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 An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (NCT01703988), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01703988 |
| Phase | Phase 1, Phase 2 |
| Condition | Spinal Muscular Atrophy |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 34 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Biogen |
| Results posted | Yes |
2. Clinical Question
Population
Participants with spinal muscular atrophy were enrolled. The registry record reports 34 enrolled participants; the safety population was defined as enrolled participants who received at least 1 dose of study drug. The adverse-event results are reported across four dose cohorts.
Intervention
Participants received nusinersen by intrathecal injection at one of four dose levels: 3 mg, 6 mg, 9 mg, or 12 mg. Doses were evaluated sequentially. The schedules differed: the 3 mg, 6 mg, and 12 mg cohorts were scheduled for doses on Days 1, 29, and 85, while the 9 mg cohort was scheduled for doses on Days 1 and 85.
Comparator
There was no placebo or untreated control arm in the registry description. The dose cohorts were not randomized, and the record cautions that they are not like-for-like control comparisons. Comparisons among cohorts therefore cannot isolate the effect of dose from other differences between sequential groups.
Primary question
The primary safety question was how many participants experienced adverse events, serious adverse events, discontinuations due to adverse events, and each highest severity category during the study. The registry also lists pharmacokinetic outcomes. The posted safety counts describe events observed during treatment; they do not establish whether an event was caused by nusinersen or whether risks differ by dose.
3. Trial Design
This was a Phase 1/Phase 2, open-label, non-randomized, parallel-group study of nusinersen in participants with spinal muscular atrophy. The registry record lists Biogen as sponsor and describes four dose levels evaluated sequentially. All participants received active drug; there was no concurrent placebo or untreated control group in the arm descriptions.
The planned intrathecal schedules varied by cohort. The 3 mg, 6 mg, and 12 mg groups were scheduled to receive injections on Days 1, 29, and 85. The 9 mg group was scheduled to receive injections on Days 1 and 85. The record describes approximately 8 participants per dose cohort. The posted arm counts are 8 for 3 mg, 8 for 6 mg, 9 for 9 mg, and 9 for 12 mg.
The study began on 2012-10-31, had primary completion on 2015-01-31, and is listed as completed. The primary outcome timeframe says participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days.
Because dose groups were sequential and non-randomized, they should not be treated as exchangeable groups in a controlled comparison. Open-label conduct also means participants and study staff were not masked to treatment. Details of allocation procedures beyond the non-randomized designation, dose-escalation decision criteria, and any dose-limiting toxicity rules 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.
Overall Study
| Stage | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg |
|---|---|---|---|---|
| STARTED | 8 | 8 | 9 | 9 |
| COMPLETED | 8 | 8 | 9 | 8 |
| NOT COMPLETED | 0 | 0 | 0 | 1 |
Reasons for not completing this period:
| Reason | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg |
|---|---|---|---|---|
| Investigator Judgment | 0 | 0 | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety Population, defined as all enrolled participants who received at least 1 dose of study drug.
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 | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 8 | 8 | 9 | 9 | 34 | |
| Age, Continuous | years | 8.6 (SD 5.4) | 8.1 (SD 5.2) | 6.0 (SD 4.0) | 6.9 (SD 4.3) | 7.4 (SD 4.6) |
| Sex: Female, Male: Female | Participants | 4 | 3 | 4 | 3 | 14 |
| Sex: Female, Male: Male | Participants | 4 | 5 | 5 | 6 | 20 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs, measured over Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome counts participants with adverse events, serious adverse events, discontinuations due to adverse events, and the highest severity of adverse events. It is a participant-count endpoint: the focus is whether a participant experienced an event in a category, rather than the total number of separate event episodes. The outcome is assessed in the safety population, defined in the registry as all enrolled participants who received at least 1 dose of study drug.
An adverse event is defined as an unfavorable and unintended sign, symptom, or disease temporally associated with the study or investigational drug, whether or not considered related to the drug. A serious adverse event is an adverse event meeting specified criteria, including death, life-threatening events, inpatient hospitalization or its prolongation, persistent or significant incapacity, congenital anomaly or birth defect, or another important medical event in the judgment of the investigator. Severity was assessed as mild, moderate, or severe.
Safety outcomes are used to describe the kinds and frequency of harms observed during exposure, an important focus in a dose-range study. These counts can identify events warranting further evaluation, but without a randomized control they cannot by themselves determine whether treatment caused an event. The record does not report the posted count results for discontinuations due to adverse events or highest severity categories.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted serious adverse-event counts are 2 participants among 8 in the 3 mg cohort, 0 among 8 in the 6 mg cohort, 0 among 9 in the 9 mg cohort, and 1 among 9 in the 12 mg cohort. These are small cohort counts, so each observed participant represents a substantial part of the count within a cohort. The registry also reports other adverse events in 8 of 8 participants at 3 mg, 6 of 8 at 6 mg, 9 of 9 at 9 mg, and 9 of 9 at 12 mg.
