Extension Study to Assess the Safety and Efficacy of Pasireotide in Participants With Cushing's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Extension Study to Assess the Safety and Efficacy of Pasireotide in Participants With Cushing's Disease (NCT00171951), a na phase 2 study. The primary outcome is Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits.

2. Clinical Question

3. Trial Design

This was a Phase 2, single-group, open-label extension study of pasireotide in participants with Cushing's disease. The registry record identifies Novartis Pharmaceuticals as the sponsor and lists enrollment of 19 participants. The study is marked completed; its recorded start date is 2004-08-13 and its primary completion date is 2013-07-08. Those dates describe the registry record and do not, by themselves, give each participant's treatment duration.

The design does not include a randomized control arm, and masking is listed as none. Allocation is recorded as not applicable. The study therefore describes outcomes among participants receiving pasireotide rather than estimating a randomized treatment contrast. Its two dose labels should not be interpreted as independent comparison groups: the arm description indicates use of 600 μg twice daily subcutaneously, with an increase to 900 μg twice daily subcutaneously if UFC levels increased. This dose adjustment makes a direct comparison between the listed dose groups especially difficult to interpret.

The registry describes the study as an extension, and the primary efficacy population refers to core-baseline measurements. Details of the parent study, participant movement into the extension, treatment exposure over time, and the full conduct of the extension are not reported in the registry record. The available description is therefore not sufficient to reconstruct the sequence of treatment and measurement for every participant.

The primary endpoint was the percentage of responders at Month 6, based on UFC. Listed secondary outcomes include adverse events, serum cortisol, pasireotide trough concentrations in UFC responders, plasma ACTH, and biomarker measures. The record lists seven outcome measures in total but no analysis entries. It does not report a statistical analysis plan or a sample-size justification.

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: The study included participants with Cushing's disease who received 15 days of pasireotide treatment in the Core Study CSOM230B2208 (NCT00088608). This study was an extension study of the Core Study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Primary Efficacy Population included participants from ITT whose mean UFC at core-baseline, based on at least 2 UFC samples, was \>1.0x upper limit of normal (ULN) or for whom the one and only UFC sample available at baseline was \>2.0xULN.

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: Intent-to-treat (ITT) population included all participants who completed 15 days of treatment in Core study and experienced significant clinical benefit from treatment and received at least 1 dose in the Extension Period.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Responders With Mean Urinary Free Cortisol (UFC) Within Normal Limits, measured over Month 6.

The primary endpoint is the percentage of responders whose mean UFC was within normal limits at Month 6. UFC measures cortisol excreted in urine, and the endpoint uses two 24-hour urine samples collected at that time. A participant qualifies as a responder when the mean of those samples falls within the registry's stated normal range of 55 to 276 nmol/day. The primary efficacy population was restricted using baseline UFC criteria: a mean based on at least two core-baseline samples had to be >1.0xULN, or the sole baseline sample had to be >2.0xULN.

As a binary endpoint, this measure classifies each participant as either meeting or not meeting the responder definition. Reporting the percentage gives a group-level description of how many participants met that criterion. The confidence interval is intended to convey uncertainty around that percentage; a wider interval generally indicates less precision, while a narrower interval indicates greater precision. Those are general statistical interpretations, not findings about this study's interval.

The registry record identifies the endpoint and its timeframe, but does not report the Month 6 responder percentage or its 95% confidence interval. Consequently, the posted record does not establish the observed responder frequency or the precision of that estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary response measure: each participant either meets the Month 6 UFC criterion or does not. The registry defines response as a mean UFC within the normal range of 55 to 276 nmol/day, calculated from two 24-hour urine samples collected at Month 6. The reported group-level quantity would be the percentage meeting that definition in the primary efficacy population. The registry record does not report the observed percentage.

What a confidence interval would communicate

In general, a confidence interval expresses the statistical uncertainty associated with an estimated quantity. For a responder percentage, it indicates a range of values compatible with the observed data under the method used to construct the interval. It is not a range containing a specified percentage of individual participant outcomes, and it does not correct limitations in study design or data collection. The registry names a 95% confidence interval for the endpoint but does not report its limits. Its width, center, and implications for precision therefore cannot be assessed.

Why the design matters

This is a single-group study, with allocation recorded as not applicable and masking recorded as none. General statistical interpretation of a single-group endpoint is descriptive: it characterizes outcomes in the participants assessed. A randomized comparison can support a treatment contrast by comparing groups formed under an allocation process; this record does not describe such a comparison. The two dose groups are not a substitute for randomized arms. The dose description indicates that participants could receive 900 μg BID SC if UFC levels increased, so assignment to the listed dose categories may reflect response or treatment decisions rather than an independent comparison.

In general, selection into a higher-dose group based on a measured outcome can make group differences difficult to interpret. The groups may differ in their clinical course or other characteristics, and the registry record does not provide an adjustment strategy to address those differences. It also does not report dose-specific primary endpoint estimates. Therefore, the available safety counts should not be used to infer a causal difference between doses.

