Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease (NCT01033227), a randomized phase 1, phase 2 study. The primary outcome is 48 Hour Sodium Nitrite Infusion Safety as Determined by Number of Participants With No Adverse Events.

2. Clinical Question

The study concerns sodium nitrite injection as an additional treatment during acute vaso-occlusive crisis associated with sickle cell disease. Its stated aim was to assess safety and whether treatment could improve small-vessel blood flow and tissue oxygenation. The posted primary outcome addresses safety; the registry record does not report a primary outcome measuring blood flow or tissue oxygenation.

The safety description specifies monitoring for a decrease in mean arterial blood pressure by 15mmHg for greater than 2 hours or development of methemoglobin greater than 5%, alongside monitoring for adverse events. Those criteria describe the intended assessment; the posted primary result is expressed as a participant count, not as separate results for each criterion.

3. Trial Design

The registry classifies the study as Phase 1 and Phase 2, randomized, unmasked, and parallel. A parallel design assigns participants to an arm that remains their assigned group during the study, while randomization is intended to allocate participants by chance. The method used to generate or conceal assignments is not reported in the registry record. Because masking is listed as none, the study is described as unmasked; who knew each assignment is not further detailed.

Five participants were enrolled. The posted arm counts are 3 in the no-drug group and 2 in the sodium nitrite injection group. The record lists Children's Hospital Los Angeles as sponsor. The study start is recorded as 2009-12, and primary completion as 2012-06. Its status is terminated. The reason for termination and whether the planned enrollment or follow-up was completed are not reported in the registry record.

The outcome timeframe is 48 hours from start of infusion. The registry does not report the duration of follow-up beyond that timeframe, the recruitment setting, the number screened or excluded, or participant-level baseline characteristics. It also does not report the target enrollment, a sample-size justification, eligibility criteria in detail, or the intended handling of protocol deviations. These omissions limit assessment of how the small enrolled group relates to the study's original plans.

The two arms and randomized classification establish the broad design, but they do not by themselves establish that the groups were comparable at baseline. With five participants, chance differences in participant characteristics could be substantial; baseline results are not reported in the registry record. No allocation ratio or randomization procedure is stated, so the observed arm sizes should be treated as the recorded counts rather than evidence about the intended allocation procedure.

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: Once consent signed subjects would not be randomized into the treatment arm until (if or when) they had their admission to the hospital for vaso-occlusive crisis (VOC).

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 48 Hour Sodium Nitrite Infusion Safety as Determined by Number of Participants With No Adverse Events, measured over 48 hours from start of infusion.

The primary endpoint is titled as the 48-hour sodium nitrite infusion safety outcome, determined by the number of participants with no adverse events. Its unit is participants, and the outcome is a count. The timeframe is 48 hours from the start of infusion. The accompanying description says that assessment included whether the infusion was tolerated without a decrease in mean arterial blood pressure by 15mmHg for greater than 2 hours or development of methemoglobin greater than 5%, as well as monitoring for adverse events.

A count is a direct way to report how many participants met a defined outcome in each arm. For a safety assessment, counting participants without adverse events conveys the observed number meeting that criterion, while the accompanying safety criteria indicate specific concerns monitored by the study. The posted counts are 3 in the no-drug arm and 2 in the sodium nitrite arm. These are descriptive arm results; the registry record does not provide a separate analysis of the blood-pressure or methemoglobin criteria.

Counts alone do not express the precision of a treatment-group comparison. They also do not describe the severity, timing, or detailed nature of each event. Those details are not reported in the registry record. The endpoint should therefore be read as a narrowly reported safety count over the stated timeframe, not as a complete account of all clinical outcomes or longer-term safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the primary outcome as binary and records it as a count of participants with an event, with the event wording framed as having no adverse events. In general, a binary outcome places each participant into one of two categories, such as meeting or not meeting a specified criterion. A count then records how many participants fall into the category of interest. In this study, the posted counts are 3 for no drug and 2 for sodium nitrite injection. They should be interpreted as descriptive outcome counts in the recorded arms.

Why is a comparison not available?

A comparison between arms requires an estimable contrast based on the outcome data and a defined analysis. The registry states that values are missing or not estimable for a two-arm comparison of this binary endpoint, and it lists 0 analyses. Therefore, no comparative estimate or inferential result is reported. It would be inappropriate to construct a new treatment effect or test result from the arm summaries. The sponsor's own analysis does not take precedence in this record because no sponsor analysis is posted and the discrepancy indicator is false.

General statistical explanation: a comparison might be expressed using an absolute difference in event proportions or another measure appropriate to the design and endpoint. Such measures summarize how outcomes differ between groups, while confidence intervals describe the uncertainty around an estimate. Neither a comparative measure nor its interval is reported. The registry's statement that the comparison is not estimable is the relevant reporting limitation; the reason for that status beyond the stated missing-or-not-estimable label is not reported in the registry record.

What does a confidence interval contribute?

General explanation: a confidence interval is a range produced by a statistical procedure to represent uncertainty around an estimated effect. Narrower intervals indicate greater precision under the assumptions of that method, while wider intervals indicate less precision. An interval is not a guarantee that the true effect lies inside it, and it does not replace consideration of study design or data quality. Because no interval is posted for the two-arm comparison, readers cannot use interval width to judge the comparative precision of these results.

