Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease (NCT01085201), a non-randomized phase 1 study. The primary outcome is Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD..

2. Clinical Question

The registry describes the study as an investigation of the safety of prolonged Lexiscan infusions in people with sickle cell disease. Its background notes that Lexiscan had been used as a fast infusion for heart stress testing, while long infusions in people with sickle cell disease had not previously been studied. The study therefore focused on dose-limiting toxicities rather than a randomized estimate of benefit against a control group.

The question covered several settings rather than a single uniform cohort. Adults without a pain crisis were studied in the first, second, and 2B stages; adults with a pain crisis were studied in Stage 3; and children with a pain crisis were studied in Stage 4. Infusion durations included 12 hours, 24 hours, and 48 hours. Because stage, duration, dose, age group, and pain-crisis status varied, observations across stages do not represent a direct comparison of otherwise similar groups.

The registry also lists secondary outcomes concerning iNKT-cell activation and pain levels during a vaso-occlusive event. It does not report a numerical primary endpoint result in the record, so the central safety question cannot be answered from a reported DLT count there.

3. Trial Design

This was a phase 1, non-randomized, unmasked, parallel-model study sponsored by Dana-Farber Cancer Institute. The registry lists the study as completed, with a start date of 2010-04 and primary completion in 2013-02. Enrollment is listed as 39. The registry record does not describe a randomized control group, and the listed stages should not be interpreted as equivalent arms in a controlled comparison.

The protocol description identifies five stages. Stage 1 enrolled adults with sickle cell disease who were not having a pain crisis and evaluated a 12-hour infusion. It used a 3+3 dose-escalation design, testing 0.24 mcg/kg/hr (dose level 0), 0.6 mcg/kg/hr (dose level 1), and 1.44 mcg/kg/hr (dose level 2). The description says escalation continued until 6 participants were treated at the maximum planned dose and that 15 patients were studied in Stage 1.

Stage 2 evaluated a 24-hour infusion in adults without a pain crisis at dose level 2. Stage 3 used a 24-hour infusion at dose level 2 in adults having a pain crisis. The registry description says 6 participants were studied in each of these stages; in each, an additional group of 3 was studied if at least 2/3 participants tolerated the dose.

Stage 2B evaluated a 48-hour infusion at dose level 2 in adults without a pain crisis, and Stage 4 evaluated a 24-hour infusion at dose level 2 in children having a pain crisis. The descriptions state that 3 participants were studied in each stage after agreement from the FDA, IRB, and DSMB, and that both stages were closed to accrual. All five stages are described as complete and closed to accrual.

The primary endpoint observation period was 30 to 54 hours plus 30-day follow-up. The registry record does not report further allocation procedures, masking, or a concurrent comparator; it explicitly identifies allocation as non-randomized and masking as none.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Patients who were assigned to Stages 1, 2 or 2b, in which subjects were studied at baseline (i.e. not in pain crisis), could be excluded if they experienced a pain crisis in the interim period between enrollment and their scheduled study date.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The number of participants was determined per protocol following a 3+3 design. In Stages 2b and 4, we received permission from the FDA, IRB, and DSMB to study only 3 subjects because we did not observe any prior DLT. One patient enrolled in Stage 2b withdrew consent during the infusion due to an unrelated toothache, and was excluded from analysis.

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 number of participants was determined per protocol following a 3+3 design. In Stages 2b and 4, we received permission from the FDA, IRB, and DSMB to study only 3 subjects because we did not observe any prior DLT. One patient enrolled in Stage 2b withdrew consent during the infusion due to an unrelated toothache, and was excluded from analysis.

6. Primary Endpoint

The registry lists the primary outcome as Dose Limiting Toxicities as a Measure of Whether Infusional Lexiscan is Safe in Individuals With SCD., measured over 30 to 54 hours plus 30-day follow-up.

The primary endpoint was the number of dose-limiting toxicities (DLTs), used as a measure of whether infusional Lexiscan was considered safe under the protocol’s tolerability rule. The registry describes the assessment period as 30 to 54 hours plus 30-day follow-up. It states that Lexiscan was considered “safe” per protocol if it was well tolerated based on the number of DLTs reported.

A DLT count is a protocol-defined safety measure: it focuses on toxicities that meet the study’s criteria for limiting treatment, rather than treating every symptom or adverse event as a DLT. The registry record does not give the detailed DLT definition, grading rules, or adjudication procedure. Those details are not reported in the registry record, so the endpoint should be understood only at the level described there.

