OPALINE : A Study Of Morbidity And Mortality At 2 Years: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for OPALINE : A Study Of Morbidity And Mortality At 2 Years (NCT02264665), a registered phase not stated study. The primary outcome is Progression-Free Survival (PFS) at 2 Years Assessed by Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 - Based on Type of Treatment at Inclusion.

2. Clinical Question

3. Trial Design

OPALINE is described as a descriptive, prospective, partly retrospective, multisite observational study conducted in France. It concerned adults treated for well-differentiated, unresectable or metastatic PNET with disease progression. The registry lists an enrollment of 144 and a completed study status. The recorded start date is 2015-05-12, and the primary completion date is 2019-11-18.

Because the study is observational, treatment was part of participants' care rather than allocated by randomization in the study. Sunitinib, everolimus and chemotherapies recommended in France are named among the treatments. The registry also lists somatostatin analogues and metabolic radiotherapy in its treatment-related outcomes and safety information. Allocation is not stated. The groups are therefore not described as randomized arms or as a like-for-like control comparison.

The primary outcome is investigator-assessed progression-free survival at two years, classified by treatment at inclusion. The registry also lists outcomes concerning tumor assessment visits and investigations, treatment changes and dose changes, and lines of treatment. These are descriptive aspects of care and follow-up. The detailed protocol, recruitment procedures, treatment-selection rules and rationale for the enrollment target are not reported in the registry record.

The record gives a broad study description but not a full account of how prospective and retrospective data were combined, how each participant's follow-up was organized, or how treatment groups were defined for every analysis. Those details are important when interpreting observational data, since differences in clinical history, disease status and treatment can influence both group membership and outcomes.

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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS included participants who met eligibility criteria, received at least 1 dose of treatment during prospective follow-up period (treatment start date must be completed, treatment stop date must be after date of inclusion if start date is prior to date of inclusion) in the study (targeted therapy or other treatment) and excluded participants with no follow-up data. Here "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

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: The full analysis (FAS) (reference) set included participants who met the eligibility criteria and had received at least 1 dose of the treatment documented during the prospective follow-up period (the treatment start date must be completed and the treatment stop date must be after the date of inclusion if the start date is prior to the date of inclusion) in the study (targeted therapy or other treatment) and excluded the participants with no follow-up data.

6. Primary Endpoint

The registry lists the primary outcome as Progression-Free Survival (PFS) at 2 Years Assessed by Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 - Based on Type of Treatment at Inclusion, measured over At 2 years of prospective follow-up.

The primary endpoint is progression-free survival (PFS) at two years, expressed as a percentage of participants and assessed by the investigator using RECIST v1.1. PFS is defined as the time from the start of the treatment line ongoing at inclusion to the first documentation of disease progression or death from any cause while receiving that main treatment. It therefore combines tumor progression and death into one time-to-event outcome.

The registry specifies RECIST v1.1 progression criteria, including at least a 20% increase in the sum of target-lesion diameters relative to the smallest sum on study treatment, with an absolute increase of at least 5 millimeters. Progression may also be based on unequivocal progression of existing non-target lesions or the appearance of one or more new target or non-target lesions.

PFS is used in trials and observational studies to describe how long participants remain alive without documented disease progression. It incorporates the timing of events, rather than counting only whether an event occurred by a single date. Participants without a recorded event may be censored at their last recorded time to progression or last tumor or disease assessment, as stated in the record. The registry names a Kaplan-Meier analysis and a 95% confidence interval, but does not report the resulting two-year PFS estimate or interval. The endpoint's numerical result and precision therefore cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as a time-to-event outcome and states that it was analyzed using the Kaplan-Meier method. In general, time-to-event analysis uses both whether an event occurred and the time until that event. For this endpoint, an event is the first documented disease progression or death from any cause, under the definition in the record. A two-year PFS percentage summarizes the estimated proportion remaining alive without a documented progression through the specified follow-up point.

What does Kaplan-Meier estimation do?

