Open Label Treatment Extension Study With SAR245408 or SAR245409 as a Monotherapy or as a Combination Regimen: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open Label Treatment Extension Study With SAR245408 or SAR245409 as a Monotherapy or as a Combination Regimen (NCT01587040), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

This is a safety question in a selected group who had already reached an extension study after completing an earlier trial. It is not a question about whether one regimen is more effective than another. The record describes treatment continuation until disease progression, unacceptable toxicity, withdrawal of consent, or availability of commercial supplies. The maximum exposure listed was 1959 days for the SAR245408 groups and 1917 days for the SAR245409 groups.

Because allocation was non-randomized and the study was open-label, the treatment groups may differ in ways that affect their safety results. The record does not report random assignment or masking. The posted results therefore describe adverse-event experience in each group; they do not establish that differences between groups were caused by the drugs or regimens.

3. Trial Design

This completed study, NCT01587040, was an international, multicenter, open-label treatment-extension study. It enrolled 61 participants and included Phase 1 and Phase 2 treatment histories. Participants had completed a parent study and continued treatment with SAR245408 or SAR245409, alone or in a combination regimen. The record lists Sanofi as the sponsor.

The design was non-randomized, unmasked, and parallel. The four groups were SAR245408 monotherapy, SAR245408 combination regimen, SAR245409 monotherapy, and SAR245409 combination regimen. Participants received the dose established in the parent study or the dose specified in the group description: SAR245408 400 mg once daily and SAR245409 50 mg twice daily. In each group, treatment could continue until disease progression, unacceptable toxicity, withdrawal of consent, or commercial supplies became available.

The record lists a maximum exposure of 1959 days for SAR245408 and 1917 days for SAR245409. These are maximum durations, not a description of typical exposure or the time each participant remained on treatment. The distribution of treatment duration is not reported in the registry record.

The primary objective was to assess long-term safety and tolerability in participants who were benefiting from treatment. This extension design follows participants from earlier trials rather than enrolling a new, broadly selected population. That context matters: entry into the extension depended on completing a parent study and continuing treatment, so the results describe this selected group. The registry record does not report a randomized allocation process, a concurrent control group, or blinding. It also does not report a detailed statistical analysis plan or sample-size justification.

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: Participants who received IMP for \<2 cycles in parental study, and participants who took a daily dose of IMP higher than their established dose entered treatment-extension study on Day 1 of initiation period; participants who received IMP \>=2 cycles in parental study entered treatment-extension study on Day 1 of extension period.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on safety population that included all participants who took at least 1 dose of study drug during the study.

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: Analysis was performed on safety population that included all participants who took at least 1 dose of study drug during the study.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAEs), measured over From Baseline up to 30 days after the last dose (maximum exposure: 1959 days).

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs). It counts participants, rather than the total number of event episodes. An adverse event was defined as an untoward medical occurrence in a participant who received investigational medicinal product, without requiring that the event be considered caused by treatment.

A TEAE was an adverse event that developed, worsened, or became serious during the on-treatment period, defined as treatment through 30 days after the last dose of any investigational medicinal product. The stated timeframe runs from baseline through 30 days after the last dose, with maximum exposure listed as 1959 days. The definition includes participants with both serious and non-serious events, and includes participants with treatment-emergent serious adverse events. Events leading to death, dose reduction or delay, discontinuation, and events considered related to treatment were also reported.

Counting participants with events is useful for describing how many people experienced harm during treatment and follow-up. It does not describe the number of separate events each person had, the duration of an event, or its probability of occurring under a different treatment. In this extension study, the endpoint supports a descriptive safety account; without randomization or a control group, it cannot by itself establish comparative safety or causation.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level safety outcome: whether a participant had a treatment-emergent adverse event during the defined period. The registry reports counts of participants with serious events and with other events by treatment group. These are descriptive summaries, not estimates from a randomized comparison. The primary outcome is framed as a count of participants, so it should not be confused with the total number of distinct adverse-event episodes.

What does a participant count tell us?

In general, a participant count answers how many people in a group experienced at least one event within the specified observation window. A person with several events may still contribute only once to a count of participants with any event. Separate summaries may also classify events by seriousness or other characteristics. The registry defines a serious adverse event by outcomes such as death, a life-threatening event, initial or prolonged inpatient hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or another medically important event.

The TEAE definition is based on timing, not necessarily causation. An event qualified if it developed, worsened, or became serious while on treatment, through 30 days after the last dose of any investigational medicinal product. The registry explicitly says an adverse event was counted without regard to the possibility of a causal relationship. Thus, an event can be treatment-emergent without being established as treatment-related.