The stages varied in dose, infusion duration, age group, and pain-crisis status. Those distinctions matter when interpreting a count: the same number of events can have different meaning in groups of different sizes or under different exposure conditions. A pooled count would also obscure which stage and regimen the events arose under. The registry’s primary endpoint description is stage-aware, but a numerical DLT result by stage is not reported in the registry record.

Serious adverse event counts are reported separately by stage. They are not automatically the same as DLT counts: a serious event may or may not satisfy the protocol’s DLT definition, and the registry does not state that the two measures are interchangeable. The available serious-event information therefore cannot be substituted for the missing primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-limiting toxicity count represent?

A DLT is a safety event that meets a protocol’s threshold for limiting treatment. The endpoint is a count, not a measure of average change in a laboratory value or symptom score. Its interpretation depends on how the trial defines a DLT, how events are graded, the time window used to identify them, and whether they are attributed to treatment. The registry gives the endpoint name and observation period, but the detailed criteria and event-adjudication process are not reported in the registry record.

The registry’s stated tolerability rule links its safety judgment to the number of DLTs. That does not mean every adverse event is a DLT, or that every serious adverse event meets the DLT definition. Since the record reports serious adverse event figures separately and does not describe their overlap with DLTs, those measures must remain distinct in interpretation.

Why is the 3+3 design relevant?

Stage 1 is described as a 3+3 dose-escalation study. In general, a 3+3 design evaluates dose levels in small groups and uses observed toxicities to guide whether escalation proceeds. The registry describes three tested dose levels and says escalation continued until 6 participants were treated at the maximum planned dose. It also describes a tolerance condition for adding participants in Stages 2 and 3. These rules explain the protocol’s enrollment approach; they do not provide an estimate of how well the design detects uncommon harms.

In general, small early-phase cohorts are intended to characterize tolerability and guide study decisions, not to provide precise estimates of event frequency. A small number of observed events can correspond to substantial uncertainty about the underlying frequency. Confidence intervals, when available, express the range of values compatible with the data under a specified method; no confidence intervals for the DLT outcome are reported in the registry record.

How should the stage groups be understood?

The stages are cohorts with differing infusion durations and participant settings, not randomized arms. Stage 1 included adults without a pain crisis and evaluated dose escalation. Stage 2 and Stage 2B also involved adults without a pain crisis but used different infusion durations. Stage 3 involved adults having a pain crisis, while Stage 4 involved children having a pain crisis. This structure allows a descriptive account of the study’s staged evaluation, but it does not create a controlled comparison of one regimen against another.

In general, comparisons across groups are most interpretable when the groups differ only in the factor being studied and are otherwise made comparable by design. That is not the design described in this registry record. Stage-specific event counts should therefore be read as observations within each cohort, not as evidence that one duration, dose, age group, or clinical setting caused a difference in risk.

What do the serious-event counts describe?

The serious adverse event data list a number at risk and a number affected for each stage. These are descriptive group counts. The record also lists serious-event terms and percentages, but does not map each term to a particular stage in the summary. No death counts are reported in the registry record. These figures should not be combined with the DLT endpoint unless the registry explicitly defines their relationship, which it does not.

General statistical principle: event counts depend on both the number of people observed and the observation period. A count on its own does not describe a rate unless the relevant denominator and time-at-risk definition are clear. The registry supplies group counts at risk for serious adverse events, but it does not report person-time or a rate analysis. The primary endpoint’s observation window is stated as 30 to 54 hours plus 30-day follow-up; the serious-event reporting should not be assumed to use an identical window unless specified.

What do the sample-size illustrations mean?

The record’s sample-size assumptions describe planning illustrations computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, the stated convention is to show a total number of events; for other outcomes, it is to show participants per arm. These are hypothetical planning calculations, not results from this trial’s randomized comparison, because this study was non-randomized and the listed stages are not like-for-like control arms.

Any sample-size values derived under those assumptions are planning illustrations, not observed power. Observed power is not a substitute for a confidence interval or an estimate of uncertainty, and it cannot repair the absence of a reported primary endpoint result. The registry record does not report the trial’s own sample-size justification or a randomized comparison that would support interpreting such calculations as the design basis for this study.