Interpreting adverse-event counts

The adverse-event information includes counts of participants with at least one event in each listed group. The record reports 2 of 19 participants with a serious adverse event and 19 of 19 with another adverse event in the 600 μg BID SC group. It reports 2 of 8 and 8 of 8, respectively, in the 900 μg BID SC group. These counts describe participants, not necessarily the total number of events: one participant may have experienced more than one event. The record also reports zero deaths in each group. It does not provide enough detail to infer event timing, recurrence, exposure-adjusted rates, or treatment attribution.

The listed serious event terms have percentages attached, but the registry entry does not report the denominator or calculation details for those percentages. A percentage without a clearly stated denominator and event-count context does not provide a complete basis for comparing risks. The listed terms should therefore be treated as descriptive registry entries rather than as a ranked or fully quantified safety profile.

Planning calculations and analysis plans

General sample-size planning estimates ask how many participants per arm might be needed to detect a specified effect under stated assumptions. The registry's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect defined as a stated fraction of the observed effect. These are planning illustrations, not evidence that the original study used those assumptions. They are not observed power and do not establish that the study was designed with a particular sample size. The record does not report the trial's own sample-size justification, and the single-group design differs from the two-arm planning setup.

In general, power is a property of a design and an assumed effect size; it is not a measure of whether an observed result is true. Retrospective calculations based on an observed effect can be misleading because the observed estimate is itself uncertain. Planning estimates should instead be read as conditional illustrations under their assumptions. No numerical planning estimates are included in the registry entries described for this analysis.

The registry lists seven outcome measures and no analysis entries. This does not establish which analyses were conducted outside the registry record. The record does not report the statistical methods used for the primary endpoint, confidence-interval construction, covariate adjustment, or handling of repeated measurements. It also does not report an interim-analysis plan. These omissions mean that the precision and analytic choices behind any unposted estimate cannot be reconstructed from the registry record.

UFC is measured repeatedly in the endpoint definition, with two samples contributing to the Month 6 mean. In general, averaging repeated measurements can reduce the influence of short-term variation, while the use of a threshold converts a continuous measure into a responder classification. That classification can make the outcome easier to interpret against a defined normal range, but it also discards information about how far a participant's value lies from the threshold. These are general properties of the endpoint, not claims about the observed data in this study.

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("Pasireotide 600 μg BID SC or Ramp up Dose 900 μg B")
n      <- c(18)
events <- c(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  Pasireotide 600 μg BID SC or Ramp up Dose 900 μg B  18  4  22.2  6.4  47.6  9.0  45.2  9.1  45.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven outcome measures, including the Month 6 UFC responder endpoint and secondary measures concerning adverse events, serum cortisol, pasireotide trough concentrations among UFC responders, ACTH, and biomarker development. It lists no analysis entries. The record does not report a multiplicity strategy, such as whether outcomes were prioritized, whether testing was adjusted across outcomes, or whether secondary analyses were considered exploratory. Without that information, the chance of false-positive findings across multiple statistical tests cannot be assessed from the registry record. No claims about statistical significance across outcomes can be made from the listed outcome descriptions alone.

The primary efficacy population is described using core-baseline UFC criteria and is drawn from the intention-to-treat population. The registry does not report the number of participants who met those criteria or the number included in the Month 6 endpoint analysis. It also does not report how participants without the required Month 6 urine samples were handled, whether any values were imputed, or whether the analysis used a particular missing-data assumption. These details matter because a responder percentage depends on who is included in its denominator and how missing endpoint measurements are treated.

In general, missing-data methods can affect both the estimate and its uncertainty, especially when the likelihood of missing measurement is related to a participant's health status or treatment course. Complete-case analysis, imputation, and other approaches rely on different assumptions. The registry record does not identify which approach, if any, was used here, so none should be attributed to this study.

The registry also does not report whether the primary efficacy analysis followed the stated population definition in practice, or whether additional populations were used. The distinction between planned population and analyzed population is important, but the record does not provide the counts needed to evaluate it.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: urinary tract infection (12.5%), skin injury (12.5%), type 2 diabetes mellitus (12.5%), convulsion (5.3%), pneumothorax (5.3%).

The registry lists serious adverse events separately from other adverse events. For the 600 μg BID SC group, 2 of 19 participants had at least one serious adverse event, and 19 of 19 had at least one other adverse event. For the 900 μg BID SC group, the corresponding entries are 2 of 8 and 8 of 8. The record lists zero deaths in each group. These are participant counts within the registry's labeled groups, not estimates from a randomized comparison.

The listed serious event terms are urinary tract infection, skin injury, type 2 diabetes mellitus, convulsion, and pneumothorax. The registry attaches percentages to these terms, including 12.5% for urinary tract infection, skin injury, and type 2 diabetes mellitus, and 5.3% for convulsion and pneumothorax. The record does not report the denominator or event-count details underlying these term percentages. They should not be interpreted as comparative risks or used to infer treatment causation.

In general, adverse-event counts are affected by the length and completeness of observation, exposure, definitions, and how events are collected. Those details are not fully reported in the registry record. The 600 μg and 900 μg groups also do not provide a like-for-like safety comparison because the study is not randomized and the dose could be increased in response to UFC levels.

