This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Novel Use Of Hydroxyurea in an African Region With Malaria (NCT01976416), a randomized phase 3 study. The primary outcome is Number of Malaria Episodes.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01976416 |
| Phase | Phase 3 |
| Condition | Sickle Cell Anemia, Sickle Cell Disease, Malaria |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 208 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Indiana University |
| Results posted | Yes |
2. Clinical Question
Population
Children with sickle cell anemia in a malaria-endemic region within sub-Saharan Africa. The registry lists sickle cell anemia, sickle cell disease, and malaria among the conditions.
Intervention
Hydroxyurea at a fixed dose of 20 ± 2.5 mg/kg/day, taken once daily in tablet form for twelve months.
Comparator
Placebo, also described as a fixed dose of 20 ± 2.5 mg/kg/day in tablet form for twelve months.
Primary question
How many malaria episodes were recorded over 12 months in each treatment arm, and what can the posted results establish about the difference between the arms?
The trial’s stated goal was to investigate the safety and efficacy of hydroxyurea for children with sickle cell anemia in a malaria-endemic region of sub-Saharan Africa. Its primary outcome was titled “Number of Malaria Episodes,” with a 12-month timeframe. The registry defines malaria principally by finding P. falciparum or P. malariae on a peripheral smear when a child was brought for medical evaluation of fever. It also says that suspected infections with P. vivax, P. ovale, or P. knowlesi would be recorded, although those parasites were not known to be present in the region.
The posted outcome values are 5 for hydroxyurea and 7 for placebo. These values describe the recorded endpoint as entered in the registry, but the record does not provide an accompanying comparison estimate, confidence interval, or significance test. It also describes incidence per 100 patient years, while the posted outcome unit is malaria episodes; the record does not clarify whether the arm values are episode totals, rates, or another summarized measure. The clinical question is therefore important, but the available results do not fully quantify the comparative effect or its precision.
3. Trial Design
This was a phase 3, randomized, parallel-group trial with quadruple masking. The registry lists Indiana University as sponsor and records the study status as completed. The study start is listed as 2014-09 and primary completion as 2016-10. Registry enrollment is 208. The posted arm counts are 104 for hydroxyurea and 103 for placebo; the registry does not explain the relationship between these arm counts and the enrollment figure.
The hydroxyurea arm received a fixed dose of 20 ± 2.5 mg/kg/day once daily, in tablet form, for twelve months. The placebo arm description gives the same fixed-dose range and schedule. Those descriptions indicate the intended treatment period and administration, but the record does not report adherence, treatment interruptions, or how dosing was adjusted in practice.
Random allocation is a design feature intended to make treatment groups comparable on average at the point of assignment. Masking is intended to limit the influence of treatment knowledge on participants, care teams, and outcome assessment. The registry labels the study quadruple-masked, but does not identify the masked roles or describe how masking was maintained. The record also does not report the randomization method, allocation concealment procedures, study sites, or participant flow by arm.
The clinical setting is described as a malaria-endemic region within sub-Saharan Africa, but no specific location is named in the registry record. The brief summary explains that the study addressed a setting in which the record says prior studies had not been conducted. It does not establish that the current findings apply to all children with sickle cell anemia or to settings with different malaria exposure, diagnostic practices, or care systems.
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
| Stage | Hydroxyurea | Placebo |
|---|---|---|
| STARTED | 104 | 104 |
| COMPLETED | 102 | 102 |
| NOT COMPLETED | 2 | 2 |
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.
| Characteristic | Unit | Hydroxyurea | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 104 | 103 | 207 | |
| Age, Customized: Age 1.00-3.99 years | Participants | 104 | 103 | 207 |
| Sex: Female, Male: Female | Participants | 49 | 46 | 95 |
| Sex: Female, Male: Male | Participants | 55 | 57 | 112 |
| Race and Ethnicity Not Collected | Participants | — | — | 0 |
| Region of Enrollment: Uganda | participants | 104 | 103 | 207 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Malaria Episodes, measured over 12 months.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | malaria episodes |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is titled “Number of Malaria Episodes” and has a 12-month timeframe. The registry defines malaria as the presence of P. falciparum or P. malariae on a peripheral smear in a child brought for medical evaluation of fever. It states that other named malaria parasites were not known to be present in the region, while suspected infections with those parasites would also be recorded.