General statistical principle: an assumption such as equal allocation specifies how a hypothetical future study would divide participants between groups. A normal approximation is a mathematical method for estimating sample size under stated conditions. Such assumptions are not evidence that the current trial used those methods in its protocol, nor do they establish that the current study was adequately powered for a particular effect.

What analysis details are absent?

The registry lists zero analyses. It does not report an inferential model, adjusted analysis, confidence interval, hypothesis test, or analysis population for the primary endpoint. It also does not report an interim-analysis plan or the detailed statistical analysis plan. These omissions limit the degree to which the posted results can be independently evaluated. The methods that are reported are the staged enrollment and dose-escalation rules; other statistical procedures are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures: the primary dose-limiting toxicity outcome and two secondary topics, involving iNKT-cell activation markers and pain levels during a vaso-occlusive event. It lists zero analyses. No multiplicity adjustment, hierarchy among secondary outcomes, or strategy for interpreting multiple tests is reported in the registry record. Without reported analyses, there are no posted test results on which to assess multiplicity in practice.

General statistical principle: when several outcomes or comparisons are tested, the chance of at least one apparently unusual result can rise unless the analysis plan accounts for the number and structure of tests. A prespecified hierarchy or adjustment can help control that issue. The registry record does not state whether such a plan was used, so none should be assumed.

Missing-data handling is not reported in the registry record. The primary endpoint description mentions a participant in Stage 2B who withdrew consent during the infusion, but the text is truncated after describing the reason. The record does not explain how that participant was handled in the DLT analysis, whether endpoint data were available after withdrawal, or how missing observations were classified.

Analysis populations are also not reported in the registry record. There is no stated intention-to-treat, per-protocol, safety, or other analysis population definition. Since the study was non-randomized, there is no randomized allocation set to interpret as an intention-to-treat population. The enrollment listing alone does not specify which participants contributed to each outcome analysis.

These gaps matter because outcome definitions, missing-data rules, and analysis populations determine which observations contribute to a reported estimate. The registry record does not contain the details needed to reconstruct those decisions for the primary endpoint or the secondary outcomes.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: sickle cell crisis with prolonged hospitalization - grade 2 (16.7%), uncomplicated vaso-occlusive crisis requiring hospitalization - grade 3 (16.7%), rib pain, leading to hospitalization - grade 3 (16.7%).

The serious adverse event group data report 0 affected among 15 at risk in Stage 1, 2 among 6 in Stage 2, 0 among 3 in Stage 2B, 1 among 6 in Stage 3, and 0 among 3 in Stage 4. These are counts for the stage groups as listed in the registry. They describe reported serious adverse events, not necessarily dose-limiting toxicities.

The registry lists three top serious-event terms, each reported as 16.7%: sickle cell crisis with prolonged hospitalization - Grade 2; uncomplicated vaso-occlusive crisis requiring hospitalization - Grade 3; and rib pain, leading to hospitalization - Grade 3. The record does not specify in this summary which stage each term belongs to, so the terms should not be assigned to individual groups. The percentage for a term is not a comparison with an untreated group.

The study had no randomized comparator, and the stages differed in duration and participant setting. The counts therefore do not estimate a controlled treatment effect. The record does not report death counts. It also does not provide enough detail to infer whether an event was judged related to Lexiscan or met the primary DLT definition.

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

The record establishes that Lexiscan was evaluated as an infusion in a phase 1 study involving people with sickle cell disease, across stages that varied in duration, dose, age group, and pain-crisis status. It documents a protocol focused on dose-limiting toxicities and provides stage-specific serious adverse event counts. Those details describe the scope and structure of the study; they do not, by themselves, establish a treatment effect.

The primary endpoint’s numerical result is not reported in the registry record. Consequently, the stated protocol rule for judging tolerability cannot be applied from the posted primary endpoint data. The serious adverse event counts should not be used as a substitute, because the record does not state that serious adverse events and DLTs are equivalent or provide their overlap.

The study was non-randomized and unmasked. It did not include a like-for-like control comparison in the registry description. As a result, the reported event counts cannot establish what would have happened without Lexiscan, and differences between stages cannot isolate the effect of dose or infusion duration. Stage composition also differed: some cohorts were adults without a pain crisis, while others were adults or children having a pain crisis.