In general, the Kaplan-Meier method estimates event-free probability over follow-up while accounting for participants whose event status is not observed through the full period. Such participants may be censored: their available follow-up contributes information up to the last time they were known to be free of an event, but their later outcome is unknown. The registry states that participants without an event were censored at the last recorded time to progression or the last tumor or disease assessment. It does not report the number censored, their follow-up distribution or the reasons for missing later assessments.

Censoring is not the same as observing that a participant remained event-free for the rest of the study. It records that the participant's event-free status was known only up to a point. In general, Kaplan-Meier estimates rely on censoring not being related to a participant's underlying event risk in a way that would bias the estimate, after accounting for relevant information. The registry record does not describe checks of this assumption or provide details of censoring patterns.

How should the confidence interval be read?

The endpoint specifies a 95% confidence interval. In general, a confidence interval expresses the statistical uncertainty associated with an estimate under the analysis method. It does not show the range of individual participant outcomes, and it does not by itself establish that a difference between treatment groups is clinically important. Its width conveys precision: wider intervals indicate greater uncertainty about the estimate. Since the interval itself is not reported, the precision of the primary result cannot be evaluated.

The record gives the RECIST v1.1 definition of progression. It includes an increase of at least 20% in the sum of target-lesion diameters, relative to the smallest sum on study treatment, together with an absolute increase of at least 5 millimeters. It also includes unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. These criteria make the event definition explicit, but the record does not describe investigator training, central review, adjudication, or how disagreements in assessment were handled.

What does observational treatment grouping imply?

In general, observational comparisons describe outcomes among participants who received different care in ordinary practice. Unlike random allocation, treatment choice may depend on clinical features that also relate to prognosis. This creates the possibility of confounding: differences in outcomes may reflect differences between participants as well as differences in treatments. The record names treatment groups but does not report a randomized assignment, a matching procedure, or an adjusted causal comparison. Allocation is not stated, and the record cautions that the groups are not a like-for-like control comparison.

The primary outcome is grouped by type of treatment at inclusion, while some safety information is grouped by treatments received during the study. Those descriptions refer to distinct groupings and should not be conflated. The registry does not give enough detail to determine how changes in treatment were handled in every analysis or whether participants could contribute to more than one exposure grouping.

Are the planning figures trial results?

In general, sample-size calculations are planning illustrations based on assumptions about an effect, significance level, allocation and statistical method. They do not describe observed outcomes or establish the power of a completed study. The registry gives assumptions for a planning illustration, including a two-sided significance level of 0.05, equal allocation and a normal approximation. It states that the effect to detect is a fraction of the observed effect, and distinguishes the event-based planning approach for time-to-event outcomes from participant counts per arm for other outcomes. These assumptions are not the study's own design justification. The trial's sample-size justification and its own planning assumptions are not reported in the registry record.

The registry lists zero analyses, and it does not provide a PFS estimate, confidence interval, or treatment-effect analysis. Accordingly, the stated statistical method can be explained, but the numerical result and its interpretation cannot be reconstructed from the 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("Everolimus (Targeted Therapy) at Inclusion", "Sunitinib (Targeted Therapy) at Inclusion", "Chemotherapy (Other Treatment) at Inclusion", "Somatostatin Analogues (Other Treatment) at Inclus")
n      <- c(32, 23, 50, 27)
events <- c(8, 4, 18, 10)
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  Everolimus (Targeted Therapy) at Inclusion  32  8  25.0  11.5  43.4  13.3  42.1  13.3  42.3
ARM  Sunitinib (Targeted Therapy) at Inclusion  23  4  17.4  5.0  38.8  7.0  37.1  7.1  37.4
ARM  Chemotherapy (Other Treatment) at Inclusion  50  18  36.0  22.9  50.8  24.1  49.9  24.1  49.9
ARM  Somatostatin Analogues (Other Treatment) at Inclus  27  10  37.0  19.4  57.6  21.5  55.8  21.5  55.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures, including the primary PFS outcome and secondary outcomes about tumor-assessment practices, treatment changes, dose changes and treatment lines. When a study examines multiple outcomes or comparisons, the chance of finding an apparently notable result by chance can increase. In general, a prespecified multiplicity strategy may address this issue, for example by defining which outcome is primary or adjusting how multiple comparisons are interpreted. A multiplicity strategy is not reported in the registry record. The record lists zero analyses, so no analysis-specific multiplicity procedures or results are available to assess.