Counting episodes can describe the burden of clinically recognized malaria events during follow-up. In this trial, that outcome is relevant to the stated research question because the study took place in a malaria-endemic region and aimed to evaluate hydroxyurea in children with sickle cell anemia. The registry description says incidence would be reported as cases per 100 patient years. That rate-based framing can account for differing observation time, because participants may contribute unequal time under observation; this is a general statistical reason to express event incidence using person-time.
The posted endpoint unit is malaria episodes, and the values are 5 for hydroxyurea and 7 for placebo. The registry does not clarify whether these are total episodes, rates, or another summary, and it gives no dispersion estimate or arm-level patient-time denominator. As a result, the values alone do not show how the endpoint was aggregated or how precisely the arm results were estimated. The record also does not describe the handling of recurrent episodes, missed visits, or episodes diagnosed outside the study’s stated fever-evaluation process.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry reports primary outcome values of 5 in the hydroxyurea arm and 7 in the placebo arm. These are the posted results for the endpoint titled “Number of Malaria Episodes” over 12 months. The record does not supply a treatment-effect estimate, confidence interval, p-value, or statistical test for this outcome. The values therefore support a descriptive statement about what was posted, but not a conclusion about the statistical strength or precision of a difference between arms.
The registry’s endpoint description says incidence would be reported as cases per 100 patient years, but the outcome unit is listed as malaria episodes. The record does not identify the posted values as rates or explain whether they are raw event totals or another summary. Without that clarification, it would be inappropriate to treat the values as rates, calculate a rate ratio, or infer how much follow-up time contributed to each arm’s result.
Randomization and masking are relevant design strengths in principle: random assignment is intended to reduce systematic differences between groups, and masking can limit behavior or assessment influenced by treatment knowledge. These features do not substitute for a reported analysis. Interpretation of comparative results also depends on how outcomes were ascertained, how missing observations and recurrent events were handled, and what analysis population was used. Those details are not reported in the registry record.
The available sample counts are 104 in the hydroxyurea arm and 103 in the placebo arm, while overall enrollment is listed as 208. These counts describe the registry record; they do not establish how many participants completed follow-up or contributed data to the primary endpoint. No participant-flow accounting is posted in the information available for this outcome.
The registry lists six participants affected by serious adverse events in each arm, with 104 and 103 at risk, respectively. It lists deaths of 2 in the hydroxyurea group and 1 in the placebo group. These are separate safety descriptions and should not be taken as a complete assessment of comparative safety, because the record does not give a statistical comparison, event timing, causality assessments, or enough detail to connect particular events to individual participants.
Planning illustrations based on an observed effect are hypothetical design calculations, not evidence of the trial’s achieved power. The registry record does not report a sample-size justification, the planned effect size, or the study’s original power assumptions. Taken together, the posted material permits a limited description of the reported endpoint values and safety counts, but leaves important uncertainty about effect estimation, endpoint construction, and analysis conduct.
9. Statistical Methods Explained
The registry identifies a randomized, parallel-group trial with quadruple masking. It posts arm-level values for the primary outcome but does not report an inferential analysis for that endpoint. Statistical interpretation therefore begins by separating the observed descriptions from conclusions that would require an estimate of uncertainty or a prespecified comparison.
What does an arm-level value tell the reader?
An arm-level value describes the outcome in one treatment group. The registry posts 5 for hydroxyurea and 7 for placebo for “Number of Malaria Episodes.” A treatment comparison would ordinarily require an estimate of how the outcome differs between groups, along with a measure of uncertainty. The record does not post such an estimate or its uncertainty. The two values alone cannot show whether a difference is compatible with chance variation, nor how precisely the underlying outcome has been estimated.
The endpoint is a count outcome: it concerns occurrences of malaria episodes rather than a continuous measurement such as weight. Counts can be analyzed in several ways, depending on the study question and data structure. For example, an analysis might compare total counts, account for observation time, or model repeated episodes within participants. These are general approaches, not claims about the analysis used in this trial. The registry does not identify the statistical model or explain the unit represented by each posted value.
Why does the person-time description matter?
