Pharmacokinetics and Safety of SAR441236: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics and Safety of SAR441236 (NCT03705169), a randomized phase 1 study. The primary outcome is Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) That is Related to Study Treatment..

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase I, first-in-human study of SAR441236 in participants with HIV. It was randomized, double-masked, and parallel-group, with enrollment of 52. The record describes the study as terminated. It lists a start date of 2019-05-20 and primary completion on 2022-04-04. The sponsor was the National Institute of Allergy and Infectious Diseases (NIAID).

The study included multiple cohorts and administration approaches. Arm A included IV dosing at 1 mg/kg, 3 mg/kg, and 10 mg/kg as a single infusion on Day 0, as well as a 30 mg/kg regimen administered on Day 0 and every 12 weeks for a total of four doses. Arm A also included pooled placebo participants. Participants in these cohorts continued non-study-provided ART.

Arm B included 1 mg/kg and 30 mg/kg SAR441236, each given as a single IV infusion on Day 0. ART was initiated or re-initiated by Day 28. The listed secondary outcomes for these cohorts concern plasma HIV-1 RNA during SAR441236 monotherapy among viremic participants. Arm C assessed subcutaneous injections at 0.3 mg/kg and 1 mg/kg, with pooled placebo participants; participants continued non-study-provided ART.

The primary safety follow-up window varied with regimen: through up to 24 weeks after study treatment for single-dose cohorts, and up to 36 weeks after the fourth study treatment for the multi-dose cohort in Arm A. The registry record does not report the rationale for the cohort sequence, randomization details, or the number allocated to each cohort beyond the outcome-specific group sizes.

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 enrolled in Arms A and C were randomized 2:1 SAR441236:placebo. Participants who enrolled in Arm B were not randomized and were assigned open-label SAR4412326. For analysis, participants receiving placebo (of any dose-volume equivalent) are pooled within arm per the pre-specified analysis plan.

Only the first 6 of 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants exposed to SAR441236/placebo. Those receiving placebo of any dose-volume equivalent are pooled w/in arm per the analysis plan. The highest dose in ArmA (Cohort 4) was designed to with dual safety objectives: 1) evaluate the safety of a single dose for 12 weeks and 2) evaluate the safety of multiple doses if the initial dose proved safe.

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: Only participants receiving study treatment were included in the analysis. For analysis, participants receiving placebo (of any dose-volume equivalent) are pooled within arm per the pre-specified analysis plan.

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) That is Related to Study Treatment., measured over Measured from Day 0 through entire study follow-up, up to 24 weeks post study treatment administration for single dose cohorts (all arms) and up to 36 weeks after the fourth study treatment administration for the multi-dose cohort (Arm A only)..

The primary endpoint is the proportion of participants experiencing a grade 3 or higher adverse event judged to be at least possibly related to study treatment. The registry defines grade 3 as severe, grade 4 as potentially life-threatening, and grade 5 as death. Relatedness was judged by the core safety team, which was blinded to active or placebo treatment in Arms A and C. The endpoint covers the specified study follow-up: up to 24 weeks after study treatment in single-dose cohorts and up to 36 weeks after the fourth administration in the Arm A multi-dose cohort.

This kind of endpoint is used to describe the occurrence of serious-severity events considered potentially associated with treatment. It combines event severity and an assessment of relatedness; it is not the same as counting every adverse event or every serious adverse event. The registry also reports other adverse-event information, but those counts should not be substituted for the primary endpoint.

Every posted primary-endpoint estimate is 0.0. The reported 95% confidence intervals nevertheless extend above zero, with upper limits varying across groups. A zero observed proportion means no qualifying event was recorded in that group for this endpoint; it does not mean the underlying event probability is known to be zero. The uncertainty is especially important when interpreting groups with few participants.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a proportion estimate describe?

