A Phase 1 Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 1 Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome (NCT02697240), a na phase 1 study. The primary outcome is Number of Participants With Adverse Events.

2. Clinical Question

The registry’s rationale describes sickle cell disease as involving red blood cell sickling and vaso-occlusion, which can be associated with pain or organ complications such as acute chest syndrome. It also describes low nitric oxide as a feature associated with sickle cell disease and citrulline as a substance known to increase nitric oxide. These statements explain the study’s rationale; they are not outcomes measured by the primary endpoint.

The statistical question is narrower than whether citrulline changes the course of sickle cell disease. With no comparator group, the posted results describe adverse events among participants receiving the infusion, rather than a contrast between treatments. The registry does not report a dose-specific safety comparison or an estimate of treatment effect. The actual dose-escalation sequence and criteria used to identify a highest safe dose are not reported in the registry record.

3. Trial Design

This was a Phase 1 dose-escalation study of continuous intravenous L-citrulline in people with sickle cell disease during a pain crisis or acute chest syndrome. The registry lists a single-group model, no allocation, and no masking. It reports four participants enrolled and a completed status. The recorded study start was 2016-02, and primary completion was 2017-04.

Participants received intravenous citrulline as a bolus over 5 minutes, followed by a continuous infusion for the next 23 hours. The registry does not report the dose levels, how participants were assigned to dose levels, or whether any dose-escalation decisions were made during the study. The protocol’s stopping rules and definition of a dose-limiting toxicity are not reported in the registry record. The title identifies the study as dose escalation, but the title alone does not establish how that process was conducted.

The single-group structure means the safety findings are descriptive of participants treated in the study. There is no concurrent untreated or active-comparator group for estimating how event counts might differ under another treatment or under usual care. The absence of masking is recorded, but the registry does not report whether any outcome assessment procedures were otherwise standardized beyond the stated use of the NCI Common Terminology Criteria for Adverse Events to determine event number and severity.

The registry lists two outcome measures and no analyses. The primary outcome is the number of participants with adverse events, assessed over 30 days. Details of the other outcome measure are not reported in the registry record. The record does not report a statistical analysis plan, a sample-size justification for the enrolled study, or whether any interim analyses were planned or conducted. A planning illustration is described separately, but it is not the observed design or an observed-power calculation.

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 Number of Participants With Adverse Events, measured over 30 days.

The primary endpoint is the number of participants with adverse events during a 30-day timeframe. The registry says that the number and severity of adverse events would be determined according to the NCI Common Terminology Criteria for Adverse Events. The measure is a participant count: it concerns how many participants experienced an event, rather than how many separate event episodes occurred.

In general, counting participants with adverse events is useful in early-phase safety assessment because it records whether any participant experienced an event during the defined observation period. Recording severity alongside occurrence can distinguish events by seriousness or grade, although the registry does not report the detailed grading results for the primary endpoint. The posted safety summary separately reports serious and other adverse-event counts.

A count does not, by itself, show when an event began, how long it lasted, whether it resolved, or whether it was judged related to the infusion. Those details are not reported in the registry record. Nor does a participant count estimate the frequency of events in a broader population with precision, particularly when the study enrolled four participants and had no comparator group. The endpoint is therefore best read as a descriptive safety measure for the participants observed, not as a comparison of risk between treatments.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry is primarily descriptive. It records the number of enrolled participants and reports safety counts, but it does not report inferential analyses. That distinction matters: descriptive counts characterize the observed participants, while inferential methods attempt to quantify uncertainty or compare groups under stated assumptions. No comparison group is present in this study, and no inferential estimate is reported in the registry record.

What does a participant count represent?

The primary endpoint counts participants with adverse events over 30 days. A participant who experiences an event is counted as a person affected; the endpoint is not a count of every event episode. In general, participant-level counts can be easier to interpret than event totals when a person may experience repeated events, but they do not describe event frequency, duration, or recurrence. The registry does not report those additional details.

The safety summary separates serious adverse events, other adverse events, and deaths. In the intravenous citrulline group, the posted counts are one participant with a serious adverse event, zero with other adverse events, and zero deaths. These categories should be presented as recorded, without assuming that they describe every aspect of the overall adverse-event endpoint. The specific rules used to classify an event as serious are not detailed in the registry record. The primary endpoint description states that number and severity would be determined according to the NCI Common Terminology Criteria for Adverse Events.

Why does the single-group design matter?

A single-group study can report what happened among the participants who received the intervention, but it cannot directly estimate a difference from a control group. General statistical comparisons rely on a contrast, such as a difference between groups, and an analysis plan that defines how uncertainty will be quantified. Neither a control-group contrast nor an inferential result is reported. The record also identifies no allocation and no masking. Those design features do not turn the observed counts into causal estimates.

