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 A Study of Intravenously Administered Tamiflu (Oseltamivir) in Patients Over 13 Years of Age With Influenza (NCT01050257), a randomized phase 3 study. The primary outcome is Number of Participants With Adverse Events (AEs), Serious Adverse Events(SAEs, AEs Leading to Withdrawal, and Death.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01050257 |
| Phase | Phase 3 |
| Condition | Influenza |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 118 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Hoffmann-La Roche |
| Results posted | Yes |
2. Clinical Question
Population
Patients aged 13 years or older with influenza were eligible for the study. The registry describes adult and adolescent patients in the randomized groups and a separate group for patients with moderate or severe renal impairment or renal failure. The safety population included participants who received treatment and had at least one post-treatment safety assessment.
Intervention
Participants in one randomized group received oseltamivir 100 mg intravenously every 12 hours. At the investigator’s discretion after 3 days of treatment, they could continue intravenous treatment or switch to oral oseltamivir. The other randomized group received 200 mg intravenously every 12 hours, with a possible oral switch after 3 days. The planned treatment period was 5 days, with possible extension in some circumstances.
Comparator
The randomized dose comparison was 100 mg versus 200 mg of intravenous oseltamivir. The renal-impairment group received open-label oseltamivir at doses adjusted for renal status; it was not described as a randomized comparison group.
Primary question
The primary outcome concerned the number of participants with adverse events, serious adverse events, adverse events leading to withdrawal, and death, assessed up to 30 days. The study also planned to assess pharmacokinetics, viral shedding and titer, and fever outcomes. The registry record does not provide a single comparative estimate or statistical test for the primary safety question.
3. Trial Design
This was a phase 3, multicenter, parallel-group study with randomized allocation and double masking for the dose assignment in the randomized groups. The registry describes the study as partially randomized: adult and adolescent participants were randomized to intravenous oseltamivir 100 mg or 200 mg, while participants with moderate or severe renal impairment or renal failure could enter a non-randomized, open-label group. The two randomized dose groups were blinded to assigned dose; the renal-impairment group was open label.
The intravenous regimens were given every 12 hours. Treatment was planned for 5 days. After 3 days, or 6 doses, participants could continue intravenous treatment or switch to oral oseltamivir according to the arm description and investigator discretion. The summary also describes a possible treatment extension of a further 5 days if necessary. Renal-group dosing and frequency were adjusted according to renal status, but the specific regimens are not reported in the registry record.
Enrollment was 118. The study status is completed. The recorded start is 2010-01 and primary completion is 2012-09. The registry does not report the number enrolled in each randomized group as an enrollment result separate from the safety denominators, nor does it explain any difference between total enrollment and the safety population counts.
The primary outcome was a safety measure assessed up to 30 days. Other listed outcomes included pharmacokinetics, viral shedding by culture and RT-PCR, change in influenza titer at Day 4, and fever occurrence and resolution. The registry record does not report detailed allocation procedures, concealment, the exact masking procedures, or a prespecified statistical analysis plan.
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: This study included a 5 day treatment period and an optional extension. Participants were considered to have completed treatment if they completed the 5-day course of treatment (IV and/or oral).
Overall Study
| Stage | Oseltamivir (TAMIFLU®) 100 mg | Oseltamivir (TAMIFLU®) 200 mg | Oseltamivir Open Label |
|---|---|---|---|
| STARTED | 50 | 53 | 15 |
| Received Treatment | 49 | 50 | 14 |
| Safety Population: Actual Dose Received | 48 | 51 | 14 |
| Intent-to-treat Infected Confirmed | 30 | 32 | 10 |
| Switched to Oral Treatment | 28 | 31 | 3 |
| COMPLETED | 39 | 40 | 8 |
| NOT COMPLETED | 11 | 13 | 7 |
Reasons for not completing this period:
| Reason | Oseltamivir (TAMIFLU®) 100 mg | Oseltamivir (TAMIFLU®) 200 mg | Oseltamivir Open Label |
|---|---|---|---|
| Adverse Event | 4 | 4 | 2 |
| Admin/Other (did not switch to oral) | 6 | 2 | 2 |
| Withdrawal by Subject | 0 | 3 | 0 |
| No reason specified | 0 | 0 | 2 |
| Refused treatment/ Did not Cooperate | 1 | 1 | 0 |
| Violation criteria | 0 | 1 | 0 |
| Failure to return | 0 | 2 | 0 |
| Death | 0 | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who received treatment and had at least one post-treatment safety assessment. One patient in the 100 mg group actually received 200 mg and is included in the 200 mg group for safety.