The small arm counts matter to that interpretation. General explanation: when an outcome is uncommon or a study includes few participants, each person's result can have a large influence on the observed group summary. Estimates can therefore be unstable, and conventional approximations may perform poorly with sparse data. The registry does not report a statistical method used to address sparse data, nor does it report a comparative estimate that could be assessed for this issue.

What can be inferred from the safety counts?

The posted adverse-event summaries list 0 serious adverse events among 3 participants at risk in the no-drug arm and 0 among 2 participants at risk in the sodium nitrite arm. For other adverse events, the listed affected counts are also 0 among 3 and 0 among 2, respectively. These are observed counts, not adjusted estimates. They provide no detailed event-level description, and the registry does not post a statistical comparison of these safety categories.

General explanation: descriptive summaries answer what was observed in the recorded participants. Inferential methods attempt to quantify how uncertain a comparison may be beyond those participants, under stated assumptions. Neither a zero count nor an unadjusted descriptive summary establishes the frequency of an event in a broader population. With no posted comparative analysis, there is no basis in the registry record for a formal statistical conclusion about relative safety.

How should planning illustrations be understood?

The stated planning framework describes an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It describes effects to detect as stated fractions of the observed effect; for time-to-event outcomes it specifies total events, and for other outcomes participants per arm. This is a planning framework, not the study's own design justification. No sample-size justification is reported in the registry record. The registry entries do not give a specific planning estimate to interpret for this endpoint, and the unestimable comparison means that a planning illustration based on an observed comparative effect should not be treated as evidence of adequate power.

General explanation: sample-size calculations depend on assumptions about the effect to detect, outcome variability or event frequency, allocation, and the chosen error rate. They describe planning under those assumptions. They do not measure the probability that a completed study has demonstrated an effect, and they are not observed power. In particular, a planning illustration cannot make a non-estimable result informative by itself. Interpretation must remain anchored to the actual posted outcomes and the absence of a comparative analysis.

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("No Drug", "Sodium Nitrite Injection, USP")
n      <- c(3, 2)
events <- c(3, 2)
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  No Drug  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Sodium Nitrite Injection, USP  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 2 outcome measures and identifies 1 secondary outcome, labeled only as Secondary End Point. The definition, timeframe, and result for that secondary outcome are not reported in the registry record. The record also does not report a multiplicity procedure, such as an adjustment or hierarchy for interpreting several outcomes. Without those details, readers cannot determine how secondary outcomes were selected or how multiple statistical tests, if any, were handled.

There are 0 analyses listed. For the primary binary endpoint, the registry states that values are missing or not estimable for a two-arm comparison. This is an absence of a reported comparative analysis, not a reported finding of no difference. The available arm counts remain descriptive. No imputation method or other missing-data procedure is reported in the registry record, and the reason the two-arm comparison could not be estimated is not specified beyond the registry label.

The registry does not report the analysis population, such as whether results were intended to include all randomized participants or a defined subset. It also does not report how withdrawals, protocol deviations, or missing participant outcomes were handled. The posted arm totals and endpoint counts do not resolve these questions. The number of participants enrolled is recorded, but further information on participant flow, completion of follow-up, and outcome availability is not reported in the registry record.

General statistical explanation: multiplicity matters when several outcomes or tests are considered, because repeated testing can increase the chance of a misleading positive result unless interpretation accounts for the testing strategy. Missing-data methods matter because the analysis can depend on why observations are unavailable and how they are handled. Those general concerns cannot be evaluated for this study from the registry entries. The record does not describe the prespecified analysis plan, interim analyses, or rules for selecting outcomes; those details are 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 0% reporting threshold.

The serious adverse-event summaries report 0 affected participants among 3 at risk in the no-drug group and 0 among 2 at risk in the sodium nitrite group. For other adverse events, the affected counts are likewise 0 among 3 and 0 among 2. The registry lists no serious adverse-event terms. Death counts are not reported in the registry record.

These figures describe the participants represented in each arm and the categories recorded in the adverse-event summary. They should not be read as proof that serious or other adverse events cannot occur, or as evidence that risk is the same in both arms. The groups are very small, and the record supplies no comparative safety estimate or uncertainty interval. The absence of listed event terms also means that event-specific patterns cannot be assessed from these entries.

The primary endpoint description additionally names monitoring for a decrease in mean arterial blood pressure by 15mmHg for greater than 2 hours and development of methemoglobin greater than 5%. The registry does not provide separate counts for those criteria. Thus, the adverse-event counts should not be mistaken for a detailed report of every monitored safety measure. They are limited summaries over the recorded assessment, whose timeframe is 48 hours from start of infusion.

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

The result establishes what the registry records for the enrolled participants: 3 participants in the no-drug arm and 2 in the sodium nitrite arm had no adverse events according to the posted primary outcome. The adverse-event summaries list no affected participants for serious or other adverse events in either arm. These counts are descriptive and should be kept separate from claims about a treatment effect.