The registry says incidence would be reported as cases per 100 patient years. A rate uses accumulated time at risk in its denominator, which can be useful when participants have different follow-up durations. This is a general concept: two groups can have the same event count but different rates if their observed time differs. The record does not post patient-time totals or confirm that the values 5 and 7 are incidence rates. It is therefore not possible to reconstruct or verify a rate comparison from the posted information.
Malaria episodes may recur within the same participant. Recurrent events are statistically distinct from a simple yes-or-no outcome because one participant can contribute more than one event, and those events may not be independent. General methods for recurrent counts can account for within-participant clustering or over-dispersion. Over-dispersion occurs when observed count variability exceeds what a simpler model assumes; ignoring it can make uncertainty estimates too optimistic. No recurrent-event method, dispersion estimate, or related modeling choice is reported in the registry record, so none can be attributed to this trial.
How should confidence intervals and tests be understood?
In general, a confidence interval describes the range of effect estimates compatible with the data under a specified statistical method and its assumptions. It communicates precision as well as the direction and scale of an estimate. A p-value, when reported, measures how unusual the data would be under a specified null model; it is not a direct measure of clinical importance. Neither a confidence interval nor a p-value is posted for the primary outcome. The registry therefore does not establish whether a formal comparison was performed or what its result was.
For count outcomes, the appropriate effect measure depends on the analysis question and assumptions. A rate ratio compares event rates when follow-up time is included; a rate difference expresses their absolute separation. Other summaries may be appropriate for participant-level outcomes or total counts. These are general statistical definitions only. Because the registry does not clearly identify the nature of the posted values or provide the underlying denominators, no such effect measure should be inferred from the arm values.
What can randomization and masking support?
Random allocation is generally intended to balance both measured and unmeasured prognostic factors across treatment groups in expectation. Masking can reduce the risk that knowledge of assignment affects care, reporting, or outcome assessment. These design features support a fair comparison when implemented successfully, but they do not demonstrate that groups were balanced in the realized sample or that all outcome assessments were unbiased. The registry record does not describe the randomization sequence, concealment, masked roles, or masking checks.
The study is labeled phase 3, randomized, parallel, and quadruple-masked. Those labels describe broad features of design, not the full statistical plan. The registry does not report model specifications, covariate adjustment, the approach to repeated malaria episodes, or whether an intention-to-treat analysis was planned. No statistical analysis plan is included in the available record.
What do the planning illustrations represent?
Planning illustrations based on an observed effect are hypothetical calculations for future design, not observed trial outcomes and not “observed power.” The record describes the illustration assumptions as a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Such calculations depend on the assumed effect and model; they do not recover the trial’s original design rationale. The registry does not report the original sample-size justification or its assumptions.
In general, a planning calculation estimates how many participants per arm might be needed to detect an assumed effect at a chosen power under specified assumptions. It should not be read as evidence that the completed trial had that power, or that the assumed effect is the true effect. Here, the posted outcome lacks a reported comparison estimate and precision measure, so the registry record does not support a full assessment of the assumptions underlying a planning calculation.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists one primary outcome measure and no posted secondary outcomes. It also reports no posted analyses. These statements describe what appears in the registry record; they do not establish whether additional outcomes or analyses were prespecified elsewhere, collected, or conducted but not posted. The statistical analysis plan and details of any planned outcome hierarchy are not reported in the registry record.
Multiplicity arises when several outcomes, treatment contrasts, time points, or subgroup analyses are tested. Repeated testing can increase the chance of finding at least one apparently unusual result by chance. Whether an adjustment is needed depends on the analysis plan and the scientific goals. Because the registry does not give a set of inferential analyses or state how multiple comparisons were handled, multiplicity control cannot be assessed from this record.
Missing-data methods and analysis populations are also not reported. The registry gives arm counts of 104 and 103, but does not say how many participants had evaluable primary-outcome data, how much follow-up time they contributed, or whether anyone withdrew or was excluded. It does not describe imputation, censoring, or sensitivity analyses. These details matter because incomplete follow-up can affect the interpretation of episode counts and person-time rates.