These figures describe participants with events, not the total number of event episodes or the duration of each event. The serious-event counts do not show a consistent increase across the listed dose levels, but that pattern should not be interpreted as evidence that dose has no relationship to risk. The cohorts were non-randomized and enrolled sequentially, and the registry specifically cautions that the arms are not like-for-like control comparisons. Differences in participants, follow-up, or other factors could contribute to differences in observed counts; the record does not provide information to assess those possibilities.
The registry lists serious-event terms including Drug hypersensitivity at 12.5%, Pneumonia at 12.5%, and Post lumbar puncture syndrome at 11.1%. Those term percentages are reported as registry values; their denominators and detailed event-level context are not reported in the registry record. They should not be combined with the participant counts or interpreted as treatment-attributable risks without that context.
The record does not report the count of deaths, discontinuations due to adverse events, or participants in each highest severity category. No inferential analysis is listed. Consequently, the available safety results are descriptive rather than estimates from a comparative statistical test. They do not establish causal effects or provide a precise estimate of the relative safety of the dose levels.
9. Statistical Methods Explained
Safety results in this study are presented as participant counts in dose cohorts. This is a descriptive approach: it reports what was observed in the safety population without, by itself, estimating a causal treatment effect. The registry defines that population as enrolled participants who received at least 1 dose of study drug. Its primary outcome concerns participants with adverse events, serious adverse events, adverse-event discontinuations, and the highest severity of adverse events.
What does a participant count represent?
A participant count records whether people experienced an outcome category during the study. It is different from an event count: one participant can experience more than one event, while a participant-level outcome generally counts that person once within the stated category. The posted results give counts of participants with serious adverse events and other adverse events. They do not provide the episode-level detail needed to describe event recurrence, timing, duration, or the relationship between different events in the same participant.
For a binary outcome such as experiencing at least one event, a proportion can be useful for describing how common the outcome was within an observed group. However, no additional percentages should be inferred from a small cohort without accounting for uncertainty, and a percentage alone does not communicate how imprecise a result may be. Confidence intervals, when calculated, describe uncertainty around an estimate under the assumptions of the method; they do not remove the design limitations or turn an observed association into a causal effect. No confidence intervals or inferential comparisons are reported in the registry record.
Why does the design matter?
Random allocation helps balance measured and unmeasured characteristics across groups on average. This trial is listed as non-randomized and open-label, with dose levels evaluated sequentially. Thus, the cohorts are not randomized comparisons, and the registry cautions against treating them as like-for-like controls. A difference in observed counts across cohorts could reflect dose, characteristics of participants, changes over the course of sequential enrollment, or other factors. The registry record does not report information sufficient to separate these explanations.
Open-label conduct means treatment assignment was not masked. Knowledge of treatment can affect how symptoms are noticed, reported, assessed, or recorded. The registry’s adverse-event definition includes events whether or not they are considered related to the investigational drug, so an event count should not be read as a count of events caused by treatment. The available results do not classify the reported counts by whether the investigator or sponsor considered each event drug-related.
How should sparse counts be read?
When observed counts are small, estimates based on them can be unstable: a change in the status of one participant can materially change the apparent pattern. A zero observed count in a cohort means that no participants in that cohort were recorded with the specified outcome in the posted results; it does not establish that the underlying risk is zero. Conversely, a count in a cohort does not demonstrate that treatment caused the event. These are general principles for interpreting sparse binary safety outcomes, not additional findings from this trial.
The registry lists serious adverse-event terms with percentages, but does not report their denominators or detailed event-level context. Without those details, the term percentages should be read as reported labels rather than used to reconstruct participant-level risk. Nor should event-term percentages be added together: terms may refer to events rather than mutually exclusive groups of participants.
What do planning calculations mean?
Sample-size calculations based on an observed effect are planning illustrations, not observed power and not evidence that the trial was adequately powered for a particular comparison. The stated planning approach uses a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For non-time-to-event outcomes, such illustrations are expressed as participants per arm for 80% power or another stated target; time-to-event calculations use a total number of events. The trial’s own sample-size justification and design assumptions are not reported in the registry record.
Because this record has no randomized control comparison and no listed statistical analyses, a conventional treatment-effect interpretation is not supported by the posted safety counts alone. The appropriate statistical emphasis is on describing the observed counts, the population and follow-up to which they apply, and the uncertainty and design constraints around comparisons.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists a primary safety outcome covering several related summaries: adverse events, serious adverse events, discontinuations due to adverse events, and highest severity. It also lists pharmacokinetic outcomes involving plasma, cerebrospinal fluid, and urine. These multiple outcome measures create opportunities for many separate descriptions or comparisons. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a prespecified strategy for controlling the chance of false-positive findings across multiple tests. It also lists no analyses.
