The Darbepoetin Alfa for Ischemic Surgical Complications (DISC) Dose Finding Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Darbepoetin Alfa for Ischemic Surgical Complications (DISC) Dose Finding Trial (NCT00647998), a non-randomized phase 2 study. The primary outcome is Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25.

2. Clinical Question

The clinical rationale in the registry is that surgery creates an opportunity to administer a proposed neuroprotectant before a possible ischemic injury. It also notes that lumbar cerebrospinal fluid drains used in these procedures allow access to cerebrospinal fluid for monitoring injury markers and medication penetration. These statements describe the study rationale, not evidence that the intervention changed clinical outcomes.

The trial was a pilot dose-finding study, but the registry record describes only the intervention dose and does not report a dose comparison or the basis for choosing the dose. Its non-randomized allocation and lack of a posted primary-outcome result are central to interpreting what can be learned from the record.

3. Trial Design

This was a phase 2, parallel-group trial with non-randomized allocation and no masking. The registry lists darbepoetin alfa and standard care as the interventions. The darbepoetin group is described as receiving 1mg/kg intravenously immediately prior to surgery; standard care is described as no darbepoetin. The record reports enrollment of 18 and a completed status.

The study focused on patients undergoing descending thoracic aortic or thoracoabdominal aortic surgery. The registry’s rationale emphasizes that these operations can involve brain or spinal cord ischemia and that a cerebrospinal fluid drain allows access to cerebrospinal fluid. These are features of the setting and rationale, not reported evidence of treatment effect.

The primary endpoint was assessed at discharge from the hospital and counted participants with death or neurologic disability, using NIHSS and ASIA motor-score thresholds to define disability. Secondary outcomes listed in the record were cerebrospinal fluid S100beta and hemoglobin. The registry record does not provide results for the primary endpoint or those secondary outcomes.

Because allocation was not randomized, differences between groups could reflect how participants entered each arm or other group differences, as well as any intervention effect. The record does not describe assignment procedures, baseline comparability, masking of outcome assessors, or adjustment for potential confounding. Those details are not reported in the registry record.

The record identifies the trial as a dose-finding pilot, but does not report a formal dose-ranging comparison, sample-size justification, or statistical analysis plan. Its design therefore supports a cautious description of the study’s objective and recorded outcomes, not a strong causal comparison between darbepoetin and standard care.

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.

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 Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25, measured over Discharge from the hospital.

The primary endpoint counts participants who experienced death or neurologic disability by hospital discharge. Disability was defined using either an NIHSS >4 or an ASIA lower-extremity motor score <25. The registry describes NIHSS as a validated quasi-ordinal measure of stroke severity and says a score >4 is generally considered moderate or severe. It describes the ASIA score as a cumulative assessment of strength in muscles in each leg and notes that a score <25 is associated with impaired ambulation.

Combining death with neurologic disability creates an endpoint that captures serious outcomes relevant to brain and spinal cord ischemia in the surgical setting. The NIHSS and ASIA criteria address different aspects of neurologic function, while the death component captures an outcome for which neurologic scoring may not be possible. The registry record does not explain why these particular thresholds or this composite were selected.

Interpretation requires the actual number of participants meeting the endpoint in each group, together with the analysis population and any uncertainty estimates. Those primary-outcome results are not reported in the registry record. The endpoint definition alone therefore describes what was intended to be measured, but not what occurred or whether groups differed.

The specified timeframe is discharge from the hospital. This anchors the outcome to a clinical transition, but does not describe outcomes after discharge. Longer-term neurologic status is not reported as part of this primary endpoint in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial’s primary outcome is binary at the participant level: a participant either met the composite definition of death or neurologic disability at hospital discharge, or did not. The registry identifies the outcome measure as a count of participants. For a binary outcome, group-specific counts and the corresponding numbers assessed are basic descriptive information. Here, the registry record does not report the primary-outcome counts, so the event frequency and any between-group estimate cannot be described.