The record does not state whether the primary analysis followed intention-to-treat principles, included only participants with observed outcomes, or used another population. It also does not explain whether participants were analyzed according to randomized assignment or treatment received. Without those details, it is not possible to determine how the reported arm values relate to all randomized participants or to assess the robustness of the outcome comparison.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Hydroxyurea | 6 | 104 | 5.8% |
| Placebo | 6 | 103 | 5.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Hydroxyurea | 2 of 104 |
| Placebo | 1 of 103 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Hydroxyurea | 76 of 104 |
| Placebo | 88 of 103 |
Most frequent serious adverse event terms
| Event term | Organ system | Hydroxyurea | Placebo |
|---|---|---|---|
| Bacteremia | Infections and infestations | 2 of 104 | 2 of 103 |
| Pneumonia | Respiratory, thoracic and mediastinal disorders | 1 of 104 | 2 of 103 |
| Acute Splenic Squestration | Blood and lymphatic system disorders | 2 of 104 | 0 of 103 |
| Vaso-Occlusive Crisis | Blood and lymphatic system disorders | 0 of 104 | 1 of 103 |
| Anemia | Blood and lymphatic system disorders | 0 of 104 | 1 of 103 |
| Sudden Death | General disorders | 1 of 104 | 0 of 103 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Hydroxyurea | Placebo |
|---|---|---|---|
| Upper Respiratory Tract Infection | Respiratory, thoracic and mediastinal disorders | 54 of 104 | 62 of 103 |
| Vaso-Occlusive Crisis | Blood and lymphatic system disorders | 38 of 104 | 59 of 103 |
| Anemia | Blood and lymphatic system disorders | 25 of 104 | 42 of 103 |
| Pneumonia | Respiratory, thoracic and mediastinal disorders | 21 of 104 | 24 of 103 |
| Gastrointestinal-related | Gastrointestinal disorders | 13 of 104 | 12 of 103 |
| Other infections | Infections and infestations | 7 of 104 | 14 of 103 |
| Clinical Sepsis | Infections and infestations | 6 of 104 | 13 of 103 |
| Others (e.g., injury) | Injury, poisoning and procedural complications | 7 of 104 | 9 of 103 |
| Thrombocytopenia | Blood and lymphatic system disorders | 11 of 104 | 4 of 103 |
| Malaria | Blood and lymphatic system disorders | 3 of 104 | 7 of 103 |
Serious events with the highest arm-level rate: bacteremia (1.9%), pneumonia (1.9%), acute splenic squestration (1.9%), vaso-occlusive crisis (1.0%), anemia (1.0%).
The registry reports serious adverse events for 6 participants in the hydroxyurea group, with 104 listed at risk, and for 6 participants in the placebo group, with 103 listed at risk. It separately lists 2 deaths in the hydroxyurea arm and 1 in the placebo arm. The record does not provide a statistical comparison for these figures, event timing, or an assessment of whether events were considered related to treatment.
The listed serious-event terms include Bacteremia, Pneumonia, and Acute Splenic Squestration at 1.9% each, and Vaso-Occlusive Crisis, Anemia, and Sudden Death at 1.0% each. These are registry-listed terms and percentages. The record does not explain the percentage denominator or whether individuals could contribute to more than one term, so the terms should not be added together or interpreted as mutually exclusive categories.
The registry also reports other adverse events affecting 76 participants in the hydroxyurea group and 88 in the placebo group. These figures are not a substitute for the serious-event counts and are not accompanied by a comparative analysis. Taken together, the counts are descriptive safety information. They do not alone establish a treatment-related cause, the relative frequency of events over time, or a complete safety profile.
12. What the Result Does, and Does Not, Mean
The posted results give a limited account of the primary endpoint: the registry records values of 5 for hydroxyurea and 7 for placebo for malaria episodes over 12 months. Those values do not come with a reported treatment-effect estimate, confidence interval, or significance test. The registry also says incidence would be expressed per 100 patient years, but does not clarify whether these two values are rates or another summary. Thus, the results do not establish the magnitude or precision of a comparative effect.
The trial’s randomized and masked design is relevant to causal interpretation in principle. If allocation and masking were implemented as intended, they could reduce certain sources of bias. The registry record does not give enough operational detail to assess implementation, nor does it report analysis populations, missing-data handling, or an inferential model. A design label cannot fill in those analytic details.