The record describes censoring for participants without a PFS event: follow-up was censored at the last recorded time to progression or last tumor or disease assessment. This explains one way incomplete follow-up was handled for the time-to-event endpoint. It does not describe other missing-data procedures, the amount of missing outcome information, or sensitivity analyses addressing missingness. Whether participants had incomplete assessments or how those cases were treated beyond the stated censoring rule is not reported in the registry record.

The primary population description begins by defining the FAS as eligible participants who received at least one dose during prospective follow-up and specifies conditions involving treatment start and stop dates. The registry text does not give the complete population definition. It also does not report the number analyzed for PFS, exclusions from that analysis, or how participants with unavailable endpoint information were counted. The enrollment of 144 is not necessarily the analysis denominator.

These omissions limit reproducibility and assessment of potential bias. Without the full analysis-population definition, participant flow, missing-data details and multiplicity plan, readers cannot determine how closely the reported analysis—if results were available—would follow a prespecified approach.

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: neoplasm progression (18.2%), disease progression (12.3%), vomiting (9.1%), device related sepsis (9.1%), general physical health deterioration (7.7%).

The registry reports safety counts by treatment received during the study. For everolimus, it lists 52 participants at risk for serious events, with 21 affected; the other-event figures are 52 at risk and 39 affected, and 4 deaths are listed. For sunitinib, the corresponding figures are 36 and 9 for serious events, 36 and 29 for other events, and 3 deaths. For chemotherapy, they are 82 and 26, 82 and 56, and 15 deaths. For somatostatin analogues, they are 65 and 24, 65 and 41, and 14 deaths.

For metabolic radiotherapy, the record lists 11 at risk and 3 affected for serious events, 11 at risk and 4 affected for other events, and 2 deaths. For other than study treatment, it lists 16 and 3 for serious events, 16 and 8 for other events, and 1 death. The registry also names serious-event terms with percentages, including neoplasm progression at 18.2%, disease progression at 12.3%, vomiting at 9.1%, device related sepsis at 9.1%, general physical health deterioration at 7.7% and overdose at 6.2%. The denominator for these term percentages is not reported.

These are descriptive counts, not evidence of comparative risk. The exposure groupings are not described as randomized or mutually exclusive, and the record does not report causal attribution. The counts should not be interpreted as proof that a treatment caused an event or as a basis for ranking treatments.

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

The registry record establishes that OPALINE was a completed observational study of adults with progressive, well-differentiated, unresectable or metastatic PNET in France. It identifies two-year investigator-assessed PFS as the primary endpoint and specifies the event definition, use of RECIST v1.1, Kaplan-Meier analysis and a 95% confidence interval. These details clarify what the planned endpoint represents and how it was to be analyzed.

The registry does not report the PFS estimate or confidence interval. It therefore does not support a conclusion about the observed proportion of participants with PFS at two years, the precision of that estimate, or differences among treatment groups. The lack of numerical outcome results in the registry record is distinct from a finding of no effect: the record simply does not give the primary result needed to assess the question.

Even if group-specific results were available, this observational design would not by itself establish that treatment caused an outcome difference. Treatment selection may be related to participant characteristics and disease course. The registry does not state that allocation was randomized, and it identifies the treatment groups as not being like-for-like controls. Descriptive differences would need to be interpreted with those design limits in mind.

The safety figures likewise describe events and deaths within treatment-exposure groupings. They do not establish that an event was caused by a treatment, and they do not allow a valid comparative safety ranking. The registry record does not provide all details needed to interpret denominators, overlap between exposure groups, or attribution.

In general, an endpoint definition, analysis method and sample-size planning assumptions are not substitutes for observed results. The stated assumptions for a planning illustration cannot be read as evidence of observed power or as a justification for the study's enrollment. The record's value is in documenting the study question, design and outcome definitions; its missing numerical findings limit assessment of what the study observed.

