Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients (NCT03280056), a randomized phase 3 study. The primary outcome is The Proportion of NurOwn® Treated Participants With a ≥1.25 Points/Month Improvement in Post-treatment Slope vs. Pre-treatment Slope in ALSFRS-R Score at 28 Weeks Following the First Treatment as Compared to Placebo.

2. Clinical Question

The primary question focuses on change in the rate of functional decline rather than only on the score at a single visit. The registry record identifies the comparison, threshold and assessment timeframe, but does not report the outcome counts or an effect estimate for the two groups. Therefore, the size and precision of the primary comparison cannot be described from the registry record.

3. Trial Design

This was a phase 3, randomized, double-blind, placebo-controlled, multicenter study with a parallel-group design. The registry record lists an enrollment of 196 participants and a completed status. The study start date was 2017-08-28, and the primary completion date was 2020-09-29. Quadruple masking is recorded, but the registry record does not report which specific roles were masked.

Participants were assigned to NurOwn® (MSC-NTF cells) or placebo. The active intervention used autologous bone marrow-derived mesenchymal stromal cells, which were enriched from the participant’s own bone marrow, propagated ex vivo and induced to secrete neurotrophic factors. The treatment description states that the cells were administered intrathecally. The two arm descriptions specify three intrathecal administrations at bi-monthly intervals. Bone marrow aspiration is also listed as an intervention.

The registry record identifies ALS as the condition under study. It defines the primary analysis population as a modified intent-to-treat population consisting of randomized and treated participants with at least three ALSFRS-R assessments, including one before baseline, a baseline assessment and one after treatment. That definition is narrower than randomization alone: a participant also had to be treated and meet the assessment requirement. The registry record does not report the number of participants included in this population or the number excluded from it.

Further details about allocation procedures, treatment adherence, center-level handling, protocol deviations and the statistical analysis plan are not reported in the registry record. Randomization and masking describe important design features, but do not by themselves establish how every analysis was carried out.

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: The most common reasons that participants did not meet inclusion criteria were failure to meet the SVC inclusion criterion at the Screening Visit or the required pre-treatment decline in ALSFRSR total score at the randomization visit. From the ITT population, 3 participants in the NurOwn group and 4 participants in the placebo group discontinued prior to treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The modified intent-to-treat (mITT) population was defined as all participants who were randomized, treated and had at least three ALSFRS-R assessments: one pre-treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment and one post-treatment assessment.

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: Demographic characteristics were balanced between NurOwn and placebo treatment groups with no statistically significant differences at baseline.

6. Primary Endpoint

The registry lists the primary outcome as The Proportion of NurOwn® Treated Participants With a ≥1.25 Points/Month Improvement in Post-treatment Slope vs. Pre-treatment Slope in ALSFRS-R Score at 28 Weeks Following the First Treatment as Compared to Placebo, measured over 28 weeks following the first intrathecal injection.

The primary endpoint is the proportion of NurOwn®-treated participants whose post-treatment ALSFRS-R slope improved by at least 1.25 points per month compared with their pre-treatment slope, assessed at 28 weeks following the first intrathecal injection. The primary question compares this proportion with the corresponding placebo result. The registry record does not report either group’s endpoint count or proportion.

ALSFRS-R is a validated ordinal rating scale covering 12 functional activities relevant to ALS. Each activity is rated from 0 to 4, and the total score ranges from 0 to 48, with higher scores indicating better function. The registry description notes that changes in the score have been associated with changes in strength and quality-of-life measures and have predicted survival.

Using a slope makes the endpoint about the rate of score change across assessments, while the threshold turns that change into a binary outcome: participants either meet the specified improvement criterion or do not. This can make the result easier to express as a proportion, but it also means that the endpoint does not show how far individual participants’ slopes varied around the threshold. The registry record does not report the analysis details needed to assess how slopes were estimated or how participants with incomplete measurements were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level. A participant either meets the stated improvement threshold for the ALSFRS-R slope or does not. For a binary endpoint, an arm-level result is commonly expressed as a count and a proportion. A comparison can then describe how those proportions differ or relate, with an uncertainty interval to show the precision of the estimated contrast. These are general statistical concepts; the registry record does not report the primary arm-level counts, proportions, contrast, confidence interval or test result.

What does the slope threshold represent?

A slope describes the direction and rate of change in a measure across time. Here, the endpoint compares the participant’s post-treatment ALSFRS-R slope with the pre-treatment slope and applies a threshold of at least 1.25 points per month of improvement. Turning this continuous change into a meet-or-not-meet classification simplifies the outcome into a proportion. It also discards detail: two participants on the same side of the threshold can have different slope changes, and participants near the cutoff may be classified differently despite having similar underlying values. The registry record does not report the exact slope-estimation procedure or how the assessment schedule entered that calculation.

Why does uncertainty matter?

