Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism (NCT02001051), a randomized phase 2 study. The primary outcome is Proportion of Patients That Have Normalization and/or Improvement of Metabolic Complications After Adrenalectomy.

2. Clinical Question

The trial asks whether adrenalectomy is associated with normalization or improvement of metabolic complications among people with subclinical hypercortisolism. The registry identifies the complications of interest as hypertension, diabetes, osteoporosis, hypercholesterolemia, and obesity, and sets assessment at 6 months. Its primary endpoint description defines the intended comparison as 35% of patients improving with surgery versus 5% who do not have surgery.

This is a question about a defined clinical outcome, not simply whether a tumor is removed. The endpoint combines several metabolic conditions, so a participant could potentially qualify through improvement in one or more of those conditions. The registry does not report the detailed decision rules for classifying improvement, how multiple complications were combined, or whether the assessment required a particular degree of change. Those details are not reported in the registry record.

The registry also lists secondary questions about adrenal cancer detection, diagnosis by FDG PET/CT, diagnostic testing, quality of life, deep venous thrombosis, and dermal thickness. They broaden the scientific scope beyond the primary metabolic endpoint. With enrollment of 4 and no analyses posted, the available results do not provide a dependable answer to the primary comparison or those secondary questions.

3. Trial Design

This is a randomized, open-label, parallel Phase 2 trial sponsored by the National Cancer Institute (NCI). The registry lists enrollment of 4 and status as terminated. The recorded start date is 2013-11-27, and the primary completion date is 2017-08-22. The reason for termination is not reported in the registry record.

The brief description says participants would be screened with medical history, blood tests, and CT imaging, then complete a baseline visit with blood and urine tests and scans. It describes surgery either soon after enrollment or 6 months later, with follow-up visits after surgery and annual visits during later follow-up. The description is truncated, so the complete visit schedule and all procedural details are not reported in the registry record. The primary endpoint timeframe is stated separately as 6 months.

Randomization means that assignment to the study strategies is intended to occur by chance. In general, this can reduce systematic differences between groups at the start of a study. It does not ensure that groups will be similar in every characteristic, particularly when enrollment is very small. The method used to generate the allocation sequence, any allocation concealment procedures, and the number assigned to each group at randomization are not reported in the registry record.

The registry identifies an Operative Arm and a Delayed Operative Arm, and lists adrenalectomy and observation among the interventions. It does not supply a complete account of the treatment actually received by each participant or the timing of each operation. The distinction matters because the primary endpoint refers to surgery compared with no surgery, whereas the arm title describes delayed operation. The intended comparison can be described from the registry, but its implementation cannot be fully reconstructed from the record.

No masking is listed. In general, an open-label design means participants and study staff are not masked to treatment assignment. For an outcome based on clinical measurements, knowledge of assignment may matter if measurement or classification involves judgment. Whether outcome assessors were independent or masked is not reported in the registry record. The protocol, eligibility details beyond the brief description, and prespecified statistical plan are also not reported in the registry record.

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: One participant was enrolled to the delayed operative arm but did not complete. The participant did not have biochemical evidence of subclinical Cushing's and therefore was not eligible.

Overall Study

Reasons for not completing this period:

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 Proportion of Patients That Have Normalization and/or Improvement of Metabolic Complications After Adrenalectomy, measured over Assessed at 6 months.

The primary endpoint is the proportion of participants with normalization and/or improvement in metabolic complications after adrenalectomy. The conditions named are hypertension, diabetes, osteoporosis, hypercholesterolemia, and obesity. Assessment is specified at 6 months. This endpoint is intended to capture changes in health conditions associated with excess cortisol rather than focusing only on the adrenal tumor itself.

A proportion is a binary-outcome summary: each participant is classified as meeting or not meeting an outcome definition, and the result describes the share classified as having the event. In general, this can be easy to interpret clinically, but its meaning depends on a clear and consistently applied definition of the event. Here, the registry states that improvement is defined as 35% of patients improving with surgery versus 5% who do not have surgery. It does not report the condition-specific thresholds, how normalization differs from improvement, how multiple complications are combined, or how missing measurements are handled.