A proportion expresses how many participants in a defined group met an endpoint relative to the participants included in that endpoint analysis. For this outcome, the event must meet the registry definition: grade 3 or higher and judged at least possibly related to study treatment. The reported estimates are 0.0 for every listed group. Because the event was not observed in these groups, the point estimates sit at zero, but the estimate alone does not indicate how large the true event rate might be.

Group size matters when interpreting a zero estimate. With few participants, an event that could occur infrequently may simply not be observed in the group being studied. A larger group can generally provide more information about an event rate, but the registry groups remain small. The group sizes for this endpoint range from 2.0 to 10.0 participants, so each participant represents a substantial part of the group’s observed experience.

How should the confidence intervals be read?

A confidence interval describes uncertainty around an estimate under the method used to calculate it. It is not a guarantee that the true value lies within the interval, nor does it show the range of individual participant outcomes. The registry reports 95% confidence intervals for the proportions. Their lower limits are 0.0, matching the observed estimates, while their upper limits range from 0.31 to 0.84. Thus, the posted results do not support treating the zero point estimates as proof that the event rate is zero.

The intervals differ across groups, in part alongside the varying group sizes. They are not evidence by themselves that one dose is safer than another. A formal comparison would need an appropriate estimate and uncertainty for the contrast between groups. The registry record does not report an estimable two-arm result for this binary endpoint, so the individual group intervals should not be used as a substitute for a treatment comparison.

What is the distinction between the endpoint and other adverse-event counts?

The primary endpoint has multiple conditions: an event must reach grade 3 or higher and be judged at least possibly related to study treatment. The separate safety listing includes serious adverse events and other adverse events. Seriousness is not interchangeable with severity grade, and the record does not indicate that every serious event met the primary endpoint’s grade and relatedness requirements. The lists therefore answer different safety questions and can have different counts and denominators.

The registry reports 95% confidence intervals for the primary proportions, but the particular calculation method is not reported in the registry record. It is also not reported whether any adjustment was made for the multiple doses, routes, cohorts, or outcomes. The precision of an interval should be interpreted as uncertainty for the stated endpoint and group, not as a guarantee that unrecorded or unmeasured events are excluded.

What do the planning calculations mean?

Planning sample-size illustrations are distinct from the trial’s observed enrollment and are not observed power. The stated planning approach uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. Such calculations are hypothetical planning exercises based on their assumptions; they do not show the probability that the completed study detected an effect, and they are not the study’s original design justification. The sample-size justification for this trial is not reported in the registry record.

For a binary proportion endpoint, an observed effect depends on the event proportions being compared. The posted primary estimates are all 0.0, and the registry does not provide a two-arm comparison estimate. The record’s planning assumptions should therefore not be mistaken for evidence of a detectable clinical effect or for a confirmatory analysis. No numerical planning results are stated in the registry record.

What can be inferred from unavailable comparisons?

The posted results indicate that values were missing or not estimable for a two-arm comparison of the binary endpoint. This means a comparative estimate is not available in the posted results. It does not establish that the groups are equivalent, and it does not give a direction or magnitude of difference. The individual group proportions and intervals remain descriptive results for their respective groups.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Arm A: 1 mg/kg SAR441236", "Arm A: 3 mg/kg for SAR441236", "Arm A: 10 mg/kg SAR441236", "Arm A: 30 mg/kg SAR441236", "Arm A: 0 mg/kg SAR441236", "Arm B: 1 mg/kg SAR441236")
n      <- c(4, 4, 4, 10, 10, 5)
events <- c(0, 0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Arm A: 1 mg/kg SAR441236  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Arm A: 3 mg/kg for SAR441236  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Arm A: 10 mg/kg SAR441236  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Arm A: 30 mg/kg SAR441236  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5
ARM  Arm A: 0 mg/kg SAR441236  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5
ARM  Arm B: 1 mg/kg SAR441236  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9

11. Multiplicity, Missing Data and Analysis Populations

The study reports multiple doses, administration routes, cohorts, and secondary outcomes. The secondary outcomes include plasma HIV-1 RNA changes and maximum reduction, anti-SAR441236 antibodies, CD4+ T-cell counts, and maximum concentration after IV infusion or subcutaneous injection. The registry record does not report how multiplicity across these outcomes or comparisons was handled. It also does not report a prespecified hierarchy of hypotheses or which results, if any, were treated as confirmatory. Individual results should therefore be read as outcome-specific findings rather than as evidence that a family of statistical tests was controlled at a stated error rate.