Missing-data handling is not reported in the registry record. The outcome timeframe states that participants were followed for the duration of the study, but the record does not describe how incomplete follow-up, missed assessments, withdrawals, or partially observed safety information were handled. It is therefore not possible to determine whether every participant had the same opportunity for events to be observed or whether any outcomes were imputed.
The safety population is defined as all enrolled participants who received at least 1 dose of study drug. A separate analysis population for efficacy is not relevant to the listed primary safety outcome, and no additional analysis-population definitions are reported. The record does not specify whether any participants were excluded from particular outcome summaries or how exclusions would have been addressed.
These omissions matter because the number of observed events depends on the population included, the duration and completeness of observation, and how outcomes are categorized. Without details on missingness and analysis procedures, the posted counts are best read as registry-reported descriptive results, not as results from a fully specified inferential analysis.
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 |
|---|---|---|---|
| Nusinersen 3 mg | 2 | 8 | 25.0% |
| Nusinersen 6 mg | 0 | 8 | 0.0% |
| Nusinersen 9 mg | 0 | 9 | 0.0% |
| Nusinersen 12 mg | 1 | 9 | 11.1% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Nusinersen 3 mg | 8 of 8 |
| Nusinersen 6 mg | 6 of 8 |
| Nusinersen 9 mg | 9 of 9 |
| Nusinersen 12 mg | 9 of 9 |
Most frequent serious adverse event terms
| Event term | Organ system | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg |
|---|---|---|---|---|---|
| Drug hypersensitivity | Immune system disorders | 1 of 8 | 0 of 8 | 0 of 9 | 0 of 9 |
| Pneumonia | Infections and infestations | 1 of 8 | 0 of 8 | 0 of 9 | 0 of 9 |
| Post lumbar puncture syndrome | Injury, poisoning and procedural complications | 0 of 8 | 0 of 8 | 0 of 9 | 1 of 9 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Nusinersen 3 mg | Nusinersen 6 mg | Nusinersen 9 mg | Nusinersen 12 mg |
|---|---|---|---|---|---|
| Post lumbar puncture syndrome | Injury, poisoning and procedural complications | 3 of 8 | 1 of 8 | 3 of 9 | 5 of 9 |
| Back pain | Musculoskeletal and connective tissue disorders | 1 of 8 | 2 of 8 | 2 of 9 | 4 of 9 |
| Puncture site pain | General disorders | 0 of 8 | 3 of 8 | 3 of 9 | 2 of 9 |
| Nasopharyngitis | Infections and infestations | 0 of 8 | 1 of 8 | 4 of 9 | 3 of 9 |
| Headache | Nervous system disorders | 4 of 8 | 2 of 8 | 1 of 9 | 0 of 9 |
| Vomiting | Gastrointestinal disorders | 1 of 8 | 1 of 8 | 2 of 9 | 2 of 9 |
| Upper respiratory tract infection | Infections and infestations | 2 of 8 | 1 of 8 | 2 of 9 | 1 of 9 |
| Constipation | Gastrointestinal disorders | 0 of 8 | 0 of 8 | 2 of 9 | 2 of 9 |
| Nausea | Gastrointestinal disorders | 2 of 8 | 0 of 8 | 2 of 9 | 0 of 9 |
| Pyrexia | General disorders | 0 of 8 | 0 of 8 | 0 of 9 | 3 of 9 |
Serious events with the highest arm-level rate: drug hypersensitivity (12.5%), pneumonia (12.5%), post lumbar puncture syndrome (11.1%).
The serious adverse-event figures are participant counts within each dose cohort: 2 of 8 in the 3 mg group, 0 of 8 in the 6 mg group, 0 of 9 in the 9 mg group, and 1 of 9 in the 12 mg group. These numbers indicate how many participants were recorded with at least one serious adverse event in each group; they do not indicate the number of separate serious events.
The registry defines serious events by criteria such as death, life-threatening events, inpatient hospitalization or its prolongation, significant incapacity, congenital anomaly or birth defect, or another important medical event in the investigator’s judgment. The reported serious-event terms include Drug hypersensitivity at 12.5%, Pneumonia at 12.5%, and Post lumbar puncture syndrome at 11.1%. The record does not report the denominators or detailed event-level context for those term percentages.
The record does not report a death count, and the counts do not establish that nusinersen caused any event. Because the dose groups were sequential and non-randomized, their counts are descriptive and not a controlled comparison of serious-event risk.
