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 Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy (NCT02386553), a na phase 2 study. The primary outcome is Time to Death or Respiratory Intervention.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02386553 |
| Phase | Phase 2 |
| Condition | Spinal Muscular Atrophy |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 25 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Biogen |
| Results posted | Yes |
2. Clinical Question
Population
Infants with genetically diagnosed and presymptomatic spinal muscular atrophy were enrolled. The stated primary analysis population was the ITT set, defined as participants who received at least 1 dose of ISIS 396443; the record clarifies that the analyzed count means participants with data available for that outcome.
Intervention
Participants received nusinersen, also identified in the study record as ISIS 396443. The intervention was administered by intrathecal injection. The study examined multiple doses, but the dose schedule and dose amounts are not reported in the registry record.
Comparator
The study is classified as single-group, with allocation listed as NA and masking as none. It therefore has no randomized control group in the registry description. The groups labeled by SMN2 copy number are not described as a like-for-like control comparison.
Primary question
The primary objective was to examine whether multiple doses could prevent or delay respiratory intervention or death. The endpoint records age at the first occurrence of either event. The registry record does not report the observed median time or its 95% confidence interval, so the magnitude and precision of the primary result cannot be assessed from the posted outcome information.
3. Trial Design
This is a phase 2, open-label, single-group study of nusinersen in infants with genetically diagnosed and presymptomatic spinal muscular atrophy. The registry record lists enrollment as 25 and identifies Biogen as the sponsor. The intervention is nusinersen, administered as an intrathecal injection. The study status is completed.
Open-label means treatment assignment was not masked from participants or study personnel, as reflected by the record’s masking designation of none. A single-group design means that the record does not describe a separate control arm for the primary comparison. Allocation is listed as NA. Accordingly, the study’s treatment experience cannot be interpreted as a randomized comparison against an untreated or alternative-treatment group.
The adverse-event group labels distinguish participants with 2 SMN2 copies from those with 3 SMN2 copies. These labels describe groups in the posted safety information; they do not create a randomized comparator. Differences between such groups could reflect differences in participant characteristics as well as other factors, and the record does not provide a controlled comparison that would separate those influences.
The stated primary objective concerns preventing or delaying the need for respiratory intervention or death. Secondary objectives concern other effects of nusinersen. Listed secondary measures include development of clinically manifested SMA, survival, motor milestones assessed using HINE and WHO criteria, changes in CHOP INTEND and HFMSE scores, and changes in weight-for-age and weight-for-length. The registry record lists 28 outcome measures overall, but the specific timing and analysis details for every measure are not reported in the registry record.
The study start date is 2015-05-18, and primary completion is listed as 2024-12-17. These dates describe the registry record; they do not establish the duration of follow-up for each participant. Participant-level follow-up details are not reported in the registry record.
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: A total of 25 participants diagnosed with Spinal Muscular Atrophy (SMA) were enrolled in the study.
Overall Study
| Stage | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| STARTED | 15 | 10 |
| COMPLETED | 13 | 9 |
| NOT COMPLETED | 2 | 1 |
Reasons for not completing this period:
| Reason | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Reason Not Specified | 1 | 1 |
| Withdrawal by parent/Guardian | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: The Intent-to-treat (ITT) set included all participants who received at least 1 dose of ISIS 396443.
| Characteristic | Unit | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|---|
| Participants analysed | 15 | 10 | 25 | |
| Age, Continuous | days | 19.5 (SD 9.29) | 22.3 (SD 12.45) | 20.6 (SD 10.51) |
| Sex: Female, Male: Female | Participants | 7 | 6 | 13 |
| Sex: Female, Male: Male | Participants | 8 | 4 | 12 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 2 | 0 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 10 | 9 | 19 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 3 | 1 | 4 |
| Race/Ethnicity, Customized: Race – American Indian or Alaska Native | Participants | 1 | 0 | 1 |
| Race/Ethnicity, Customized: Race – Asian | Participants | 1 | 2 | 3 |
| Race/Ethnicity, Customized: Race – White | Participants | 8 | 6 | 14 |
| Race/Ethnicity, Customized: Race – Other | Participants | 2 | 1 | 3 |
| Race/Ethnicity, Customized: Race – Not Reported Due to Confidentiality Regulations | Participants | 3 | 1 | 4 |
6. Primary Endpoint
The registry lists the primary outcome as Time to Death or Respiratory Intervention, measured over Screening up to Day 2891.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | months |
| Endpoint classification | Time-to-Event Analysis |
The primary endpoint is time to death or respiratory intervention. For each participant, the recorded time is age at the first occurrence of either event. The observation window is described as screening up to Day 2891. Respiratory intervention is defined as invasive or noninvasive ventilation for >=6 hours/day continuously for 7 or more days, or tracheostomy.