In general, a confidence interval conveys uncertainty around an estimate under a specified statistical model. It does not guarantee that the true value lies within the interval, and it does not correct for limitations in the design or data collection. No confidence interval is reported for these safety counts. With only four enrolled participants, even a complete count of observed events would offer limited information about the range of event patterns that could occur in a broader population.

What does dose escalation add?

The title and study description identify a dose-escalation objective. In general, dose-escalation studies examine safety across dose levels, using prespecified rules to guide whether doses are increased, held, or stopped. The particular dose levels, decision rules, and observed decisions for this study are not reported in the registry record. The available safety summary is not broken down by dose. It therefore cannot show how risk varied across dose levels or establish which dose was selected as the highest safe dose.

In general, over-dispersion arises when outcome variability exceeds what a simple model assumes; accounting for it can prevent uncertainty from being understated. No over-dispersion model or relevant dispersion estimate is reported in the registry record. Given that the reported primary endpoint is a participant count and the posted analysis count is zero, it would be inappropriate to imply that an unreported count model or adjustment was used.

How should the planning illustration be read?

The registry describes a planning illustration computed from an observed effect. Its stated assumptions are a two-sided significance level 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. The description says that time-to-event illustrations give total events, while other illustrations give participants per arm. These are planning assumptions, not reported features of the single-group trial. The record does not report the resulting sample-size values or the observed effect used for the illustration. It also does not report a study-specific sample-size justification. Planning illustrations are not observed power, and they do not demonstrate that a study had a particular probability of detecting an effect.

Overall, the supported statistical reading is limited to the recorded enrollment and safety counts. The registry does not report estimates of treatment effect, uncertainty intervals, dose-specific comparisons, or adjusted analyses. General statistical principles can clarify why those omissions limit interpretation, but they cannot supply the missing estimates or details.

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("Intravenous Citrulline")
n      <- c(4)
events <- c(4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Intravenous Citrulline  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity concerns arise when multiple outcomes, comparisons, time points, or subgroup analyses are tested. In general, conducting many statistical tests can increase the chance of at least one apparently notable finding by chance, so an analysis plan may specify which outcomes are primary and how multiple testing will be handled. The registry lists two outcome measures, but details of the other measure are not reported in the registry record. No analyses are reported, and the record does not report a multiplicity strategy, a hierarchy of tests, or subgroup analyses.

Missing-data handling is also not reported in the registry record. The posted enrollment is four, but the record details do not state whether all enrolled participants completed the 30-day assessment or how any missing observations were treated. It would not be appropriate to assume that there were no missing data simply because no missing-data method is described.

The registry does not report analysis populations, such as an intention-to-treat, per-protocol, or safety population, or explain how participants were included in each outcome analysis. The number of analyses is recorded as zero. That means no inferential results are reported in the record; it does not establish which participants contributed to each descriptive safety count. The counts should therefore be read as posted, without inferring an unreported analysis population or data-handling procedure.

These reporting gaps prevent assessment of whether outcome selection, missing observations, or analysis choices could have influenced the reported findings. They also prevent a reader from checking whether a planned statistical approach was followed. The registry does not report the relevant protocol details or analysis plan.

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 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: transaminitis (25.0%).

The intravenous citrulline group had four participants at risk in the posted safety summary. One participant was recorded with a serious adverse event; zero participants were recorded with other adverse events, and deaths were zero. The listed top serious-event term is transaminitis, reported as 25.0%. The registry does not report the denominator for that percentage in the record details available, so it should not be recalculated or assigned a different interpretation.

These figures are counts from a small group, not a comparison with another treatment. They do not establish that the intervention caused the serious event, and the registry does not report event attribution. The record also does not provide event timing, duration, resolution, recurrence, or a detailed severity grade. The endpoint description states that event number and severity would be determined using the NCI Common Terminology Criteria for Adverse Events, but detailed grades are not reported.

Zero deaths means that none were recorded in the posted safety summary; it does not establish that the study could rule out a risk of death. Likewise, zero other adverse events should be understood as the count in that category as reported, not as proof that no symptoms or clinical observations occurred. The limited enrollment and absence of a comparator restrict how far these findings can be generalized.

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

The posted results describe safety observations among four participants who received intravenous citrulline in a single-group Phase 1 study. The safety summary reports one participant with a serious adverse event, zero participants with other adverse events, and zero deaths. It also lists transaminitis as a top serious adverse-event term, with 25.0% reported. These registry entries characterize the registry’s posted counts; they do not estimate a comparative effect.

The study’s stated purpose was to identify the highest safe dose during sickle cell pain crisis or acute chest syndrome. The record does not report the administered dose levels, escalation decisions, dose-specific outcomes, or the dose identified as highest and safe. The safety counts therefore cannot establish that the stated dose-escalation objective was achieved. They also do not establish how findings might differ in participants receiving another treatment or no study infusion.