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: Demographics are based on the all enrolled patients population.
| Characteristic | Unit | Oseltamivir (TAMIFLU®) 100 mg | Oseltamivir (TAMIFLU®) 200 mg | Oseltamivir Open Label | Total |
|---|---|---|---|---|---|
| Participants analysed | 50 | 53 | 15 | 118 | |
| Age Continuous | years | 44.8 (SD 16.68) | 44.3 (SD 18.09) | 66.9 (SD 18.28) | 47.4 (SD 18.93) |
| Sex: Female, Male: Female | Participants | 25 | 27 | 8 | 60 |
| Sex: Female, Male: Male | Participants | 25 | 26 | 7 | 58 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), Serious Adverse Events(SAEs, AEs Leading to Withdrawal, and Death, measured over Up to 30 days.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Partipants |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint counts participants with adverse events, serious adverse events, adverse events leading to withdrawal, and death, with assessment up to 30 days. An adverse event was defined as an unfavorable and unintended sign, symptom, or disease associated with study-drug use, whether or not considered related to the drug. A preexisting condition that worsened during the study was also counted as an adverse event. A serious adverse event was defined using outcomes such as death, a life-threatening experience, inpatient hospitalization or its prolongation, persistent or significant disability, congenital anomaly or birth defect, or another medically significant event.
A participant count is a safety measure: it records how many participants experienced an event in a specified category. It does not by itself describe event severity, duration, causal relationship to treatment, or the number of repeated events per participant. Those distinctions require additional event-level information. The registry describes on-treatment events as those starting between the first dose and within 2 days after the last dose; off-treatment events started more than 2 days after the last dose.
The endpoint is useful for organizing safety observations during and after exposure. The posted group counts include participants with serious events and other adverse events, but the registry record does not provide all of the primary endpoint categories as separate results. It also does not report a comparative estimate or uncertainty interval for this endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety counts are descriptive. In the 100 mg group, 9 of 48 participants were recorded with serious adverse events and 17 of 48 with other adverse events. In the 200 mg group, the corresponding counts were 5 of 51 and 18 of 51. In the open-label group, 7 of 14 participants were recorded with serious adverse events and 10 of 14 with other adverse events. These counts show what was recorded in each safety group; by themselves, they do not establish that one dose caused more or fewer events than another.
The randomized comparison is between the two dose groups, but the registry record does not give a treatment-effect estimate, confidence interval, or statistical test for these safety counts. It therefore does not quantify how precisely the groups differ, or whether any observed numerical differences could reflect chance. A confidence interval, in general, describes a range of values compatible with the data under the method used; no such interval is reported for these comparisons.
The open-label renal-impairment group should not be interpreted as a third randomized dose arm. Its participants differed in renal status, treatment was open label, and doses were adjusted according to renal situation. The group’s counts therefore cannot be directly compared with the randomized groups as if assignment and participant characteristics were equivalent.
The registry lists six serious-event terms at 7.1% each: sepsis, chronic obstructive pulmonary disease, respiratory distress, ventricular fibrillation, cardiac arrest, and hypotension. The registry record does not identify the denominator or group associated with these percentages in the posted information, so they should not be assigned to a particular arm or treated as comparative rates.
Deaths are not reported as numeric counts in the group data. This should not be read as evidence that no deaths occurred. The registry also does not provide separate results for adverse events leading to withdrawal. The primary outcome title includes both categories, but the available posted counts do not resolve them individually. The study’s additional virologic, pharmacokinetic, and fever outcomes are listed, while comparative results and statistical analyses for them are not reported in the registry record.
In general, randomized assignment can support a fairer comparison between treatment groups than non-randomized assignment, when the comparison is analyzed as planned and relevant data are available. Here, the registry’s limited results do not permit a complete inferential assessment of the randomized dose comparison. The counts are best read as recorded safety observations, not as proof of equivalence, superiority, or a causal dose effect.
9. Statistical Methods Explained
Statistical methods are the rules used to turn observations into estimates and to describe uncertainty. The registry record gives the broad design and outcome definitions, but it does not report the statistical analysis plan, specific tests, adjustment methods, or confidence intervals for the outcomes. The explanations below are general; they do not imply that a particular method was used in this trial.
What does randomization contribute?
In general, randomization assigns participants to groups using a chance-based process. It is intended to make treatment groups comparable, on average, with respect to both measured and unmeasured characteristics. That can make differences in outcomes more interpretable as treatment comparisons. Randomization does not guarantee identical groups, especially in a trial with limited enrollment, and it cannot make a non-randomized group comparable to randomized groups. In this study, the 100 mg and 200 mg groups were randomized, while the renal-impairment group was non-randomized and open label. Thus the randomized dose comparison and the renal-group observations answer different kinds of questions.