The posted arm results list a value of 1.0 with n of 2 for the Operative Arm and a value of 0.0 with n of 1 for the Delayed Operative Arm. These entries are too limited to establish a stable estimate of the intended proportion or a reliable comparison. The registry record does not provide an analysis estimate, uncertainty interval, or test for the primary endpoint. The endpoint is therefore useful for identifying the intended clinical question, but the posted results do not resolve it.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, open-label, parallel Phase 2 design. In general, random assignment is used to make treatment groups comparable in expectation, while a parallel design assigns each participant to a strategy and follows that participant within that group. The record does not report how the random sequence was generated, how assignments were concealed before enrollment, or whether the assignment ratio was prespecified. The actual randomization details are not reported in the registry record.

How to read a binary proportion

The primary outcome is a proportion: whether a participant has normalization and/or improvement in metabolic complications by the specified assessment. For a binary endpoint, each participant contributes a classification under the outcome definition. The group proportion is the number meeting that definition relative to the number assessed. General interpretation depends on having complete outcome status and a stable definition applied across groups.

The registry describes the endpoint as including several possible conditions. It does not explain whether each condition was analyzed separately, whether any one improved condition was enough to count, or whether a participant had to meet a combined rule. It also does not state whether the endpoint is based on improvement from baseline, normalization to a target, or either outcome according to condition-specific criteria. Those operational details are not reported in the registry record, so the event classification cannot be independently reconstructed.

Effect estimates and uncertainty

For a comparison of binary outcomes, analysts commonly report group proportions and a contrast between them, such as a difference in proportions or a relative measure. A confidence interval can communicate how much uncertainty surrounds the estimate. In general, intervals are wider when the amount of information is limited, and may be especially unstable when there are very few participants or when outcome categories are sparse.

The registry’s posted entries are a value of 1.0 for the Operative Arm with n of 2 and a value of 0.0 for the Delayed Operative Arm with n of 1. The registry does not post a calculated comparative effect, confidence interval, or p-value. The listed outcome values therefore should be read as limited descriptive entries, not as a complete inferential analysis. The reason that a two-arm comparison is not estimable from the posted summary is that the values are missing or not estimable for that endpoint, as indicated in the record.

Sample-size illustrations

The registry record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. This is a planning framework, not evidence that the trial had adequate power and not a report of the original design justification. The registry does not report the trial’s own sample-size justification.

In general, a sample-size calculation depends on assumptions about the effect of interest, outcome variability, significance level, power, and allocation. When the observed effect comes from a very small study, it is an unstable basis for planning another study. A planning illustration should not be interpreted as observed power, nor as a guarantee that a particular effect can be detected. The registry record does not report an original target enrollment or a power calculation for the trial’s own design.

Multiplicity and secondary outcomes

Multiplicity arises when several outcomes or statistical comparisons are tested. In general, conducting many tests can increase the chance of finding an apparently notable result by chance unless the analysis plan addresses that issue. The registry lists six secondary outcomes, in addition to the primary endpoint, but does not report whether any multiplicity strategy was planned. No adjustment method or hierarchy among outcomes is reported in the registry record. With no analyses posted, there are no secondary estimates to interpret or compare.

Missing outcomes and analysis sets

Missing-data methods address participants whose outcome status is unavailable. In general, complete-case summaries use only participants with observed outcomes, while other approaches may make assumptions about missing values. The registry does not report how many participants completed the primary assessment, whether any outcome data were missing, or how missing data were handled. It also does not report whether the analysis followed randomized assignment, used participants who received treatment, or applied another analysis population definition.

These details matter because the posted arm outcome entries have different listed sample sizes, and the safety record lists different at-risk counts than the primary outcome entries. Without a participant-flow account and a prespecified analysis description, it is not possible to determine from the registry whether those counts reflect different analysis populations, incomplete follow-up, or another reporting structure. No explanation is reported in the registry record.

Dispersion and model choice

The endpoint is binary rather than a continuous measurement, so the central statistical issue is the number classified with the outcome relative to the number assessed, along with the uncertainty in that proportion and its comparison. Over-dispersion is a general concern in count or proportion models when observed variability exceeds what a chosen model assumes. It can arise when outcomes are more heterogeneous than the model allows. The registry does not report a fitted model or a dispersion assessment, and the very limited posted outcome entries do not support evaluating such features.