Why does the design affect interpretation?

In general, random assignment can help make treatment groups comparable at the start of a trial. This extension was non-randomized, and the groups were not intended as like-for-like controls. Differences in their observed counts can reflect differences in the participants, treatment histories, exposure, or other factors, as well as chance. The record does not report enough information to assess those factors fully. The open-label design also means masking was absent; the registry does not report procedures that would separate knowledge of treatment from event assessment.

Exposure time is relevant to safety interpretation. Participants could remain on treatment until specified stopping conditions, and the listed maximum exposure differs by drug. A participant treated longer has more time in which an event can be observed. The registry gives maximum exposure but does not report individual exposure duration or person-time summaries in this record. A raw participant count therefore does not adjust for differences in time at risk.

What can uncertainty summaries add?

In general, a confidence interval describes a range of values compatible with a statistical estimate under the model and assumptions used. It can communicate precision, which a point estimate or count alone does not. No confidence intervals or inferential analyses are reported for the safety counts in this record. With the small group sizes, especially the combination-regimen groups, the observed counts offer limited detail about how stable group-specific estimates might be in other participants.

General methods for comparing event rates may account for different exposure times, and methods for count outcomes may need to account for over-dispersion when variability exceeds a model’s assumptions. Those are general considerations, not methods identified for this trial. The registry record does not report rate models, over-dispersion adjustments, covariate adjustment, or a formal comparative analysis. There is therefore no basis to attribute a specific model or test to the posted results.

Are the posted groups a treatment comparison?

No. The study had no randomized allocation and the registry flags the arms as not a like-for-like control comparison. Describing each group separately preserves the information in the record without implying that one regimen is safer or less safe than another. A difference in raw counts is not, by itself, evidence of a causal difference. The sample-size planning illustrations elsewhere on the page are not observed power and cannot repair the absence of randomization or a control comparison.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 0 analyses. It does not report a multiplicity strategy, such as which outcomes or comparisons were considered primary for formal testing or whether any adjustment was planned. The record also does not report a detailed statistical analysis plan. Therefore, no claim can be made about control of false-positive findings across multiple outcomes or comparisons.

Missing-data handling is not reported in the registry record. The record does not describe how participants with incomplete follow-up, missing event assessments, or partial exposure were handled, nor does it report imputation or sensitivity analyses. The posted counts should be interpreted as recorded summaries, not as results shown to be robust to missingness.

The primary endpoint’s population is the safety population, defined as all participants who took at least 1 dose of study drug during the study. This is appropriate to describing observed safety experience among treated participants, but it is not the same as an analysis of all enrolled participants regardless of treatment exposure. The record does not report a separate intention-to-treat population or provide further population-specific analysis details.

In general, multiplicity matters when many outcomes or comparisons are examined because the chance of at least one apparently notable result can increase. Missingness also matters when the likelihood of an unobserved outcome relates to treatment or health status. These are general statistical considerations; the registry does not report whether either issue was addressed analytically in this study.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: catheter site infection (33.3%), anaemia (11.8%), pneumonia (11.8%), pleural effusion (11.8%), neutropenia (5.9%).

The serious-event counts are reported as participants affected out of participants at risk in each group. For SAR245408 monotherapy, 9 of 17 participants had serious events; for SAR245408 combination regimen, 1 of 3 did. For SAR245409 monotherapy, 10 of 37 did; for SAR245409 combination regimen, 0 of 4 did. These are observed group counts, not randomized estimates of comparative risk.

The other-event counts are 15 of 17, 3 of 3, 34 of 37, and 3 of 4, respectively, in the same group order. The registry’s description says TEAEs include participants with serious and non-serious events. The record does not fully define the boundaries of the separate “other” category in the information reported, so these counts should be read using the registry’s category labels.

Deaths are listed separately: 1, 0, 3, and 0 in the same group order. A death count does not establish that treatment caused the death. The top serious-event terms are reported as percentages, but their denominator is not specified in the record information presented. The terms and percentages should therefore not be treated as population-wide rates or directly translated into participant counts.

In general, serious-event classifications indicate regulatory seriousness criteria and are distinct from severity grades. The registry describes grades 3 as severe and 4 as life-threatening or disabling. A serious event is not necessarily grade 3 or 4, and the posted figures should not be read as a complete account of severity.

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

The results show that treatment-emergent adverse events were recorded in each of the four extension groups, with the registry reporting participant counts for serious events, other events, and deaths. They also show that the group sizes varied, and that the combination-regimen groups contained few participants. The serious-event term list provides additional descriptive information about events represented in the registry.