What does a participant count tell the reader?
A count of participants with an event is a binary summary at the participant level: each person is classified according to whether they experienced the specified event category. A count does not reveal the total number of event episodes, how long events lasted, whether one participant had several events, or how investigators judged relatedness. Those details may matter when interpreting safety. The registry defines adverse events and serious adverse events, but event-level results and comparative estimates are not reported in the registry record.
How would uncertainty be assessed?
In general, an estimate is more informative when accompanied by an uncertainty measure. A confidence interval describes the range of values compatible with the observed data under a specified statistical model and procedure. For a safety comparison, an interval around a difference or another contrast can indicate both the direction and precision of the estimated group difference. A p-value, when used, summarizes how surprising the data would be under a stated null hypothesis and model; it does not measure the probability that the null hypothesis is true or the size of a treatment effect. The registry record does not report confidence intervals, p-values, or comparative estimates for the posted safety counts.
Why does the analysis population matter?
The primary outcome description defines the safety population as participants who received treatment and had at least one post-treatment safety assessment. The registry also states that one participant assigned to the 100 mg group actually received 200 mg and was included in the 200 mg group for safety. This is a treatment-received classification for that safety summary. In general, analyses based on treatment received can differ from analyses based on randomized assignment. An analysis by randomized assignment preserves the original comparison created by randomization, while a safety analysis by treatment received can better describe exposure but may no longer retain all benefits of random assignment. The registry does not report a separate efficacy analysis population or explain any additional population rules.
Why can the open-label group not serve as a direct dose control?
In general, a non-randomized comparison can be affected by differences in participant characteristics and clinical circumstances. Here, the open-label group was for moderate or severe renal impairment or renal failure, with dosing adjusted for renal status. Those features distinguish it from the randomized groups. Its event counts can describe observations in that group, but a raw comparison with either randomized group would mix treatment differences with differences in eligibility and clinical status. The registry record does not report an adjusted comparison addressing those differences.
What is the role of masking?
In general, masking can reduce the influence of knowledge of treatment assignment on participant reports, clinical management, and outcome assessment. The registry says investigators and patients were blinded to the assigned dose in the randomized groups. The renal-impairment group was open label. The record does not describe exactly which other trial personnel were masked or how the masking was maintained.
Why can over-dispersion matter?
General statistical note: count data can vary more than a simple model expects, a property often called over-dispersion. When present, it can make uncertainty estimates that assume less variability too narrow. The primary endpoint is described as the number of participants with events, rather than a count of repeated event episodes, and the registry does not report a model for count outcomes or any over-dispersion assessment. There is therefore no basis to say that a particular over-dispersion method was used.
What can be concluded from an unreported test?
A missing statistical test is not a negative test result. Without the planned analysis and its output, the reader cannot infer whether a comparison was statistically significant, whether a prespecified threshold was met, or whether the study was designed to establish equivalence or non-inferiority. The registry record does not report those features. The available count data remain descriptive rather than a complete inferential analysis.
10. Multiplicity, Missing Data and Analysis Populations
The study lists multiple outcomes beyond the primary safety endpoint: pharmacokinetics, viral shedding by culture or RT-PCR, change in influenza titer at Day 4, fever during the study, and time to fever resolution among participants who had fever at baseline. The registry gives 11 outcome measures, but reports no analyses. The primary outcome itself names several event categories: adverse events, serious adverse events, adverse events leading to withdrawal, and death.
When many outcomes or comparisons are tested, the chance of obtaining at least one apparently unusual result can increase. General statistical practice may address this through a prespecified hierarchy, adjustment, or a clear distinction between confirmatory and exploratory outcomes. The registry record does not report whether multiplicity was addressed, which outcomes were designated as confirmatory, or how any testing hierarchy was defined. No adjustment should be assumed.
The registry defines the safety population as treated participants with at least one post-treatment safety assessment. This identifies who was included in that safety summary, but the record does not describe how missing observations were handled for other outcomes, whether any participants lacked follow-up, or whether imputation or sensitivity analyses were used. Missing data methods are not reported in the registry record.
The registry record also does not report a full statistical analysis plan, the planned primary contrast, a sample-size justification, interim analyses, or a stopping rule. Those omissions prevent a reader from judging whether reported analyses followed prespecified methods or how the study’s enrollment was linked to a target level of precision. No claim about statistical power can be made from the posted counts alone.