The registry lists secondary outcomes related to iNKT-cell activation and pain levels, but does not report analyses for them. The record therefore does not support conclusions about those outcomes either. It also does not report confidence intervals, a statistical analysis plan, missing-data procedures, or analysis-population definitions.

General interpretation: a small, staged early-phase safety study can contribute descriptive information about exposures and events observed under its protocol. The precision and scope of that information depend on the number observed, follow-up, definitions, and design. The posted record supports describing the study’s design and reported serious-event counts, but it does not support a claim that Lexiscan does or does not work, or a definitive conclusion about safety.

13. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is a safety question addressed through staged dose escalation rather than a randomized comparison. Stage 1 used a 3+3 design across three dose levels, and later stages evaluated different durations and participant settings. This structure is useful to recognize when interpreting the record: its main statistical task was not to estimate a treatment difference between comparable groups.

The trial also illustrates why endpoint labels matter. The primary measure was the number of dose-limiting toxicities, while the posted safety figures describe serious adverse events. Those are related safety concepts but are not interchangeable without a reported definition connecting them. Keeping them separate prevents a descriptive adverse-event count from being mistaken for the primary endpoint result.

The stages varied in infusion length, dose context, age group, and pain-crisis status. This makes stage-specific reporting important and limits direct comparisons across cohorts. A pooled summary could conceal that the groups experienced different exposures and clinical circumstances; a comparison across stages would not have the protection of randomization.

The record also highlights the limits of registry reporting for statistical interpretation. It lists the endpoint and staged design but gives no numerical DLT result, no analyses, and no reported details on multiplicity, missing-data handling, or analysis populations. Without those elements, readers cannot evaluate the primary endpoint estimate or its precision. The serious adverse event figures remain descriptive rather than comparative.

For biostatisticians and clinical researchers, the key lesson is to distinguish a protocol’s decision rule from an outcome result, a safety-event summary from a DLT count, and a planning illustration from evidence generated by the trial. These distinctions are essential when a study has small, non-randomized cohorts and the registry record does not report its primary analysis.

14. 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 principal limitation in interpreting this trial record is that the numerical result for its stated primary endpoint, dose-limiting toxicities, is not reported in the registry record. The registry describes the endpoint and its observation period, but does not provide the count needed to assess the protocol’s tolerability rule. Serious adverse event counts do not resolve this omission because their relationship to DLTs is not reported.

The design is non-randomized, unmasked, and lacks a like-for-like control comparison. The stages also differ in dose or duration and in participant characteristics, including age group and pain-crisis status. Stage comparisons therefore cannot isolate the effect of a single treatment feature or be interpreted as randomized treatment contrasts.

The serious-event summary does not assign the listed event terms to stages, and death counts are not reported in the registry record. The registry does not report event attribution, detailed DLT criteria, confidence intervals, an analysis plan, multiplicity procedures, missing-data handling, or analysis-population definitions. It lists zero analyses, and secondary outcome results are not reported in the record.

The primary endpoint description includes an incomplete sentence about a Stage 2B withdrawal, ending after the words “due to an unr”. The remaining explanation is not reported in the registry record, so the reason and analytic handling should not be inferred. These reporting gaps constrain interpretation independently of the study’s design.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Adenosine 2A Agonist Lexiscan in Children and Adults With Sickle Cell Disease — NCT01085201.
• Registry record last updated 2014-03-07; status last verified 2014-02.
• Results first posted 2014-03-07.
• 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.

18. Record Summary

The registry record describes NCT01085201, a completed phase 1, non-randomized, unmasked study sponsored by Dana-Farber Cancer Institute. It lists enrollment as 39, a start date of 2010-04, and primary completion in 2013-02. The study evaluated infusional Lexiscan in adults and children with sickle cell disease across five stages, with durations from 12 hours to 48 hours and varying pain-crisis settings.

The primary outcome was the number of dose-limiting toxicities during 30 to 54 hours plus 30-day follow-up. The registry describes a 3+3 dose-escalation approach in Stage 1 and additional stage-specific enrollment rules, but does not report a numerical DLT result or any analyses. Serious adverse event counts are listed by stage, alongside three serious-event terms reported at 16.7% each. These data are descriptive and do not constitute a randomized comparison.

Results for the listed secondary outcome topics, analysis populations, missing-data handling, and multiplicity procedures are not reported in the registry record.