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

The registry record establishes the study's intended primary question and endpoint definition, but it does not report the primary responder percentage or the 95% confidence interval. As a result, the posted information does not quantify the frequency of Month 6 UFC normalization in the defined primary efficacy population. It also does not show how precisely that frequency was estimated. The endpoint's stated normal range and baseline eligibility criteria describe what was to be measured, not the observed result.

The safety entries provide descriptive counts for participants with serious and other adverse events, as well as a list of serious event terms. They do not establish whether events were caused by pasireotide, nor do they support a controlled comparison between the listed dose groups. The group labels reflect a study in which 900 μg BID SC could be used after UFC levels increased, rather than randomized dose allocation. The listed counts should therefore be read as observations in the registry, not as evidence of a dose-related difference.

In general, a single-group extension study can contribute information about outcomes observed during continued or extended treatment, but it cannot by itself distinguish treatment effects from other causes of change. Interpretation also depends on who entered the extension, how long participants were observed, which measurements were available, and how missing data were handled. Those details are not fully reported in the registry record.

The record does not provide enough statistical detail to evaluate the analysis of the primary endpoint, the treatment of missing measurements, multiplicity across outcomes, or the original sample-size rationale. The planning assumptions describe hypothetical calculations and should not be confused with observed power or with the trial's own design. The main conclusion from the registry material is therefore about what was specified and what was recorded: a Month 6 responder endpoint was defined, safety counts were listed, and the primary numerical efficacy result is not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between defining an endpoint and reporting its result. The registry gives a specific responder rule based on the mean of two 24-hour UFC samples and a stated normal range, but does not report the responder percentage or confidence interval. A detailed endpoint definition cannot substitute for the estimate needed to understand the observed frequency or its precision.

The extension design also highlights the limits of interpreting dose groups. A single-group, open-label study does not create a randomized contrast, and the description indicates that dose could increase if UFC levels rose. This means the dose labels are connected to treatment decisions and participant response. The listed group counts can describe the registry's safety entries, but they do not by themselves identify what would have happened under a different dose.

The record's safety information illustrates why denominators and definitions matter. It reports participant counts for serious and other adverse events, but the denominator and event-count context for the listed serious-event percentages are not reported. Without those details, the percentages cannot be fully evaluated or compared. General statistical interpretation requires attention to who was observed, for how long, and how event information was collected.

Finally, the registry distinguishes outcome descriptions from analysis documentation: it lists seven outcome measures but no analysis entries. Missing-data procedures, multiplicity handling, the primary analysis method, and sample-size justification are not reported in the registry record. These omissions do not establish what investigators did outside the registry, but they limit reproducibility and independent assessment of the posted results. The study therefore illustrates how registry transparency depends not only on naming outcomes, but also on reporting estimates, uncertainty, analysis populations, and methods.

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 most immediate limitation is that the registry record does not report the primary Month 6 responder percentage or its 95% confidence interval. The endpoint can be described, but its observed frequency and precision cannot be assessed. The record also does not give the number of participants meeting the primary efficacy population criteria or the number contributing Month 6 samples.

The design is single-group, open-label, and has no randomized control group. Therefore, the record does not provide a controlled estimate of the effect of pasireotide. The listed dose groups should not be treated as randomized comparison arms: the dose description indicates that participants could receive 900 μg BID SC when UFC levels increased. The registry does not report dose-specific efficacy estimates or an adjustment method that would make such a comparison interpretable.

Information needed to evaluate safety fully is also limited. The record lists participant counts with events and deaths, but does not provide event timing, duration, recurrence, exposure-adjusted rates, or treatment attribution. It lists percentages for serious event terms without reporting the denominator or underlying event counts for those terms. The period of observation for each participant is not specified in the available description.

The registry does not report the primary statistical method, confidence-interval construction, missing-data handling, multiplicity strategy, interim-analysis plan, or sample-size justification. It also does not report whether all listed outcomes were analyzed or how analyses were selected. These limitations constrain reproducibility and interpretation of any unreported results. They do not establish that analyses were not performed; they identify information not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Extension Study to Assess the Safety and Efficacy of Pasireotide in Participants With Cushing's Disease — NCT00171951.
• Registry record last updated 2021-06-02; status last verified 2021-05.
• Results first posted 2021-06-02.
• 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

The registry record identifies NCT00171951 as a completed Phase 2, open-label, single-group extension study of pasireotide in Cushing's disease, sponsored by Novartis Pharmaceuticals. Enrollment was 19. The recorded start date is 2004-08-13, and the primary completion date is 2013-07-08.

The primary endpoint was the percentage of responders with mean UFC within normal limits at Month 6, defined using two 24-hour urine samples and a normal range of 55 to 276 nmol/day. The responder percentage and its 95% confidence interval are not reported in the registry record. The record lists adverse-event counts for the 600 μg BID SC and 900 μg BID SC groups, with zero deaths in each group, but these are not randomized comparison arms. The record lists seven outcome measures and no analysis entries. Statistical methods, missing-data procedures, multiplicity handling, and sample-size justification are not reported in the registry record.