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 |
|---|---|---|---|
| Oseltamivir (TAMIFLU®) 100 mg | 9 | 48 | 18.8% |
| Oseltamivir (TAMIFLU®) 200 mg | 5 | 51 | 9.8% |
| Oseltamivir Open Label | 7 | 14 | 50.0% |
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 |
|---|---|
| Oseltamivir (TAMIFLU®) 100 mg | 17 of 48 |
| Oseltamivir (TAMIFLU®) 200 mg | 18 of 51 |
| Oseltamivir Open Label | 10 of 14 |
Most frequent serious adverse event terms
| Event term | Organ system | Oseltamivir (TAMIFLU®) 100 mg | Oseltamivir (TAMIFLU®) 200 mg | Oseltamivir Open Label |
|---|---|---|---|---|
| Sepsis | Infections and infestations | 1 of 48 | 0 of 51 | 1 of 14 |
| Sinus bradycardia | Cardiac disorders | 2 of 48 | 0 of 51 | 0 of 14 |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | 0 of 48 | 1 of 51 | 1 of 14 |
| Renal failure acute | Renal and urinary disorders | 1 of 48 | 0 of 51 | 0 of 14 |
| Deep vein thrombosis | Vascular disorders | 1 of 48 | 0 of 51 | 0 of 14 |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | 1 of 48 | 0 of 51 | 0 of 14 |
| Cerebrovascular accident | Nervous system disorders | 1 of 48 | 0 of 51 | 0 of 14 |
| Parainfluenzae virus infection | Infections and infestations | 1 of 48 | 0 of 51 | 0 of 14 |
| Atrial fibrillation | Cardiac disorders | 1 of 48 | 0 of 51 | 0 of 14 |
| Abortion threatened | Pregnancy, puerperium and perinatal conditions | 1 of 48 | 0 of 51 | 0 of 14 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Oseltamivir (TAMIFLU®) 100 mg | Oseltamivir (TAMIFLU®) 200 mg | Oseltamivir Open Label |
|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | 6 of 48 | 1 of 51 | 1 of 14 |
| Vomiting | Gastrointestinal disorders | 3 of 48 | 4 of 51 | 0 of 14 |
| Headache | Nervous system disorders | 1 of 48 | 4 of 51 | 2 of 14 |
| Infusion site pain | General disorders | 3 of 48 | 4 of 51 | 0 of 14 |
| Constipation | Gastrointestinal disorders | 2 of 48 | 3 of 51 | 1 of 14 |
| Anxiety | Psychiatric disorders | 4 of 48 | 1 of 51 | 1 of 14 |
| Back pain | Musculoskeletal and connective tissue disorders | 3 of 48 | 1 of 51 | 2 of 14 |
| Diarrhoea | Gastrointestinal disorders | 4 of 48 | 1 of 51 | 0 of 14 |
| Hypertension | Vascular disorders | 3 of 48 | 1 of 51 | 1 of 14 |
| Anaemia | Blood and lymphatic system disorders | 1 of 48 | 0 of 51 | 2 of 14 |
Serious events with the highest arm-level rate: sepsis (7.1%), chronic obstructive pulmonary disease (7.1%), respiratory distress (7.1%), ventricular fibrillation (7.1%), cardiac arrest (7.1%).
The safety group counts report 9 of 48 participants with serious adverse events and 17 of 48 with other adverse events in the 100 mg group; 5 of 51 and 18 of 51, respectively, in the 200 mg group; and 7 of 14 and 10 of 14 in the open-label group. These are participant counts, not a count of every event episode. A participant may have experienced more than one event, but the registry record does not give event totals for these groupings.
The randomized dose groups can be read as descriptive safety summaries for their treated participants. The open-label group had renal impairment or renal failure and dose adjustment according to renal status, so its counts are not a randomized dose comparison. The safety population also assigned one participant who received 200 mg to the 200 mg group, despite initial placement in the 100 mg group.
The listed serious-event terms—sepsis, chronic obstructive pulmonary disease, respiratory distress, ventricular fibrillation, cardiac arrest, and hypotension—are each accompanied by 7.1%. The registry record does not identify the denominator or treatment group for these percentages. Numeric death counts and withdrawal-specific counts are not reported, so neither should be interpreted as zero.
12. What the Result Does, and Does Not, Mean
The registry supports a limited descriptive reading of safety. It records participants with serious and other adverse events in the two randomized dose groups and the separate open-label renal-impairment group. It also defines adverse events and the safety population, and gives a follow-up timeframe of up to 30 days. These are useful details for understanding what the posted safety summaries represent.
The record does not report a direct statistical comparison between the randomized doses, a confidence interval, or a p-value. It therefore does not establish whether the observed count differences reflect a treatment effect or random variation. Nor does the absence of a reported comparative analysis establish that the doses have equal safety. Evidence of equivalence would require a suitable design, a prespecified margin, and an analysis whose uncertainty is compatible with that margin; these details are not reported in the registry record.