The record reports missing or not estimable values for a two-arm comparison of the binary primary endpoint. That limitation concerns the comparative result; it does not explain why a comparison could not be estimated. The reason is not reported in the registry record. Participant-level missing outcome data, missing-data assumptions, imputation methods, and sensitivity analyses are also not reported in the registry record.

The primary endpoint population is described as all participants exposed to SAR441236 or placebo. Placebo participants of any dose-volume equivalent are pooled within arm according to the analysis plan. The record does not provide further detail on analysis-population exclusions, handling of participants with incomplete follow-up, or the precise denominators used for every outcome. The endpoint arm listings give group sizes from 2.0 to 10.0 participants; separate adverse-event listings sometimes report different at-risk counts. Those outcome-specific counts should be interpreted in their own context rather than assumed to represent an identical analysis set.

The registry record does not report an interim-analysis plan, stopping boundary, or the statistical consequences of study termination. These absences prevent assessment of whether repeated looks at the data or early termination affected the reported inferential procedures.

12. 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: malignant melanoma (25.0%), soft tissue infection (20.0%), pneumonia (9.1%), suicidal ideation (9.1%).

The serious adverse-event listing gives the number at risk and the number affected separately from the primary endpoint. For the listed groups, the serious-event counts are: Arm A 1 mg/kg, 1 of 4; Arm A 3 mg/kg, 0 of 4; Arm A 10 mg/kg, 0 of 4; Arm A 30 mg/kg, 2 of 11; Arm A placebo, 0 of 10; Arm B 1 mg/kg, 1 of 5; Arm B 30 mg/kg, 0 of 2; Arm C 0.3 mg/kg, 0 of 4; Arm C 1 mg/kg, 0 of 4; and Arm C placebo, 0 of 4. The record also lists other adverse events separately, with affected counts ranging from 0 to 8 across the groups.

These figures are not the primary endpoint proportions. Serious adverse events are not necessarily grade 3 or higher events judged at least possibly related to study treatment. The primary endpoint’s attribution and severity rules must both be met. The registry lists no deaths in these adverse-event groups. It also lists malignant melanoma at 25.0%, soft tissue infection at 20.0%, pneumonia at 9.1%, and suicidal ideation at 9.1% among the top serious-event terms; the denominator for those percentages is not reported in the registry record.

The safety listing reports 11 at risk in Arm A 30 mg/kg, while the primary endpoint listing reports 10.0 participants for that group. These are outcome-specific listings and should not be treated as interchangeable denominators; the reason for the difference is not reported in the registry record.

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

The primary endpoint results show that no participant in the listed endpoint groups was recorded as having a grade 3 or higher adverse event judged at least possibly related to study treatment during the defined follow-up. Each group’s reported proportion is 0.0. This is a description of the observed data, not proof that the underlying rate is zero. The 95% confidence intervals extend above zero, and the group sizes are limited.

The results do not establish that SAR441236 is free of safety risks, nor do they show that the treatment is safer or less safe than placebo. A comparative estimate is not available in the posted results for the binary endpoint. The data also do not establish that all adverse events were absent: the separate safety listing records serious and other adverse events, which use definitions distinct from the primary endpoint.

The findings are specific to the regimens, populations, and follow-up windows described in the registry. They include IV and subcutaneous administration, single-dose and multi-dose cohorts, and differing ART arrangements. The primary safety endpoint’s follow-up was up to 24 weeks after treatment for single-dose cohorts and up to 36 weeks after the fourth administration in the Arm A multi-dose cohort. The results should not be generalized beyond those recorded study circumstances without additional evidence.