A time-to-event endpoint captures both whether an event occurred and when it occurred. Using age at the first qualifying event gives the endpoint a clinically interpretable time scale, while combining death and respiratory intervention means that either event can determine the endpoint. The composite therefore represents time until the first of the listed outcomes, not separate estimates of time to death and time to respiratory intervention.
For a time-to-event outcome, the median is the time by which half of the relevant event-time distribution has occurred, under the statistical definition used for survival data. A confidence interval describes uncertainty around that estimate. It is not a range that guarantees where an individual participant’s event time will fall.
The primary measure is specified as a median with a 95% confidence interval, but the median and interval are not reported in the registry record. The number of participants with outcome data and details about any participants whose follow-up ended before an event are also not reported in the registry record. Without those results, the endpoint definition can be described, but its observed value and precision cannot be evaluated.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record defines a clinically consequential time-to-event endpoint, but does not report the primary median or its 95% confidence interval. As a result, the posted information does not establish how long participants remained free of respiratory intervention or death, nor how precisely that time was estimated. The endpoint definition and follow-up window alone are not evidence of the outcome magnitude.
The distinction between an endpoint’s definition and its result is important. A protocol or registry may specify what is counted and how time is measured without displaying the resulting estimate. In this record, age at the first qualifying respiratory intervention or death is the measure of interest. The record does not provide an estimate that can be compared with another population or benchmark. The event counts for the primary endpoint are also not reported in the registry record.
This is a single-group, open-label study. The registry does not describe a randomized control group, and the allocation field is NA. A before-and-after description or comparison across the SMN2 copy-number groups would not, on its own, provide the same causal evidence as a randomized comparison. Group differences can arise from participant characteristics, clinical course, or other influences; the record does not supply a controlled design that would address those explanations.
The posted safety information lists serious-event and other-event counts by SMN2 copy-number group, along with percentages for selected serious-event terms. Those figures describe what was recorded in the listed groups. They do not establish that an event was caused by treatment, and they do not provide a comparative risk estimate against a control group. The record reports zero deaths in each of the two listed groups, but that safety summary does not substitute for the missing primary time-to-event estimate.
The record identifies secondary outcomes involving clinical manifestation, survival, motor milestones, motor-function scales, and growth measures. However, outcome names are not outcome findings. The registry record does not report the numerical results for these secondary measures in the information available for this analysis. Consequently, neither the direction nor the size of any changes can be described.
The absence of posted estimates is an information limitation, not evidence that no events or changes occurred. It also does not justify concluding that the intervention was effective or ineffective. Interpretation should remain limited to the study design, endpoint definition, and safety figures that are actually reported.
9. Statistical Methods Explained
Time-to-event analysis is used when the outcome is the time until an event, rather than a measurement taken at a single visit. In this study, the event is the first occurrence of respiratory intervention or death, and time is measured as participant age. This approach can account for differing follow-up times, provided the analysis correctly handles participants whose event has not been observed by the end of follow-up.
What does censoring mean in general?
In general, a participant is censored when the event of interest has not been observed before their available follow-up ends. The recorded information then indicates that the event time exceeds the observed follow-up, rather than identifying the eventual event time. Time-to-event methods can use such partial information. Their interpretation depends on the analysis approach and assumptions about follow-up and censoring. The registry record does not report how censoring was handled, how many observations were censored, or the analysis method used to estimate the median.
What does a median time estimate convey?
In general, the median of a time-to-event distribution marks the point at which the estimated event-free proportion reaches half. It is a summary of the event-time distribution, not an average event time and not a prediction for any particular participant. If the median is not reached during the observed follow-up, it may not be estimable from that follow-up. Whether that occurred in this study is not reported in the registry record.
A 95% confidence interval conveys statistical uncertainty around an estimated quantity under the method’s assumptions. It is not an individual-level range and does not mean that a particular participant’s event time has a 95% chance of lying in that interval. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. The registry specifies a 95% confidence interval for the primary median but does not report its bounds, so the precision cannot be assessed.