What does non-randomized allocation mean?

In general, random allocation uses chance to assign participants to groups. This can reduce systematic differences between groups, although it does not guarantee that every characteristic will be balanced. Non-randomized allocation does not have that protection. Participants in the groups may differ in clinical characteristics, timing, or other factors related to both treatment and outcome. Such differences can distort an unadjusted comparison.

The registry specifies non-randomized allocation but does not describe how assignment occurred. It also does not report baseline group characteristics, covariate adjustment, or a method for controlling confounding. Those details are not reported in the registry record. Therefore, a comparison between the arms would not by itself identify a causal treatment effect, even if outcome counts were available.

What can a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimated effect. A narrower interval indicates greater precision under the assumptions of the method; a wider interval indicates less precision. The interval does not resolve bias from non-randomized allocation, and its interpretation depends on the analysis model and data. The registry record does not report a confidence interval or other uncertainty estimate for the primary endpoint.

A p-value, in general, summarizes how compatible observed data are with a specified statistical null model. It is not the probability that the null hypothesis is true, nor does it measure clinical importance. The registry record does not report a primary-outcome p-value. No significance conclusion can be drawn from the absence of such a result.

Why does the outcome definition matter?

The endpoint combines death with neurologic disability defined using NIHSS or ASIA criteria. A composite can capture more than one clinically important event type in a single outcome, but its interpretation depends on which components occurred and how often. The registry record does not give component-specific primary-endpoint results. It is therefore not possible to determine whether any hypothetical difference in the composite would be driven by death, the stroke-severity threshold, the motor-score threshold, or a combination.

The thresholds in the record are explicit: NIHSS >4 and ASIA lower-extremity motor score <25. In general, threshold-based outcomes simplify classification but can conceal variation among participants on either side of a cutoff. The record does not describe additional analyses using continuous scores or alternative thresholds.

How should the safety counts be read?

The posted serious adverse-event figures are counts of affected participants and participants at risk by group. They are descriptive, not an adjusted estimate of comparative risk. In general, an adverse-event comparison is easier to interpret when the event definitions, collection period, severity criteria, and handling of repeated events are clear. The registry record does not report those details. It records 4 of 9 at risk affected in the darbepoetin group and 3 of 9 at risk affected in standard care, while other adverse events are recorded as 0 in each group. These counts alone do not show whether the difference reflects treatment, chance, group composition, or other factors.

The serious-event terms spinal ischemia and stroke are each listed at 22.2%. The record does not specify whether these percentages represent participants or events, whether terms overlap, or how they are distributed across groups. They should not be treated as independent observations or added together. The record also does not report deaths in the safety listing.

What do the planning assumptions mean?

In general, a sample-size calculation estimates the amount of information needed to detect a chosen effect under stated assumptions. The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation between the arms, and a normal approximation; it says the effect to detect is a stated fraction of the observed effect. These are described as planning illustrations computed from the observed effect, not as the trial’s own design. The record does not report the resulting planning estimates in the registry record for this analysis, and they should not be confused with observed power.

Planning illustrations are conditional on their assumptions. In general, using an observed effect as the basis for a future planning scenario does not make that effect more reliable; observed effects can be unstable, particularly when data are limited. Such illustrations are not a substitute for a prospective sample-size justification. The registry record does not report the trial’s sample-size justification or a protocol-based statistical plan.

Over-dispersion is a general concern when count data vary more than an assumed statistical model allows; it can make model-based uncertainty too optimistic if ignored. The primary outcome is described as a count of participants with an event, rather than a recurrent-event count, and no such model or over-dispersion analysis is reported. No additional distributional assumption should be inferred from the endpoint description.