The listed secondary outcomes cover pharmacokinetics, immunogenicity, CD4+ T-cell counts, and plasma HIV-1 RNA. The primary endpoint results do not answer those questions. Nor do they explain the study’s termination: its reason is not reported in the registry record. Overall, these data describe a small Phase I safety experience with uncertainty around the rate of uncommon qualifying events, rather than a definitive comparison of treatment effects.

14. Why This Trial Matters Statistically

This study illustrates why an observed zero event count is not the same as evidence that an event cannot occur. Every posted primary-endpoint estimate is 0.0, yet the confidence intervals extend above zero. With group sizes ranging from 2.0 to 10.0, the information available for estimating event rates is limited. Reporting the interval alongside the point estimate helps readers see that uncertainty remains even when no qualifying event was recorded.

It also demonstrates the importance of defining an endpoint precisely. The primary outcome requires both a severity threshold and a judgment of treatment relatedness. The separate serious-event counts do not automatically satisfy those criteria. Keeping those definitions distinct prevents readers from treating all safety summaries as interchangeable.

The trial’s varied routes, dose levels, schedules, and ART arrangements make context important when comparing descriptive results across cohorts. The posted record does not provide an estimable two-arm comparison for the binary endpoint, so the separate proportions should not be mistaken for a controlled estimate of a dose or treatment difference. This is a useful reminder that group-by-group results and direct comparative inference are different statistical tasks.

Finally, the registry record does not report details of multiplicity control, missing-data handling, or the reason for termination. Those absences limit what can be concluded about the analysis plan and interpretation of the full set of outcomes. For early-phase research, transparent reporting of group sizes, endpoint definitions, uncertainty, and analysis decisions is essential to place sparse safety observations in context.

15. 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 primary endpoint groups are small, with listed sizes from 2.0 to 10.0 participants. Consequently, zero observed qualifying events do not precisely establish a low underlying event rate. The reported 95% confidence intervals have upper limits as high as 0.84, indicating substantial remaining uncertainty on the reported scale.

The study includes multiple dose levels, routes, schedules, cohorts, and ART arrangements. These differences complicate direct comparisons across groups, particularly because the posted results do not include an estimable two-arm comparison for the binary endpoint. A pooled treatment estimate is not reported in the registry record.

The primary outcome requires an event to be grade 3 or higher and judged at least possibly related to study treatment. Relatedness was assessed by the core safety team, blinded to active or placebo treatment in Arms A and C. The registry does not report further detail on adjudication procedures or agreement between assessors. The primary endpoint should therefore be understood as the registry-defined safety measure, not as a complete count of all adverse events.

Some outcome-specific group sizes differ across the primary-endpoint and adverse-event listings, including Arm A 30 mg/kg. The reason for this difference is not reported in the registry record. The record also does not report participant-level missingness, missing-data methods, analysis exclusions, the rationale for sample size, multiplicity procedures, or the reason the study was terminated. These gaps limit interpretation of the analysis process and the completeness of follow-up, without changing the descriptive results that are posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pharmacokinetics and Safety of SAR441236 — NCT03705169.
• Registry record last updated 2024-01-12; status last verified 2024-01.
• Results first posted 2024-01-12.
• 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.

19. Record Summary

The registry describes NCT03705169 as a randomized, double-masked, parallel-group Phase I first-in-human study of SAR441236 in participants with HIV-1 infection. Enrollment was 52, and the status is terminated. The study included IV and subcutaneous SAR441236 regimens, placebo groups, and different ART arrangements across cohorts.

The primary endpoint was the proportion experiencing a grade 3 or higher adverse event judged at least possibly related to study treatment. Every listed group had a reported estimate of 0.0, with 95% confidence intervals extending above zero. The posted group sizes were small, and a two-arm comparison was not estimable in the posted results. Separate safety listings report serious and other adverse events; these are not interchangeable with the primary endpoint. The registry record does not report the reason for termination or several details of the statistical analysis plan.