Why combine respiratory intervention and death?
A composite endpoint treats any of its specified events as an endpoint event. Here, either a qualifying respiratory intervention or death defines the first event time. A composite can capture more than one clinically important outcome in a single measure, but it does not show how much each component contributes. Separate component results would be needed to understand the event pattern for respiratory intervention and for death. Those primary component results are not reported in the registry record.
The respiratory-intervention definition sets a threshold for what qualifies: invasive or noninvasive ventilation for >=6 hours/day continuously for 7 or more days, or tracheostomy. This operational definition helps make event classification more consistent. The registry record does not report additional adjudication procedures or details on how borderline cases were resolved.
How should the single-group design shape interpretation?
In general, randomization helps balance measured and unmeasured prognostic factors between treatment groups, on average. This study is listed as single-group, with allocation NA and masking none, so the registry does not describe a randomized comparator. A change over time or an observed event pattern cannot by itself isolate a treatment effect from natural history, selection, concurrent care, or other influences. The study’s stated objective is not a substitute for a controlled estimate.
The adverse-event information is split by SMN2 copy number. Such descriptive groupings can help show how recorded safety events are distributed, but they are not a randomized contrast. No claim of a difference between these groups should be made without appropriate outcome definitions, uncertainty estimates, and an analysis suited to the design. Those comparison details are not reported in the registry record.
What do the planning assumptions mean?
The posted sample-size assumptions describe a planning illustration based on the observed effect, not the study’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. For time-to-event illustrations, the stated quantity is the total number of events using the Schoenfeld approach; other illustrations are expressed as participants per arm.
These are general planning assumptions, not evidence that the trial was designed or conducted with two randomized arms. The actual study is listed as single-group, and the assumptions do not change that design. A planning illustration does not describe observed power, does not show that the planned precision was achieved, and should not be interpreted as a trial result. Numerical planning values are not reported in the registry record described for this analysis.
Why do confidence intervals matter?
In general, an estimate without an uncertainty measure can conceal substantial imprecision. A confidence interval helps readers judge which values are compatible with the data and analysis assumptions. It does not correct bias from an uncontrolled design, incomplete reporting, or an unsuitable analysis. In this study, the record identifies the requested interval type for the primary endpoint but omits the interval itself. Thus neither the primary estimate nor its precision can be judged from the posted result information.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists numerous outcomes, including the primary time-to-event measure and secondary measures of clinical manifestation, survival, motor milestones, motor function, and growth. It reports 28 outcome measures overall and zero analyses in the analysis summary. The presence of many outcomes creates a general multiplicity concern: when many hypotheses are tested, the chance of at least one apparently notable result can increase if no adjustment or prespecified interpretation strategy is used.
The statistical plan for handling multiplicity is not reported in the registry record. It is therefore not possible to determine whether outcomes were prioritized, whether any adjustment was planned, or how secondary results were intended to support conclusions. The record’s list of secondary outcomes should not be treated as a list of statistically demonstrated effects.
Missing-data handling is also not reported in the registry record. For the primary outcome, the population description says the analyzed count refers to participants with data available for outcome analysis, but does not state the count with available data or explain how missing observations were addressed. Follow-up completeness, withdrawal details, and censoring methods are not reported in the registry record.
The ITT set is defined as participants who received at least 1 dose of ISIS 396443, with the added clarification about data availability for the outcome. This is the population description attached to the primary outcome; the record does not provide a fuller account of analysis populations or deviations from treatment. Without analysis details, it is not possible to assess how missingness, protocol deviations, or the choice of analysis population may affect the reported estimates. In this case, the primary estimate itself is not reported, so those assessment questions remain unresolved.