In general, a small descriptive safety study can identify events observed during the study and may inform questions for further investigation. It cannot reliably characterize uncommon events when only a small number of participants are observed. No confidence interval, comparative analysis, or statistical test is reported. The registry also does not report event attribution, detailed timing, or resolution, limiting interpretation of the relationship between the infusion and the event.

The record’s rationale about nitric oxide and citrulline is background for the study, not proof of a clinical benefit. The reported primary endpoint concerns adverse events, not pain relief, acute chest syndrome outcomes, or changes in nitric oxide. Those efficacy or biological outcomes are not reported in the registry record as described in the registry entries. The findings should therefore be read as a limited safety description, not as evidence for a treatment effect or a conclusion about clinical benefit.

The separate planning illustration does not change that interpretation. Its stated assumptions refer to two-arm planning, whereas the trial is described as single-group. No resulting participant counts are reported, and such calculations are planning illustrations rather than observed power or observed trial results.

14. Why This Trial Matters Statistically

This study raises a useful statistical distinction between a safety objective and the strength of evidence available to support a safety conclusion. A Phase 1 dose-escalation study focuses on safety across doses, but meaningful interpretation depends on knowing the dose levels, the escalation rules, and the events observed at each level. The registry identifies the dose-escalation aim but does not report those operational details or a dose-specific safety summary.

The trial also illustrates what can and cannot be learned from a single-group design. Counts can document events observed among participants who received an intervention. Without a comparator, however, those counts cannot show how the event pattern compares with another treatment or estimate a treatment contrast. This is especially important when the purpose is to interpret a safety event, because the registry does not report whether the serious event was judged related to the infusion.

The enrollment of four makes precision a central concern. In general, small studies can describe observed cases but provide limited information about the distribution of outcomes in a broader population. A count of zero in a category does not show that the event is impossible, and a recorded event does not by itself establish a stable event rate. No uncertainty intervals are reported to quantify precision.

Finally, the record distinguishes trial findings from planning assumptions. The planning illustration uses a two-arm framework, but the registered design is single-group, and no calculated sample-size values are reported. That contrast is a reminder that planning scenarios should not be mistaken for the study’s observed design, analysis, or power. Careful statistical reading keeps the reported counts, the study objective, and the unreported design details separate.

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 direct limitation is the small enrollment: four participants. That provides only a narrow description of safety observations and limits precision. The registry reports no comparator group, so the safety counts cannot be used to estimate a difference between citrulline and another treatment or no treatment. No masking is recorded.

The title and objective indicate dose escalation, but the actual dose levels, assignment sequence, escalation criteria, stopping rules, and dose-specific outcomes are not reported in the registry record. Without those details, the central question of which dose was considered the highest safe dose cannot be evaluated from the posted counts. The record also does not report whether the serious event was judged related to the intervention.

Event detail is limited. The registry gives a 30-day timeframe for the primary endpoint and says severity would be determined using the NCI Common Terminology Criteria for Adverse Events. Detailed severity grades, event timing, duration, resolution, and recurrence are not reported in the registry record. The reported percentage for transaminitis has no denominator stated in the record details available.

The record lists two outcome measures but does not report details of the second measure. It reports no analyses and does not describe analysis populations, missing-data handling, multiplicity, or an inferential analysis plan. It also does not report a study-specific sample-size justification. These omissions restrict evaluation of completeness, uncertainty, and whether the observed summaries address the planned objectives.

Finally, the planning illustration is described with equal allocation between two arms despite the registered single-group design. Its calculated values are not reported, and the assumptions should not be treated as trial results. These limitations mean the findings are best understood as a small descriptive safety record rather than a dose-comparison or efficacy analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 1 Study of Continuous Intravenous L-citrulline During Sickle Cell Pain Crisis or Acute Chest Syndrome — NCT02697240.
• Registry record last updated 2019-06-25; status last verified 2019-06.
• Results first posted 2019-04-17.
• 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 1, single-group dose-escalation study sponsored by the University of Mississippi Medical Center. It enrolled four participants with sickle cell disease experiencing a pain crisis or acute chest syndrome. The study start was 2016-02, and primary completion was 2017-04.

The intervention was intravenous citrulline, administered as a bolus over 5 minutes followed by a continuous infusion for the next 23 hours. The primary measure counted participants with adverse events over 30 days, with event number and severity assessed according to the NCI Common Terminology Criteria for Adverse Events.

The posted safety summary reports one participant with a serious adverse event, zero with other adverse events, and zero deaths. Transaminitis is listed as a top serious adverse-event term at 25.0%. The registry reports no analyses. Dose levels, dose-escalation decisions, a comparator, and the dose identified as highest and safe are not reported in the registry record.