Overall, the record gives a design label and a primary outcome description, but not the details needed to reproduce or assess an inferential analysis. The statistical plan, model, confidence-interval method, missing-data procedure, multiplicity approach, and analysis populations are not reported in the registry record.

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("Operative Arm", "Delayed Operative Arm")
n      <- c(2, 1)
events <- c(0, 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  Operative Arm  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Delayed Operative Arm  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2

11. Multiplicity, Missing Data and Analysis Populations

The registry names a primary endpoint and six secondary outcomes. The secondary questions concern adrenal cancer after adrenalectomy, diagnosis by FDG PET/CT, the optimal diagnostic test, quality of life, deep venous thrombosis, and dermal thickness. The record does not state whether these outcomes were organized into a testing hierarchy or whether any adjustment for multiple comparisons was planned.

In general, multiplicity matters when investigators examine several outcomes or several comparisons, because the chance of a result that appears notable by chance can rise as the number of tests increases. An analysis plan may address this through prespecified priorities or statistical adjustments. No such approach is reported in the registry record. Since no analyses are posted, there are no secondary findings for which adjusted or unadjusted inference can be evaluated.

The record does not report the number of participants with missing primary outcome data, the completeness of follow-up, or a method for handling missingness. It does not identify an intention-to-treat population, a per-protocol population, or another analysis set. These omissions limit interpretation because the primary outcome entries list n of 2 in one arm and n of 1 in the other, while the adverse-event entries list 2 at risk in each arm. The record does not explain the difference in reported counts.

In general, missing-data assumptions can affect estimated proportions and between-group comparisons, particularly when outcome status is unavailable for a substantial part of a small study. The registry does not report whether all randomized participants were analyzed, whether participants withdrew, or whether any sensitivity analysis was conducted. Such details are not reported in the registry record, so the effect of missingness and the population underlying each result cannot be determined.

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.

The serious adverse-event entries list 2 participants at risk in the Operative Arm and 2 in the Delayed Operative Arm. Each arm is listed with 0 serious adverse events and 0 deaths. The other-adverse-event entries also list 2 at risk in each arm and 0 other adverse events in each. These are the registry’s posted safety counts.

A zero count in a small group is a description of the events recorded in that group; it does not establish that the risk of an event is zero. In general, limited exposure and few participants provide little information about uncommon harms. The registry record does not report event definitions, the safety observation period, severity details beyond the serious-event category, or whether events were assessed as related to the intervention.

The safety at-risk counts do not match the primary outcome entries, which list n of 2 and n of 1. The record does not explain the differing counts or provide a participant-flow account that would reconcile them. No serious-event terms are listed. The safety entries should therefore be interpreted as sparse registry counts, not as a precise comparison of safety between strategies.

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

The registry record establishes that a randomized Phase 2 study was undertaken to compare adrenalectomy with an observation or delayed-operative strategy for subclinical hypercortisolism. It identifies metabolic improvement at 6 months as the primary question and lists additional diagnostic, quality-of-life, cancer-detection, and safety outcomes. These details describe the study’s aims and structure.

The posted primary outcome entries are limited to n of 2 in the Operative Arm and n of 1 in the Delayed Operative Arm, with reported values of 1.0 and 0.0, respectively. There is no posted comparative estimate or uncertainty interval. Therefore, those entries cannot establish the size or precision of a treatment effect. They should not be treated as proof of benefit, lack of benefit, or equivalence between strategies.

The endpoint definition includes 35% improvement with surgery and 5% without surgery. The registry does not clarify how those figures were derived or relate them to an inferential analysis. They are part of the endpoint description, not a substitute for analyzed results from the enrolled participants.

The safety record lists no serious adverse events, other adverse events, or deaths in the recorded at-risk groups. Because those groups are very small and the record gives limited context about ascertainment and follow-up, the absence of recorded events cannot establish the absence of risk.