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 |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | 10 | 15 | 66.7% |
| ISIS 396443 3 SMN2 Copies | 4 | 10 | 40.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| ISIS 396443 2 SMN2 Copies | 0 of 15 |
| ISIS 396443 3 SMN2 Copies | 0 of 10 |
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 |
|---|---|
| ISIS 396443 2 SMN2 Copies | 15 of 15 |
| ISIS 396443 3 SMN2 Copies | 10 of 10 |
Most frequent serious adverse event terms
| Event term | Organ system | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|---|
| Pneumonia | Infections and infestations | 5 of 15 | 0 of 10 |
| Respiratory syncytial virus infection | Infections and infestations | 2 of 15 | 1 of 10 |
| Choking | Respiratory, thoracic and mediastinal disorders | 3 of 15 | 0 of 10 |
| Pyrexia | General disorders | 2 of 15 | 0 of 10 |
| Respiratory syncytial virus bronchiolitis | Infections and infestations | 2 of 15 | 0 of 10 |
| Upper respiratory tract infection | Infections and infestations | 1 of 15 | 1 of 10 |
| Dehydration | Metabolism and nutrition disorders | 2 of 15 | 0 of 10 |
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | 2 of 15 | 0 of 10 |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | 2 of 15 | 0 of 10 |
| Tonsillectomy | Surgical and medical procedures | 2 of 15 | 0 of 10 |
Most frequent non-serious adverse event terms
| Event term | Organ system | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|---|
| Pyrexia | General disorders | 14 of 15 | 8 of 10 |
| Nasopharyngitis | Infections and infestations | 11 of 15 | 7 of 10 |
| Upper respiratory tract infection | Infections and infestations | 11 of 15 | 7 of 10 |
| Cough | Respiratory, thoracic and mediastinal disorders | 11 of 15 | 7 of 10 |
| Vomiting | Gastrointestinal disorders | 10 of 15 | 5 of 10 |
| Fall | Injury, poisoning and procedural complications | 8 of 15 | 6 of 10 |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | 7 of 15 | 5 of 10 |
| Otitis media | Infections and infestations | 6 of 15 | 5 of 10 |
| Diarrhoea | Gastrointestinal disorders | 4 of 15 | 6 of 10 |
| Influenza | Infections and infestations | 6 of 15 | 4 of 10 |
Serious events with the highest arm-level rate: pneumonia (33.3%), choking (20.0%), pyrexia (13.3%), respiratory syncytial virus bronchiolitis (13.3%), respiratory syncytial virus infection (13.3%).
The safety information is organized by SMN2 copy-number group. For the group labeled 2 SMN2 copies, the record lists 10 participants affected by serious events among 15 at risk, and 15 affected by other events among 15 at risk. For the group labeled 3 SMN2 copies, it lists 4 affected by serious events among 10 at risk, and 10 affected by other events among 10 at risk. The record lists zero deaths in each group.
These are descriptive figures, not randomized comparisons. The group labels do not identify a control arm, and the study is classified as single-group. The counts do not establish whether nusinersen caused an event, nor do they show how the figures compare with what would have occurred without treatment. The registry record does not report event-level timing, recurrence, severity grading beyond the serious-event classification, or a causal assessment for each event.
The listed serious-event terms include pneumonia (33.3%), choking (20.0%), pyrexia (13.3%), respiratory syncytial virus bronchiolitis (13.3%), respiratory syncytial virus infection (13.3%), and dehydration (13.3%). The denominator and counting convention for these term percentages are not reported in the registry record. They should therefore be read as the percentages attached to the listed terms, not converted into participant counts or interpreted as comparative risks.
Serious adverse events and other adverse events are distinct categories in the posted summary. Counts in these categories do not by themselves describe event duration, recurrence, or attribution. The safety figures offer a limited description of recorded events, not a complete evaluation of safety or a causal comparison.
12. What the Result Does, and Does Not, Mean
The record establishes that this completed phase 2 study examined multiple doses of intrathecal nusinersen in infants with genetically diagnosed and presymptomatic SMA. It identifies the primary outcome as age at the first occurrence of respiratory intervention or death, and it gives an operational definition for respiratory intervention. It also describes a range of secondary outcomes and presents safety information by SMN2 copy-number group.
It does not report the primary median or 95% confidence interval. Therefore the posted record does not show the observed time to the composite event or the precision of an estimate. The absence of that result is not evidence that the outcome did not occur, and it is not evidence of benefit or lack of benefit. It is an absence of reported primary-result information.
The design limits what can be concluded about causation. An open-label, single-group study has no randomized control group in the registry description. Observed events or changes cannot, on their own, distinguish an intervention effect from the course of the condition, participant selection, or other influences. The SMN2 copy-number groups in the safety record do not constitute a randomized control comparison.