The serious adverse event figures and death counts should also be read descriptively. Equal reported counts of serious adverse events in the arms do not establish equivalent safety, and the death counts do not establish a treatment effect. The record does not report event adjudication, attribution, timing, or a formal comparison. Likewise, the other adverse-event counts do not by themselves indicate the clinical severity or duration of those events.
The record establishes that a phase 3 randomized trial was completed, identifies its intervention and comparator, and posts selected outcome and safety values. It does not establish the effect’s statistical significance, the degree of uncertainty, the rate of malaria per patient-time, or the cause of any adverse event. It also does not provide enough information to infer how the posted figures would generalize to other populations or settings. The distinction is between describing what the registry reports and making claims that require a fuller analysis.
13. Why This Trial Matters Statistically
This trial addresses a statistical question in a setting the registry describes as malaria-endemic and within sub-Saharan Africa. Its stated motivation is that previous studies of hydroxyurea had not been conducted in such a region, despite the presence of children with sickle cell anemia there. The setting makes careful outcome definition and follow-up especially important: a malaria episode is not simply any fever, but is defined through medical evaluation and parasite findings, with additional suspected infections also recorded.
The study also illustrates why counts and rates must not be treated as interchangeable. The registry names a count endpoint and posts values of 5 and 7, while its description says incidence would be expressed per 100 patient years. A rate requires information about time at risk as well as events. Because that denominator and the meaning of the posted values are not clarified, readers cannot independently understand the intended scale of comparison.
Repeated episodes pose another general statistical challenge. If participants can experience more than one event, an analysis must account for the count structure and potentially dependent events within a participant. Over-dispersion may also matter for uncertainty estimates. The registry does not identify the method used, making this trial a useful example of why a stated endpoint alone does not fully describe an analysis.
Finally, the record distinguishes a completed randomized trial from a transparent statistical result. It reports design features and descriptive arm values, but no primary-outcome analysis, precision measure, or analysis population. This gap does not negate the study’s clinical question; it limits what can be concluded from the posted record. Readers need effect estimates, uncertainty, denominators, and analytic details to evaluate the evidence quantitatively.
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 primary outcome’s scale is not clear from the registry record. It is titled “Number of Malaria Episodes,” has a unit of malaria episodes, and is described as incidence per 100 patient years. Yet the posted arm values do not identify whether they are counts, rates, or another statistic. The record also omits patient-time denominators and a measure of variability, so the outcome cannot be independently reconstructed or its precision assessed.
The registry does not report a primary-outcome comparison, confidence interval, p-value, or statistical model. It does not identify how recurrent episodes were handled, whether the analysis accounted for different follow-up times, or how malaria episodes were counted when a participant had more than one event. The record describes the fever and smear-based definition but gives no additional detail on adjudication or consistency of ascertainment across sites.
Participant flow and analysis populations are not described. Although the registry lists enrollment as 208 and arm counts of 104 and 103, it does not state how many completed follow-up, contributed endpoint data, or were included in an analysis. Missing observations, withdrawals, adherence, dose interruptions, and treatment exposure are not reported.
The geographic location and operational details of masking and randomization are not specified. The record does not provide a sample-size justification or the original statistical analysis plan. Its safety results lack event timing, causal attribution, and an inferential comparison; the denominator for listed serious-event percentages is not explained. These limitations restrict interpretation of both comparative efficacy and safety and make generalization beyond the stated study setting uncertain.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Novel Use Of Hydroxyurea in an African Region With Malaria — NCT01976416.
- Registry record last updated 2018-12-04; status last verified 2018-11.
- Results first posted 2018-10-01.
- 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.
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18. Record Summary
NCT01976416 is a completed phase 3 randomized, parallel-group, quadruple-masked trial sponsored by Indiana University. The study compared daily hydroxyurea with placebo for twelve months in children with sickle cell anemia in a malaria-endemic region of sub-Saharan Africa. Registry enrollment is 208, with posted arm counts of 104 for hydroxyurea and 103 for placebo.
The primary outcome was the number of malaria episodes over 12 months. The registry posts values of 5 for hydroxyurea and 7 for placebo, but does not report a comparative statistical analysis or clarify whether those values are counts or rates. Serious adverse events affected 6 participants in each arm; deaths are listed as 2 and 1, respectively. No analysis plan, missing-data approach, or analysis population is reported in the registry record, limiting what can be concluded from the posted results.