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("Darbepoetin Alfa", "Standard Care")
n      <- c(9, 9)
events <- c(1, 3)
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  Darbepoetin Alfa  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  Standard Care  9  3  33.3  7.5  70.1  12.1  64.6  12.2  65.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary endpoint and secondary outcomes of cerebrospinal fluid S100beta and hemoglobin. It does not report results for these outcomes or explain how multiple outcomes were handled statistically. A multiplicity adjustment, if any, is not reported in the registry record.

In general, examining multiple outcomes or multiple analyses can increase the chance of finding an apparently notable result by chance. Statistical methods can address this issue, but the choice depends on the planned questions and analysis strategy. The record does not report whether a hierarchy of outcomes, adjustment procedure, or other multiplicity strategy was specified. No conclusion about multiplicity control can be drawn.

The registry record does not describe how missing outcome data were handled, whether any participants lacked discharge assessments, or which participants were included in each analysis. The analysis populations and missing-data methods are not reported in the registry record. Enrollment and safety denominators do not establish the number assessed for the primary endpoint.

In general, missing-data methods rely on assumptions about why values are missing and how missingness relates to observed or unobserved outcomes. Different assumptions can lead to different estimates. Without the missing-data pattern and analysis methods, the potential influence of missing outcomes cannot be assessed.

The record also does not report a prespecified statistical analysis plan, interim analyses, or any analysis results. These omissions leave key elements of the confirmatory interpretation unknown. They do not establish that such procedures were or were not conducted; those details are simply not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: spinal ischemia (22.2%), stroke (22.2%).

The registry records serious adverse events for both groups. Among participants at risk, 4 of 9 in the darbepoetin group and 3 of 9 in the standard-care group are recorded as affected. Other adverse events are recorded as 0 in each group. These are descriptive counts from the registry and should not be read as proof that the intervention caused, prevented, or had no effect on adverse events.

The top serious-event terms listed are spinal ischemia and stroke, each at 22.2%. The registry record does not clarify whether these terms refer to affected participants or event counts, whether participants could be represented in more than one term, or how the terms are distributed by treatment group. These percentages therefore cannot be used to reconstruct group-specific event rates.

The safety listing does not report deaths. The timeframe and detailed collection rules for these adverse events are not reported in the registry record. Nor does the record provide an adjusted safety comparison or uncertainty estimates. In general, safety counts from a non-randomized comparison can reflect differences in the groups and in event ascertainment as well as any treatment-related effects. The figures are a limited descriptive account, not a causal estimate.

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

The registry establishes that this was a completed, non-randomized phase 2 dose-finding trial of prophylactic darbepoetin alfa before specified aortic surgery. It defines a primary endpoint combining death with neurologic disability at hospital discharge and lists cerebrospinal fluid S100beta and hemoglobin as secondary outcomes. It also records serious adverse-event counts by group.

However, the primary endpoint results are not reported in the registry record. The record does not give group-specific counts of participants who died or met the neurologic disability criteria, nor does it provide an effect estimate or uncertainty interval. It therefore cannot show whether the primary outcome was more or less frequent in either arm, or how precisely any comparison might be estimated.

The safety counts are not a substitute for the missing primary-outcome results. They describe affected participants recorded for serious and other adverse events, but the non-randomized design and absence of information about event timing, ascertainment, and adjustment limit causal interpretation. The listed serious-event terms also lack enough detail to assign them to groups or determine overlap.

The record does not establish that darbepoetin alfa improves neurologic outcomes, and it also does not establish that it fails to do so. No conclusion about efficacy follows from missing primary results. Likewise, the safety figures do not establish that the intervention is safe or unsafe; they are limited descriptive entries rather than a definitive comparative assessment.

In general, conclusions about treatment effects require outcome data, a clear analysis population, an appropriate comparative method, and an assessment of uncertainty and bias. Here, the record’s non-randomized allocation raises concern about group comparability, while primary outcome data and key analysis details are unavailable. The most defensible interpretation is consequently bounded: the registry describes the study question and design, but does not provide the results needed to answer the main clinical question.