The listed adverse-event figures show counts for serious events and other events, zero deaths in both listed groups, and percentages for selected serious-event terms. They do not establish treatment attribution or comparative risk. Likewise, the names of secondary outcomes do not establish that those outcomes improved, worsened, or remained unchanged; numerical secondary results are not reported in the registry record.
In general, a study result is most informative when the estimate, its uncertainty, the analyzed population, and the methods are all available. Here, the registry gives key design and endpoint definitions but omits the main estimate and several analysis details. The conclusions that can be supported are consequently limited to what was studied and what the registry explicitly reports, rather than a judgment about treatment effect.
13. Why This Trial Matters Statistically
This trial is statistically notable for the contrast between a clearly defined time-to-event question and the absence of the corresponding primary estimate in the registry record. The endpoint specifies both the event components and the time scale, age at first occurrence. Those definitions make the target outcome understandable, but they cannot replace the median and confidence interval needed to evaluate the observed result.
The design also illustrates why the comparison structure matters. Although the safety summary divides participants by SMN2 copy number, the study is classified as single-group and does not describe a randomized control arm. A subgroup label is not equivalent to random allocation. Descriptive differences between groups should not be interpreted as treatment effects or as evidence that one group provides a counterfactual for another.
Another statistical issue is the distinction between outcome breadth and outcome evidence. The registry lists measures of clinical manifestation, survival, motor milestones, motor function, and growth. A broad set of outcomes can characterize different aspects of a disease, but interpretation depends on which outcomes were prespecified, how multiplicity was handled, how missing data were treated, and what estimates were observed. Those analysis details and numerical findings are not reported in the registry record.
The planning assumptions associated with the posted calculations also need contextual reading. They describe a hypothetical illustration based on an observed effect under assumptions involving two arms, equal allocation, and a normal approximation. The actual study is single-group. Planning illustrations can help explore design requirements in general, but they are not evidence that the study had a particular power or that its design matched the illustration.
Together, these features make the record useful for understanding the study question and its stated endpoint, while also showing why transparent reporting of estimates, uncertainty, analysis populations, and methods is essential. Without those elements, readers cannot judge the magnitude, precision, or robustness of the primary finding.
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 most important trial-specific limitation for interpreting the posted findings is that the registry record does not report the primary median time to death or respiratory intervention or its 95% confidence interval. It also does not report the number of primary events or the number of participants with available primary-outcome data. Thus the main endpoint cannot be quantitatively evaluated from the reported information.
The study is open-label and single-group, with allocation listed as NA and masking as none. There is no randomized control group described in the registry record. This limits the ability to separate treatment-associated observations from other explanations, including the underlying clinical course and differences among participants. The SMN2 copy-number categories in the safety information are not a like-for-like control comparison.
Several analysis details are absent. Censoring procedures, handling of missing data, the statistical method used to estimate the median, and the approach to multiplicity are not reported in the registry record. The record lists 28 outcome measures but reports zero analyses in the analysis summary. Numerical results for the listed secondary outcomes are not available in the information analyzed.
The safety summary is also limited. It provides group-level counts and selected serious-event term percentages but does not report the percentage denominator or counting convention for those terms. It does not give event-level timing, recurrence, or treatment attribution. The listed figures therefore support description, not causal conclusions or a comparative safety assessment.
Finally, the stated sample-size assumptions are planning illustrations, not the trial’s own design. Their two-arm assumptions do not match the registry’s single-group classification. The record does not report a sample-size justification for the actual study or clarify how the illustration relates to the study’s analyses.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy — NCT02386553.
- Registry record last updated 2025-10-20; status last verified 2025-10.
- Results first posted 2025-10-20.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
The registry record describes a completed, open-label, phase 2, single-group study of intrathecal nusinersen in infants with genetically diagnosed and presymptomatic spinal muscular atrophy. Enrollment is listed as 25. The primary objective was to examine prevention or delay of respiratory intervention or death.
The primary outcome is time, measured as age at the first occurrence of either event. The record specifies a 95% confidence interval for the median but does not report the median or interval. It also lists secondary outcomes involving clinical manifestation, survival, motor milestones, motor function, and growth.
Safety figures are reported by groups labeled 2 SMN2 copies and 3 SMN2 copies. The record lists zero deaths in each group and selected serious-event terms with percentages. These are descriptive data, not a randomized comparison. The primary result, secondary numerical results, and several statistical analysis details are not reported in the registry record.