The open-label group provides observations for participants with moderate or severe renal impairment or renal failure who received adjusted dosing. Since this group was not randomized and differs by renal status and dosing, its counts cannot isolate the effect of a dose or be interpreted as a direct comparison with the randomized groups.
The registry lists pharmacokinetic, viral, and fever outcomes, but does not report their results or analyses. The available record therefore cannot establish what those outcomes showed. Similarly, death and withdrawal-specific results are not available as numeric group counts, and the listed serious-event percentages lack a stated denominator and group assignment.
In general, clinical trial results should be interpreted in light of the outcome definition, analysis population, uncertainty, and design. Here, the reported safety numbers describe observed participants in the registry’s stated groupings. They do not support a conclusion about treatment benefit, lack of benefit, or comparative safety beyond those descriptive observations.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of why trial design and analysis population need to be read together. The two dose groups were randomized and double masked, while participants with moderate or severe renal impairment or renal failure were treated in a non-randomized, open-label group with dose adjustment. A single set of group counts therefore combines randomized comparisons with observations from a clinically distinct, non-randomized group. These groups should not be treated as interchangeable.
The primary outcome is safety-focused and contains several categories, including adverse events, serious adverse events, events leading to withdrawal, and death. A single participant count can be useful for a broad overview, but it does not describe event frequency, timing, severity distributions, or treatment relatedness in detail. The posted data also distinguish serious events from other events, while the full set of primary outcome categories is not separately reported.
The record illustrates the importance of uncertainty measures. The counts alone do not show how precise a dose comparison would be, and there are no posted estimates or tests that quantify the contrast. A numerical difference in counts is not, by itself, evidence of a reliable treatment difference. The absence of a test or interval also cannot be interpreted as evidence that the groups are equivalent.
Finally, the study lists several secondary outcomes but no analyses. This makes it important to distinguish outcomes named in a registry from outcomes with posted results. Without results, multiplicity procedures, and missing-data methods, readers cannot assess the inferential strength of those endpoints. The main statistical lesson is that descriptive safety counts, randomized assignment, and complete reporting each contribute different information; none substitutes for the others.
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 registry record has important reporting limitations for statistical interpretation. It does not provide a full statistical analysis plan, sample-size justification, planned treatment contrast, interim-analysis information, or a stopping rule. It also does not report p-values, confidence intervals, or adjusted comparisons for the safety outcomes. As a result, the posted counts cannot be evaluated as a complete inferential analysis.
The primary outcome includes several categories, but the numeric group data do not separately report adverse events leading to withdrawal or deaths. Death entries are null rather than numeric counts; that is not evidence of no deaths. The other serious-event terms are listed with the same percentage, 7.1%, but the registry record does not identify their denominator or group, limiting interpretation of those percentages.
The trial included a non-randomized, open-label group for participants with renal impairment or renal failure. Their renal status and adjusted dosing make direct comparisons with the randomized dose groups difficult. The registry does not report an adjusted analysis intended to account for those differences. For the safety summary, one participant who received 200 mg was included in that group, rather than the group to which the participant was initially assigned. This treatment-received grouping should be kept distinct from an analysis by randomized assignment.
The registry lists secondary outcomes but does not report their results or statistical analyses. It also does not describe missing-data handling, outcome-specific analysis populations, or whether follow-up was complete. The enrollment figure and safety group denominators are reported, but the record does not explain their relationship. These omissions limit assessment of precision, potential bias, and the completeness of outcome reporting.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Intravenously Administered Tamiflu (Oseltamivir) in Patients Over 13 Years of Age With Influenza — NCT01050257.
- Registry record last updated 2013-11-01; status last verified 2013-08.
- Results first posted 2013-11-01.
- 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
The registry record describes a completed phase 3, multicenter, parallel-group study of intravenous oseltamivir in patients aged 13 years or older with influenza. Enrollment was 118. The randomized, double-masked groups received 100 mg or 200 mg intravenously every 12 hours; a non-randomized, open-label group included participants with moderate or severe renal impairment or renal failure and received adjusted dosing. Treatment was planned for 5 days, with possible oral conversion and extension described in the study information.
The primary endpoint concerned participants with adverse events, serious adverse events, adverse events leading to withdrawal, and death, assessed up to 30 days. Safety counts are posted for serious and other adverse events. Pharmacokinetic, viral-shedding, viral-titer, and fever outcomes are listed, but their analyses are not reported. The registry record does not provide comparative statistical estimates, uncertainty intervals, or a full statistical analysis plan.