14. Why This Trial Matters Statistically

This trial raises a design question that is important in perioperative research: whether a proposed protective intervention can be given before a possible ischemic injury. The registry describes surgery as a setting in which administration before injury may be feasible, and identifies cerebrospinal fluid access as an opportunity to monitor markers. These points explain the study rationale, but they are not outcome evidence.

Statistically, the trial illustrates the difference between a clinical question and an answer supported by posted data. The primary endpoint is defined in detail, including its discharge timeframe and neurologic thresholds, but the registry record does not report its results. An endpoint definition tells readers what investigators intended to measure; it does not reveal the observed treatment contrast.

The non-randomized allocation is another important feature. In general, causal comparisons require attention to how participants entered each group and whether group differences could explain observed outcomes. The record does not report the assignment process or adjustment methods. This means that even a posted unadjusted difference would need careful interpretation, and the absence of primary results makes a comparative estimate unavailable altogether.

The safety figures demonstrate why counts should be read with their definitions and context. Group-specific serious-event counts are recorded, but the event-term percentages are not mapped to groups and the follow-up details are not given. Without that information, the figures cannot support a complete comparative safety assessment.

Finally, the registry’s planning description is explicitly an illustration based on the observed effect, rather than the trial’s own design justification. In general, planning calculations are conditional scenarios, not evidence that a study had adequate power or that an observed effect is stable. The record does not report a sample-size justification or statistical plan. Together, these features make transparent reporting of outcomes and methods especially important for understanding what this pilot study can contribute.

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 consequential limitation of the registry record is that it does not report the primary endpoint results. Without group-specific outcome counts, no primary comparison can be estimated or assessed for precision. Results for the listed secondary outcomes, cerebrospinal fluid S100beta and hemoglobin, are also not reported.

The trial was non-randomized and unmasked. The record does not describe allocation procedures, baseline characteristics, outcome-assessor masking, or methods to address confounding. These omissions prevent assessment of group comparability and possible bias. The record also does not provide an analysis population, missing-data handling, or detailed statistical methods.

The endpoint combines death with disability defined by NIHSS or ASIA thresholds. Component-specific primary results and longer-term outcomes are not reported in the registry record. The discharge timeframe limits the stated endpoint to the hospital period; the record does not give evidence about outcomes after discharge.

The safety information is incomplete for comparative interpretation. Event-collection timing and definitions are not reported. The serious-event terms are not linked to treatment groups, and their overlap is not described. The safety listing does not report deaths. These limitations do not imply that events were absent; they indicate that the registry record does not provide a fuller account.

Although the trial is described as dose finding, the record does not report a dose-ranging comparison or a sample-size justification. It also does not report an analysis plan, multiplicity strategy, interim analyses, or primary-outcome estimates. These limitations are specific to the information available in the registry record and constrain both clinical and statistical interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Darbepoetin Alfa for Ischemic Surgical Complications (DISC) Dose Finding Trial — NCT00647998.
• Registry record last updated 2017-06-05; status last verified 2017-05.
• Results first posted 2017-01-02.
• 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 describes a completed phase 2, parallel, non-randomized, unmasked dose-finding trial of darbepoetin alfa before descending thoracic or thoracoabdominal aortic surgery. Enrollment was 18. The intervention description states that patients received 1mg/kg intravenously immediately prior to surgery; standard care was described as no darbepoetin.

The primary outcome was death or neurologic disability at hospital discharge, defined using NIHSS >4 or ASIA lower-extremity motor score <25. Secondary outcomes listed were cerebrospinal fluid S100beta and hemoglobin. Primary and secondary outcome results are not reported in the registry record.

The safety listing records serious adverse events affecting 4 of 9 participants at risk in the darbepoetin group and 3 of 9 in standard care; other adverse events are recorded as 0 in each group. Spinal ischemia and stroke are each listed at 22.2% among the top serious-event terms. The non-randomized design and missing analysis details limit causal interpretation of these counts.