These observations address the stated aim of describing long-term safety and tolerability among participants who continued treatment after a parent study. They do not establish that a particular event was caused by either study drug. The registry’s event definition explicitly does not require a causal relationship, and its record excerpt does not provide treatment attribution for the listed deaths.

The results do not show whether SAR245408 is safer or less safe than SAR245409, or whether monotherapy is safer or less safe than a combination regimen. Such interpretations would require a defensible comparison. Here, treatment was not randomized, the groups are not like-for-like controls, and their sizes differ. The posted counts alone cannot separate treatment effects from participant characteristics, prior treatment, exposure duration, or chance.

Nor do these safety counts answer an efficacy question. The stated primary objective is safety and tolerability; the record excerpt does not provide a treatment-effect estimate for cancer outcomes. It also does not report confidence intervals or adjusted analyses for the safety results. The counts therefore describe observed events in this extension population, but do not provide a precise estimate of how event experience would differ under another treatment strategy.

In general, evidence from a treatment-extension study can help document events during continued exposure in the population that enters the extension. Its interpretation depends on who completed the parent study, who continued treatment, how long participants were observed, and how events were collected. The registry record offers some design and outcome definitions, but several details needed for broader or causal conclusions are not reported.

13. Why This Trial Matters Statistically

This study matters statistically because safety observations during extended treatment answer a different question from a short-term randomized efficacy comparison. Participants had completed a parent study and continued treatment, and the primary objective concerned long-term safety and tolerability among those benefiting from treatment. The resulting population is selected by its route into the extension, so its experience should be understood in that context.

The record also illustrates why event counts need careful interpretation. A participant count is not an event count, and an event that occurs during treatment is not necessarily caused by treatment. Seriousness, severity, and relatedness are distinct concepts. The registry provides definitions for treatment-emergent and serious events, while the group summaries and term percentages describe different aspects of reported safety experience.

Non-randomized group summaries can be useful descriptively, but they do not create a reliable treatment contrast on their own. Differences in group size, treatment history, and exposure can affect what is observed. The absence of a like-for-like randomized control is especially important when readers might otherwise compare the four regimens as though they were assigned under the same conditions.

Finally, the registry record makes visible what is not available for statistical evaluation: it reports no analyses, and does not report confidence intervals, a detailed analysis plan, missing-data procedures, or multiplicity handling. Those omissions constrain precision and interpretation. Recognizing these limits allows the counts to be read as a record of events in the extension population, rather than as proof of comparative safety or a causal treatment effect.

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 non-randomized, open-label design is the central limitation for comparisons among treatment groups. Allocation was not random, there was no like-for-like control comparison, and the registry does not report masking. Differences in counts cannot be attributed to regimen without stronger comparative evidence.

The extension population was made up of participants who completed a Phase 1 or Phase 2 parent study and continued treatment. The stated objective focused on participants benefiting from treatment. This selection limits generalization to people who would not have completed the parent study or continued into the extension. The registry does not report the number of parent-study participants who did not enter the extension or reasons for non-entry.

The combination-regimen groups were small, with 3 participants in the SAR245408 group and 4 in the SAR245409 group. Maximum exposure is reported, but actual exposure distributions and person-time are not reported in the registry record. Raw counts therefore do not account for differences in time under observation. The record also does not report confidence intervals or comparative models.

Further limitations include missing information about missing-data handling, multiplicity, and detailed statistical methods. The percentage denominators for the listed serious-event terms are not specified in the record information presented. The record’s adverse-event definition does not require causal attribution, and treatment-relatedness details for deaths are not given. These gaps constrain both the precision and the clinical interpretation of the posted safety summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Open Label Treatment Extension Study With SAR245408 or SAR245409 as a Monotherapy or as a Combination Regimen — NCT01587040.
• Registry record last updated 2022-04-19; status last verified 2022-03.
• Results first posted 2019-06-11.
• 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

NCT01587040 was a completed, international, multicenter, open-label, non-randomized treatment-extension study sponsored by Sanofi. It enrolled 61 participants who had completed a Phase 1 or Phase 2 parent study. Participants continued SAR245408 or SAR245409 as monotherapy or in a combination regimen.

The primary objective was long-term safety and tolerability. The primary outcome counted participants with treatment-emergent adverse events from baseline through 30 days after the last dose. The safety population included participants who took at least 1 dose of study drug. The registry reports serious-event, other-event, and death counts by group, along with percentages for selected serious-event terms.

The results are descriptive. Non-randomized allocation, differing group sizes, and absent comparative analyses prevent causal comparisons between regimens. Details including a statistical analysis plan, missing-data methods, multiplicity handling, and confidence intervals are not reported in the registry record.