An observed arm difference is an estimate based on trial participants, not a perfectly precise description of every participant with ALS. A confidence interval conveys statistical uncertainty around an estimate and helps readers judge which effect sizes remain compatible with the data. Its width depends on features such as the amount of information and the variability of the outcome. The registry record does not report a confidence interval for the primary endpoint, so the precision of the comparison cannot be evaluated. A p-value, if reported, would answer a different and narrower question about compatibility with a null model; it would not replace an estimate or its interval. No primary p-value is reported in the registry record.

What can the sample-size approach say?

The record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not a report of the trial’s original sample-size justification. The record does not report the protocol’s sample-size rationale, and the illustration should not be read as observed power. A planning calculation explores how a hypothetical design might perform under chosen assumptions; it does not change the uncertainty in the trial’s observed results. The record specifies that time-to-event planning tables give a total number of events, while other planning tables give participants per arm.

How should event counts be read?

For safety outcomes, the reported figures distinguish participants at risk from participants affected. A count of participants with an event is not the same as a count of event episodes: a participant may have more than one event, depending on the outcome definition. The registry record reports participant counts for serious adverse events, other adverse events and deaths, but does not provide enough detail in these entries to reconstruct event timing, recurrence, exposure-adjusted rates or causal attribution. The listed serious-event terms and percentages should therefore be read as recorded descriptions, not as evidence that a specific treatment caused an event.

Over-dispersion is a general concern for count data when variation exceeds what a simple count model assumes. It can make standard errors too small if the extra variation is ignored. That concept is relevant when analyzing event counts, but the safety summaries in the registry record are participant counts, and no model for over-dispersion is reported. It would be inappropriate to assume that such a model was used.

Likewise, the label randomized does not specify every analytical choice. The record defines a modified intent-to-treat population, but does not report the primary model, covariates, missing-data procedure, sensitivity analyses, handling of protocol deviations or whether interim analyses took place. Those methods cannot be inferred from the endpoint description. A transparent interpretation separates the reported design and definitions from statistical procedures that are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists four outcome measures and four analyses. The primary endpoint is accompanied by secondary outcomes concerning slope-based disease progression, change from baseline in ALSFRS-R at Week 28, and a combined assessment of function and survival at 28 weeks. When multiple outcomes or analyses are considered, the chance of at least one apparently unusual result can increase unless the analysis plan addresses multiplicity. This is a general statistical consideration; it does not establish that a particular adjustment was needed or applied in this trial.

The multiplicity strategy, hierarchy of outcomes, and any adjustment to significance thresholds are not reported in the registry record. The record also indicates that the primary outcome has several categories or time points and was not reduced to one comparison. As a result, there is no single primary effect estimate in the registry results that can be interpreted alongside a reported multiplicity procedure.

The primary analysis population is defined as randomized, treated participants with at least three ALSFRS-R assessments: one before baseline, a baseline assessment and one after treatment. The number meeting this definition, reasons for missing assessments, and the number excluded from the analysis are not reported in the registry record. The handling of missing outcome data, withdrawals, deaths in functional analyses and deviations from the assigned treatment is also not reported. These details matter because a modified intent-to-treat analysis can differ from an analysis of all randomized participants, and incomplete follow-up can affect the interpretation of a change-over-time endpoint.

Interim analyses, stopping rules, and the statistical analysis plan are not reported in the registry record. Their absence from the record should not be taken as evidence that such procedures did or did not exist.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: respiratory failure (5.3%), dysphagia (3.2%), disease progression (2.1%), pneumonia (2.1%), respiratory distress (2.1%).

The registry safety summary reports serious adverse events for 23 of 95 participants at risk in the NurOwn® group and 17 of 94 in the placebo group. Other adverse events are reported for 93 of 95 and 92 of 94 participants, respectively. Deaths are reported for 10 participants in the NurOwn® group and 4 in the placebo group. These are participant counts, not estimates adjusted for time exposed or for differences in follow-up.

The serious-event terms listed include respiratory failure (5.3%), dysphagia (3.2%), disease progression (2.1%), pneumonia (2.1%), respiratory distress (2.1%) and pulmonary embolism (1.1%). The registry entries do not report an arm-specific breakdown for these term percentages. The percentages therefore should not be assigned to one treatment group or used to infer a between-group comparison.

Safety counts alone do not establish causation. The registry record does not report event timing, recurrence, severity grades beyond the serious-event classification, exposure-adjusted rates or adjudication details in these summaries. The differences in the reported counts should be read descriptively and in the context of those missing details, not as proof that treatment caused or prevented an event.

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

The record establishes that this was a randomized, quadruple-masked, placebo-controlled phase 3 study of repeated NurOwn® administrations in ALS, and it defines a primary endpoint based on the proportion of participants meeting a slope-improvement threshold. It also provides selected safety counts. These registry entries describe the trial’s question and some recorded outcomes, but they do not supply the primary comparison needed to quantify the endpoint result.

