production and normalizing urinary free cortisol in people with Cushing disease. The endpoint translates that objective into an outcome that can be counted at the participant level. General statistical context: a binary endpoint can be easy to interpret as a count, but the count alone does not show how close individual measurements were to the laboratory threshold or how much values changed from baseline.

The registry record does not report the number meeting the normalization definition, individual cortisol measurements, or a statistical analysis of the primary endpoint. Consequently, the primary outcome is specified, but its observed result and precision cannot be assessed from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies the primary outcome as a participant count: the number whose 24-hour urinary free cortisol is within the laboratory’s normal range after 4 weeks. General statistical context: a count endpoint is often treated as binary at the participant level, because each person either meets the specified criterion or does not. The count and the total assessed are both important for interpretation. Here, the enrolled total is reported, but the number meeting the endpoint is not reported in the registry record.

What can a confidence interval add?

General statistical context: a confidence interval expresses uncertainty around an estimate, such as a proportion or a difference, under the assumptions of the method used. It does not show the probability that a particular fixed value is true. With a small group, the range of plausible values can be wide, especially when an event is uncommon or common. The registry does not report a confidence interval for the primary outcome, nor does it report the endpoint count needed to estimate one. No precision estimate can therefore be described from the posted primary results.

What does the single-group design permit?

The study model is single-group, allocation is NA, and masking is none. The record therefore does not describe a randomized contrast between treatment groups. General statistical context: a one-group study can record outcomes over time among treated participants, but a change from baseline does not by itself identify what would have happened to those same participants without the intervention. Natural variation, measurement conditions, and other time-related influences can also contribute to observed change. Since the registry does not report baseline and follow-up values for the primary endpoint, even the within-group change cannot be evaluated from the posted results.

A controlled comparison answers a different statistical question from a count of outcomes in one treated group. The registry expressly cautions that the arms are not a like-for-like control comparison. Accordingly, the record does not support a treatment-versus-control effect estimate. No comparative estimate, standard error, or confidence interval is reported.

How should the planning assumptions be read?

The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is a stated fraction of the observed effect. These are planning assumptions, not a description of the design used in this single-group study. The record says that the calculations are illustrations rather than the trial’s own design, and that participant counts for non-time-to-event outcomes are expressed per arm. Such counts are planning quantities; they are not observed power and do not show how informative the study results are.

General statistical context: a sample-size calculation depends on the outcome, the effect one aims to detect, variability or event frequency, the significance level, and the statistical method. Planning for a smaller effect generally requires more information than planning for a larger effect, all else being equal. That general relationship does not supply a justification for the enrollment in this study. The registry record does not report a trial-specific sample-size justification. It also does not give numerical planning counts in the information available, nor does it report the primary outcome count needed to assess an observed effect.

What does the absence of analyses mean?

The registry lists 0 analyses. This means the record does not include analysis entries; it does not establish that no analysis was ever performed outside the registry. No statistical test, estimation method, covariate adjustment, or confidence-interval method is reported in the registry record. Without such details and the corresponding outcome data, readers cannot assess whether an analysis was prespecified, how it handled the small group, or how any estimates should be interpreted.

General statistical context: when outcome data are sparse, the choice of method can matter. Approximate methods may perform poorly with very small samples, while exact or other small-sample approaches may be considered depending on the estimand and data structure. No method can be attributed to this study from the registry information. The record also does not report whether urinary cortisol was analyzed as a normalized/not-normalized classification only, as a continuous measurement, or both.

Multiplicity is relevant because the record lists a primary outcome and multiple secondary outcomes. General statistical context: when many outcomes or tests are examined, the chance of at least one apparently notable result can increase unless the interpretation or testing strategy accounts for the number and relationships of the analyses. The registry does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes. With no posted outcome analyses, the extent to which multiplicity affected interpretation cannot be assessed.

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("R-roscovitine")
n      <- c(4)
events <- c(0)
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  R-roscovitine  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including the primary urinary free cortisol endpoint and secondary outcomes concerning HbA1c, adverse events, tumor size, clinical signs and symptoms, fasting glucose, plasma ACTH, and serum cortisol. It lists 0 analyses. The record does not report a testing hierarchy, a multiplicity adjustment, or a plan for prioritizing the secondary outcomes. General statistical context: when several outcomes are tested, interpreting each result as if it were the only analysis can make chance findings more likely across the set. The registry record does not state how that issue was addressed.

The primary endpoint result and results for the listed secondary outcomes are not reported in the registry record. There are no posted estimates or analysis details from which to assess whether all enrolled participants contributed data to each outcome, how missing measurements were handled, or whether the analysis used a particular population definition. An intention-to-treat, per-protocol, or other analysis population is not reported in the registry record.

The record does not describe reasons for missing outcome data, imputation methods, sensitivity analyses, or handling of participants who did not complete follow-up. This matters because the study status is terminated and the listed outcomes include measurements at baseline and 4 weeks, but the record does not say whether all enrolled participants completed those assessments. The termination reason and the number with evaluable primary outcome data are not reported in the registry record. No inference should be made about completion or missingness from the status alone.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports 0 serious adverse events among 4 participants at risk, 2 other adverse events among 4 participants at risk, and 0 deaths in the R-roscovitine group. These figures are descriptive counts for this study group. The record does not provide serious adverse-event terms, and the other adverse events are not further described in the information available. It is therefore not possible to characterize their nature, timing, severity, or relationship to treatment from these entries.