14. Why This Trial Matters Statistically

Observational studies can describe treatment patterns and outcomes in settings where care is not assigned by a trial. OPALINE's stated focus on adults with progressive PNET and its multisite, real-world design make treatment use and follow-up practices part of the study question, alongside the primary PFS endpoint. Its secondary outcomes include tumor-assessment frequency and methods, treatment changes and dose changes, and the number and sequence of treatment lines. Such outcomes can describe how care is delivered and recorded in routine practice.

The record also illustrates why study design and result availability must be considered together. An observational comparison can be clinically informative as a description of outcomes among treated groups, but it does not automatically isolate treatment effects. If treatment choice is connected to prognosis, the groups may differ before treatment or during follow-up. The registry explicitly does not characterize the groups as a like-for-like control comparison.

Statistically, the primary endpoint is a time-to-event measure with censoring, rather than a simple count at a single follow-up visit. The record names Kaplan-Meier analysis and describes the censoring point for participants without an event. Those definitions help readers understand the intended estimand and the role of incomplete follow-up. At the same time, the missing estimate, confidence interval, participant flow and full analysis-population definition prevent evaluation of the actual result and its precision.

The safety information reinforces the distinction between descriptive reporting and causal comparison. Counts grouped by treatment exposure can document events recorded in the study, but overlapping or clinically distinct groups and the absence of randomized allocation limit direct comparisons. OPALINE therefore matters statistically as an example of the interpretive questions that arise when real-world outcome definitions, censoring and treatment selection meet an incomplete public results record.

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 primary limitation for interpreting the study's findings is that the registry record does not report the primary PFS estimate or its confidence interval. Although the endpoint, time point and method are specified, there is no numerical outcome with which to assess event-free survival or precision. The record also lists zero analyses, and no treatment-effect estimate or adjusted comparison is reported.

The analysis population is only partly described. The record states that the FAS included participants who met eligibility criteria and received at least one dose during prospective follow-up, with additional treatment-date conditions, but the definition is incomplete. It does not report how many of the 144 enrolled participants were included in the PFS analysis, how exclusions were handled, or a participant-flow account.

As an observational study, the treatment groups may differ in characteristics that are related to both treatment choice and outcome. Allocation is not stated, and the record cautions that groups are not like-for-like controls. The registry does not report a strategy to address confounding or an adjusted analysis. Consequently, a causal interpretation of treatment-group differences would not be justified from the record.

Follow-up and missing-data reporting is also limited. The stated censoring rule identifies the last recorded time to progression or last tumor or disease assessment as the censoring point for participants without events. The record does not give the number censored, follow-up completeness, reasons for missing assessments, or sensitivity analyses. It also does not describe central review or adjudication of investigator-assessed RECIST outcomes.

Finally, the registry does not report a multiplicity approach despite listing multiple outcome measures, nor does it give the study's sample-size justification. The planning assumptions describe an illustration rather than the trial's own design. These gaps restrict assessment of the analysis plan, robustness and generalizability.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: OPALINE : A Study Of Morbidity And Mortality At 2 Years — NCT02264665.
• Registry record last updated 2023-11-13; status last verified 2023-10.
• Results first posted 2023-11-13.
• 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

OPALINE is a completed, multisite observational study conducted in France among adults with progressive, well-differentiated, unresectable or metastatic PNET. The registry lists enrollment of 144, a study start date of 2015-05-12 and primary completion on 2019-11-18. Its primary endpoint is investigator-assessed PFS at two years, defined using RECIST v1.1 and analyzed by Kaplan-Meier methods.

The registry record does not report the PFS estimate, confidence interval or a treatment-effect analysis. The FAS definition is incomplete, and the number analyzed for the primary endpoint is not stated. Treatment was not described as randomized, allocation is not stated, and the treatment groups are not identified as like-for-like controls. Safety counts are presented descriptively by treatment exposure and do not establish causation. These reporting and design limits prevent assessment of the primary result's magnitude, precision or causal interpretation.