The status is terminated, and the reason is not reported in the registry record. The record also does not provide the protocol, a complete statistical analysis plan, participant flow, or an account of missing outcomes. As a result, the registry supports a description of the intended clinical question and the small set of posted entries, but not a conclusive estimate of the comparative effects or harms of the study strategies.

14. Why This Trial Matters Statistically

This trial matters statistically because it illustrates the difference between a clearly stated research question and an adequately informative result. The registry specifies a randomized comparison and a primary endpoint focused on metabolic complications. Randomization is a sound general approach for reducing systematic allocation differences, but the amount of information ultimately available is also central to what can be learned.

With enrollment of 4, the posted primary outcome information is exceptionally limited. In general, estimates from very small groups are sensitive to the outcome of each participant and have substantial uncertainty. A numerical contrast, even if calculated from the entries, would not by itself make the result precise or representative. The registry does not post a comparative estimate or uncertainty interval, so the reader cannot judge precision from an analysis result.

The record also shows why outcome definitions and analysis details matter. The primary outcome combines normalization and improvement across several metabolic conditions, yet the exact classification rules are not reported. The statistical plan, handling of missing data, analysis population, and multiplicity approach are likewise not reported. Without those details, readers cannot fully evaluate how the intended outcome would be measured or how the investigators planned to draw conclusions.

The safety counts reinforce the same point. Zero events are recorded, but the at-risk groups are small and the registry does not provide a detailed safety-analysis framework. A sparse event record is not equivalent to precise evidence about safety.

For biostatisticians and clinical researchers, the key lesson is not about a treatment conclusion. It is that design labels, endpoint descriptions, and a few posted values should be distinguished from a complete statistical analysis. The record conveys the study’s purpose, while leaving its treatment-effect estimates and many analysis decisions unresolved.

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, leaving very limited outcome information for the primary comparison. The posted primary entries list n of 2 for the Operative Arm and n of 1 for the Delayed Operative Arm, and the registry does not provide a comparative estimate or uncertainty interval. This prevents assessment of the effect’s precision.

The registry does not report why the trial was terminated, how many participants were randomized to each arm, or a flow of participants through screening, treatment, and follow-up. It is therefore not possible to determine whether the posted endpoint counts represent all randomized participants or a subset. The safety record lists 2 at risk in each arm, which does not align with the primary outcome counts; the reason is not reported in the registry record.

The primary outcome combines normalization and/or improvement in several metabolic complications. Detailed criteria, measurement procedures, and rules for combining conditions are not reported. The endpoint description includes 35% and 5%, but their derivation and analytic role are not explained in the record.

The intervention and comparator are not fully clear from the brief description and arm labels. The record mentions adrenalectomy, observation, an Operative Arm, and a Delayed Operative Arm, but does not provide a complete account of what each participant received or when. Masking is listed as none; whether outcome assessors were masked is not reported.

Finally, the statistical analysis plan, missing-data procedures, analysis populations, multiplicity strategy, and reason for termination are not reported in the registry record. The six listed secondary outcomes have no posted analyses. These limitations restrict interpretation to the study’s stated aims and sparse posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Adrenalectomy Versus Observation for Subclinical Hypercortisolism — NCT02001051.
• Registry record last updated 2018-06-14; status last verified 2018-05.
• Results first posted 2018-05-08.
• 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

NCT02001051 is a randomized, open-label, parallel Phase 2 study of adrenalectomy versus observation for subclinical hypercortisolism. It lists enrollment of 4, status as terminated, and sponsorship by the National Cancer Institute (NCI). The recorded start date is 2013-11-27, and the primary completion date is 2017-08-22.

The primary endpoint concerns normalization and/or improvement of metabolic complications assessed at 6 months. The posted arm entries are a value of 1.0 with n of 2 for the Operative Arm and a value of 0.0 with n of 1 for the Delayed Operative Arm. No comparative analysis is posted. Safety entries list 0 serious adverse events, 0 other adverse events, and 0 deaths in groups with 2 at risk per arm.

The registry lists six secondary outcomes but no analyses. The reason for termination, detailed endpoint rules, participant flow, missing-data handling, and the statistical analysis plan are not reported in the registry record. The available information describes the trial’s question and limited results, but does not support a precise treatment-effect or safety comparison.