General statistical context: a count of zero serious events in a small group does not establish that the underlying risk is zero. The observed count describes only what the registry records for the participants at risk in this study. A small group also provides limited information about uncommon events. The study has no control group, so these counts do not provide a comparative safety estimate. The registry record does not report additional safety analyses or follow-up beyond the stated entries.

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

The posted information establishes that a Phase 2, single-group study of R-roscovitine enrolled 4 participants and was terminated. It specifies a 4-week regimen and a primary endpoint based on whether 24-hour urinary free cortisol was within the laboratory’s normal range. It also records 0 serious adverse events among 4 at risk, 2 other adverse events among 4 at risk, and 0 deaths.

It does not establish how many participants reached the primary endpoint. The urinary cortisol result is not reported in the registry record. Results for the listed measures of ACTH, cortisol, glucose, HbA1c, tumor size, clinical signs, and symptoms are also not reported in the registry record. Without outcome estimates, uncertainty measures, and an analysis description, the extent or precision of any changes cannot be assessed.

Because the design is single-group and has no like-for-like control comparison, the registry does not provide a controlled estimate of treatment effect. General statistical context: observations after an intervention can describe what happened in the study group, but a causal interpretation requires careful consideration of alternative explanations and design features. No treatment conclusion follows from the design description or from the limited adverse-event counts alone.

The enrollment of 4 participants also limits how broadly the observed safety counts can be interpreted. The record does not report why the study was terminated, whether all participants completed the planned regimen, or how missing outcomes were handled. These gaps do not prove that a particular outcome occurred or that it did not occur; they limit what can be concluded from the registry record.

14. Why This Trial Matters Statistically

This study is statistically instructive because its central endpoint is clearly framed as a participant count, yet the record does not report that count. The distinction between a defined outcome and an available outcome result is important: readers can identify what investigators intended to measure without being able to assess the observed result or its uncertainty.

The single-group design also illustrates the difference between documenting outcomes after treatment and estimating a comparative effect. With no like-for-like control group, the record cannot show how outcomes would compare under another treatment or without the intervention. A baseline value is useful for describing a participant’s starting measurement, but it is not a substitute for a concurrent control group.

Enrollment of 4 participants highlights the importance of precision. General statistical context: small studies can be useful for describing feasibility or generating questions, but a small amount of outcome information usually constrains precision and the ability to characterize uncommon events. In this record, the primary outcome count and most secondary results are not reported, so even a descriptive assessment of efficacy-related outcomes is unavailable.

The safety entries are also a reminder to distinguish zero observed serious events from zero underlying risk. The counts are meaningful as a description of the recorded group, but they cannot characterize event rates precisely or establish a comparison. Finally, the record lists 11 outcomes and 0 analyses, making the absence of analysis details and multiplicity information salient. A defined analysis plan and complete outcome reporting would be needed to understand how the measures were interpreted.

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.

Several limitations are specific to the information recorded for this study. Enrollment was 4 participants, and the study had a single group with no randomized or concurrent control comparison. Masking is listed as none. These design features constrain comparative interpretation, while the small group limits the precision and breadth of descriptive safety information.

The primary outcome is specified, but its result is not reported in the registry record. The listed secondary outcomes also lack reported results in the information available. The registry lists 11 outcome measures and 0 analyses, and it does not provide statistical methods, confidence intervals, or a multiplicity strategy. The sample-size justification and analysis population are not reported in the registry record.

The study status is terminated, but the reason is not reported in the registry record. The record does not state whether all participants completed the 4-week regimen, how many had evaluable measurements at follow-up, or how missing outcome data were handled. It also does not describe participant characteristics in detail, limiting assessment of how closely the enrolled group reflects the population named in the study question.

For safety, the registry gives aggregate counts but no serious-event terms and little detail about other adverse events. The small group and absence of a comparator limit interpretation of these counts. These reporting limitations mean that the registry record can describe the planned question, design, and posted safety figures, but cannot support a detailed assessment of efficacy-related outcomes or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Treatment of Cushing's Disease With R-roscovitine — NCT02160730.
• Registry record last updated 2021-11-04; status last verified 2021-11.
• Results first posted 2021-10-29.
• 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

This Phase 2 study evaluated R-roscovitine in Cushing disease using a single-group design with no masking. The recorded regimen was 400 mg orally twice daily for 4 days every week for a total of 4 weeks. Enrollment was 4 participants; the status is terminated. The primary outcome was the number of participants with normalized 24-hour urinary free cortisol after 4 weeks.

The primary outcome result and results for the listed secondary measures are not reported in the registry record. The registry lists 11 outcome measures and 0 analyses. It records 0 serious adverse events among 4 at risk, 2 other adverse events among 4 at risk, and 0 deaths. The reason for termination, analysis population, missing-data methods, and trial-specific sample-size justification are not reported in the registry record.