The registry does not provide an estimable two-arm comparison for the binary primary endpoint and lists 0 analyses. Consequently, the results do not quantify the difference between groups or the uncertainty around such a difference. They do not establish equivalence, non-inferiority, superiority, or absence of risk. The outcome counts also do not supply separate results for the specified blood-pressure and methemoglobin criteria.

The study summary states an aim to assess whether sodium nitrite could improve small-vessel blood flow and tissue oxygenation when given as an additional treatment during acute vaso-occlusive crisis. No posted result for those aims is included in the record. The safety counts therefore should not be interpreted as evidence about those outcomes. Further clinical outcomes and longer-term safety results are not reported in the registry record.

General statistical explanation: an observed result describes the study participants, whereas a conclusion about a wider population requires attention to sampling uncertainty, study design, outcome definitions, and completeness of reporting. Small groups provide limited information about uncommon events and make group summaries sensitive to individual observations. Here, the absence of a comparative analysis further limits what can be said statistically. The study's randomized classification does not remove these limitations or replace the missing analysis.

The most defensible reading is narrow: the record presents safety counts from a randomized, unmasked, parallel study that enrolled five participants, but it does not report a usable comparative estimate for the primary endpoint. It cannot establish from these entries whether the treatment altered safety outcomes, nor can it resolve the broader physiological aims. The terminated status is recorded, but its reason and implications are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically instructive because its randomized design and its reported results answer different questions. Randomization describes how allocation was intended to occur; it does not guarantee that a very small set of participants will be balanced across groups, and it does not create precision where outcome information is sparse. The record reports five enrolled participants, with 3 in the no-drug arm and 2 in the sodium nitrite arm.

The registry provides counts for the primary safety outcome but does not provide an estimable two-arm comparison. That distinction matters: descriptive counts tell readers what was recorded in each group, whereas a comparative analysis would quantify the contrast and its uncertainty. Without that analysis, the results cannot support a precise statistical statement about differences between arms. The absence of an analysis is not itself a finding of no effect.

The case also illustrates why outcome definitions and reporting detail matter. The endpoint description identifies monitoring for adverse events and two specific safety criteria, but the posted primary result is a count of participants with no adverse events. Separate results for the blood-pressure and methemoglobin criteria are not reported. As a result, the summary cannot be used to assess each component individually.

General statistical lesson: planning calculations and observed results serve different purposes. A planning framework depends on assumptions about a target effect and analysis method; it does not substitute for a completed comparison. Likewise, zero recorded events in small groups are descriptive observations, not precise estimates of how often an event might occur elsewhere. For clinical researchers, this record highlights the value of reporting participant flow, endpoint-level results, analysis populations, uncertainty estimates, and reasons for study termination. Those details are not reported in the registry record, and their absence narrows the conclusions that can be drawn.

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 immediate limitation is the small enrollment: 5 participants in total, with 3 in the no-drug arm and 2 in the sodium nitrite arm. These counts leave little information for assessing differences between groups or characterizing uncommon safety events. The registry itself states that values for a two-arm comparison of the binary endpoint are missing or not estimable, and no analyses are listed.

The primary result is limited to the count of participants with no adverse events. Although the endpoint description names a blood-pressure decrease of 15mmHg for greater than 2 hours and methemoglobin greater than 5% as safety criteria, separate results for those measures are not reported in the registry record. Event terms, timing, severity, and further detail about adverse events are also not reported. Death counts are not reported in the registry record.

Important design and analysis details are absent. The reason for termination, target enrollment, sample-size justification, randomization method, detailed eligibility criteria, baseline characteristics, analysis populations, missing-data handling, and prespecified statistical plan are not reported in the registry record. The listed secondary outcome is generic, and its definition and result are not reported. These omissions constrain assessment of participant comparability, completeness of follow-up, and the intended interpretation of multiple outcomes.

The study summary identifies blood flow and tissue oxygenation as aims, but corresponding posted results are not reported. The primary safety timeframe is 48 hours from start of infusion; longer-term outcomes are not reported in the registry record. Together, the limited enrollment, unavailable comparative analysis, and incomplete reporting mean that the observed counts support only a narrow description of the recorded participants, not a precise broader safety or efficacy conclusion.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease — NCT01033227.
• Registry record last updated 2017-10-17; status last verified 2017-09.
• Results first posted 2017-02-08.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes NCT01033227, titled Safety and Efficacy of Sodium Nitrite in Sickle Cell Disease. It is classified as Phase 1 and Phase 2, randomized, unmasked, and parallel, with a total enrollment of 5. The study began in 2009-12, reached primary completion in 2012-06, and is listed as terminated. The sponsor is Children's Hospital Los Angeles.

The primary endpoint is the number of participants with no adverse events during a 48-hour infusion assessment. The posted counts are 3 in the no-drug arm and 2 in the sodium nitrite injection arm. The adverse-event summaries list 0 affected participants for serious and other adverse events in each arm. The record reports 0 analyses and states that a two-arm comparison for the binary endpoint is missing or not estimable. The reason for termination, detailed analysis methods, and results for the stated blood-flow and tissue-oxygenation aims are not reported in the registry record.