12. What the Result Does, and Does Not, Mean
The registry record documents safety observations in participants who received nusinersen at one of four dose levels. It reports serious adverse-event counts by dose cohort and counts of participants with other adverse events. These summaries are useful for describing what was recorded in this study and for identifying safety outcomes that may merit attention in further evaluation.
The results do not establish whether nusinersen caused an adverse event. The adverse-event definition explicitly includes events regardless of whether they were considered related to the investigational drug. The posted cohort counts are not randomized comparisons, and there is no placebo or untreated control arm in the registry description. The study therefore cannot separate events associated with treatment from events that might have occurred for other reasons.
The results also do not demonstrate that one dose level is safer than another. Cohorts were evaluated sequentially rather than randomized, and differences in participant characteristics, observation, or other factors may affect the observed counts. The record does not report inferential comparisons or uncertainty intervals for these counts. Zero observed serious adverse events in a cohort should not be interpreted as proof that no risk exists.
The primary outcome includes discontinuations due to adverse events and highest severity, but their counts are not reported in the registry record. Death counts are also not reported. The listed pharmacokinetic outcomes address drug concentrations and exposure, which are distinct from clinical safety outcomes; their result values are not included in the registry record described for this analysis.
Overall, the posted findings are descriptive safety information from a small, non-randomized dose-escalation study. They do not establish treatment benefit, a causal safety profile, or a precise comparison among dose levels.
13. Why This Trial Matters Statistically
This trial is statistically important as an example of how early dose-ranging safety information differs from evidence produced by a randomized controlled comparison. Its purpose, as described in the registry, was to assess safety, tolerability, and dose range across sequential cohorts, alongside pharmacokinetic outcomes. Such a design can organize early observations across dose levels, but the resulting cohort counts should not be interpreted as if participants had been randomly assigned to competing treatments.
The study also illustrates why denominators and outcome definitions matter. A count of participants with an event is not the same as a count of event episodes, and a serious adverse event is defined using criteria that include clinical judgment. The listed serious-event terms have percentages but lack reported denominators and event-level context in the registry record. That limits how specifically those terms can be interpreted.
Another statistical lesson is that an observed zero is not evidence of zero underlying risk, particularly when cohort sizes are limited. Likewise, a difference in counts across cohorts does not alone demonstrate a dose-response relationship. Uncertainty, sequential enrollment, lack of randomization, and open-label assessment all constrain interpretation.
Finally, planning calculations based on observed effects must remain distinct from evidence about the completed study. Such calculations are illustrations for future planning under assumptions, not observed power and not a substitute for a prospectively specified design rationale. The registry record does not report the trial’s sample-size justification or detailed statistical plan.
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 main limitation is the non-randomized, sequential design. Dose cohorts are not like-for-like control groups, so differences in observed adverse-event counts cannot be attributed to dose alone. The open-label design also leaves event reporting and assessment unmasked. There is no placebo or untreated arm in the registry description to provide a concurrent reference for events occurring during study follow-up.
The cohorts are small, and the posted outcomes are counts. Sparse counts provide limited precision and can change substantially with the classification of a participant. The registry record does not report confidence intervals, formal comparative analyses, or a statistical plan for interpreting differences across dose cohorts. It does not report the sample-size justification, dose-escalation criteria, or interim analysis procedures.
Reporting is incomplete for several elements of the primary outcome. The registry does not report the number of participants who discontinued because of adverse events, counts by highest severity, or a death count. For the serious-event terms with percentages, the denominators and event-level details are not reported in the registry record. The handling of missing outcomes, withdrawals, and unequal follow-up is also not reported.
The primary outcome timeframe states that participants were followed for the duration of the study and gives a mean (SD) treatment duration of 82.9 (15.4) days, but detailed person-time or cohort-specific follow-up information is not reported. This limits interpretation of counts as comparative rates. Overall, the registry results offer a descriptive account, with important limits on causal and dose-comparison conclusions.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy — NCT01703988.
- Registry record last updated 2021-04-13; status last verified 2021-03.
- Results first posted 2017-03-13.
- 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 describes a completed Phase 1/Phase 2, open-label, non-randomized, parallel-group study of intrathecal nusinersen in participants with spinal muscular atrophy. Four dose levels were evaluated sequentially, with different scheduled dosing days for the 9 mg cohort compared with the other cohorts.
The primary outcome concerns participant counts for adverse events, serious adverse events, adverse-event discontinuations, and highest severity. The posted results report serious adverse-event counts of 2 of 8, 0 of 8, 0 of 9, and 1 of 9 across the 3 mg, 6 mg, 9 mg, and 12 mg cohorts, respectively. Other adverse-event counts are also reported by cohort.
These data are descriptive. The registry cautions that the non-randomized arms are not like-for-like control comparisons. Several outcome details, including discontinuations and severity counts, are not reported in the registry record.