The absence of arm-level primary outcome counts, an effect estimate and a confidence interval means that neither the size of the observed functional difference nor its precision can be assessed from the registry record. It also means the record cannot support a conclusion that the groups were alike or different on the primary outcome. No such conclusion follows from enrollment, study completion, design features or safety summaries alone.

The endpoint is specific to a thresholded change in ALSFRS-R slope at a defined follow-up time. It is not the same as a full description of every participant’s functional trajectory, nor does it by itself summarize every aspect of function, survival or safety. The secondary outcomes address additional questions, but their listed presence is not a substitute for their results or for a prespecified analysis strategy.

The reported safety figures are useful as descriptive participant counts, but do not identify event causes or account for exposure time. The term percentages are not accompanied by an arm-specific breakdown in the recorded entries. Accordingly, they cannot be used to estimate a treatment-specific risk for those terms from the record alone.

These limitations concern what the registry record reports. They do not establish whether a treatment effect exists, whether the study’s analyses were favorable or unfavorable, or what an individual should do about treatment. Interpreting the trial’s efficacy requires outcome results and analysis details not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for asking about a change in the rate of functional score progression rather than relying only on one score at a single visit. A slope-based endpoint uses repeated assessments to characterize change over time. The primary outcome then applies a specified threshold and expresses the result as a proportion of participants. That combination makes the estimand—the quantity the analysis is intended to estimate—important to understand: the primary comparison concerns the proportion meeting the criterion, not the average ALSFRS-R score change for all participants.

The endpoint also illustrates a trade-off common to thresholded outcomes. A binary result can be straightforward to communicate, but it compresses variation in slope changes into two categories. The threshold determines who is counted as meeting the outcome, while the underlying continuous measurements and their variability are not visible in the binary proportion alone. Results are best interpreted with the arm counts, effect estimate and uncertainty interval, none of which are reported for the primary outcome in the registry record.

Repeated measures, incomplete follow-up and a modified intent-to-treat population make analysis choices consequential. The record’s population definition requires treatment and a minimum set of ALSFRS-R assessments. The number qualifying and the handling of missing data are not reported. Readers therefore cannot determine from the record how well the analyzed population represents all randomized participants or how sensitive the result might be to missing assessments.

Finally, multiple outcomes and analyses raise questions about prespecification and multiplicity. The registry lists four outcome measures and four analyses, but does not report the analysis hierarchy or any adjustment strategy. This makes the primary result’s statistical context difficult to evaluate even apart from the missing effect estimate. The design features are informative, but conclusions require transparent reporting of the results and analysis methods.

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.

Several trial-specific details needed to judge the primary result are not reported in the registry record. These include the arm-level primary endpoint counts and proportions, the estimated between-group comparison, its confidence interval and p-value. Without these, the magnitude, direction and precision of the primary result cannot be described.

The modified intent-to-treat definition requires participants to have been randomized, treated and to have at least three ALSFRS-R assessments, including an assessment before baseline, a baseline assessment and one after treatment. The number of participants who met this definition and the number who did not are not reported. The registry record also does not report reasons for missing assessments, the missing-data method, sensitivity analyses, or how deaths and treatment discontinuation were incorporated into analyses of function.

The primary outcome is expressed as a thresholded slope improvement. The precise method for estimating individual slopes, the handling of measurements at different times, and the approach to values near the threshold are not reported. Those details would help readers understand how the binary outcome was constructed and how robust it may be to analytic choices.

The record lists multiple outcomes and analyses but does not report the hierarchy among them, the multiplicity strategy, the statistical analysis plan, interim analyses or stopping rules. It also does not report detailed allocation procedures, treatment adherence, protocol deviations, center-level analytic handling or the roles covered by quadruple masking. These are reporting limitations: the registry record does not establish whether the procedures were absent, only that they are not reported there.

Safety summaries are also limited. The record gives participant counts, but not event timing, recurrence, exposure-adjusted rates or arm-specific assignments for the listed serious-event term percentages. These constraints limit comparisons and causal interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients — NCT03280056.
• Registry record last updated 2024-02-29; status last verified 2024-02.
• Results first posted 2024-02-29.
• 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.

18. Record Summary

NCT03280056 is a completed phase 3 randomized, quadruple-masked, parallel-group study of repeated NurOwn® (MSC-NTF cells) compared with placebo in participants with ALS. The registry record lists an enrollment of 196. The study start date was 2017-08-28, and the primary completion date was 2020-09-29.

The primary outcome concerns the proportion meeting a threshold of at least 1.25 points per month of improvement in post-treatment versus pre-treatment ALSFRS-R slope at 28 weeks following the first intrathecal injection. The record defines a modified intent-to-treat population based on randomization, treatment and ALSFRS-R assessment requirements. Arm-level primary outcome results and the details needed to assess their uncertainty are not reported in the registry record.

The record lists three secondary outcomes and reports selected safety counts, including serious adverse events, other adverse events and deaths. Multiplicity procedures, missing-data methods and further statistical analysis details are not reported in the registry record.