A Double-Blind Single-Ascending Dose (SAD) and Multiple-Ascending Dose (MAD) Study to Investigate the Safety, Tolerability, and Pharmacokinetics of RO7049389 in Healthy Chinese Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Double-Blind Single-Ascending Dose (SAD) and Multiple-Ascending Dose (MAD) Study to Investigate the Safety, Tolerability, and Pharmacokinetics of RO7049389 in Healthy Chinese Participants (NCT03570658), a randomized phase 1 study. The primary outcome is Percentage of Participants With Adverse Events.

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, placebo-controlled phase 1 study with a sequential model. The full title describes the study as sponsor-open, investigator-blinded, and subject-blinded; the registry’s masking field labels it double-blind. The record does not report additional detail about which study personnel knew treatment assignments or how masking was maintained.

The study included single-ascending-dose and multiple-ascending-dose cohorts. In the SAD cohorts, participants received a single dose of RO7049389 or matched placebo. In the MAD cohorts, participants received multiple doses of RO7049389 or matched placebo. The reported SAD dose groups were 200 mg, 400 mg, and 600 mg, and the reported MAD dose groups were 200 mg and 400 mg. A separate placebo group was reported for each dosing schedule.

The registry reports enrollment of 31 and a completed status. The recorded start date is 2018-08-24 and the primary completion date is 2019-01-28. These registry dates describe the recorded study timeline; they do not give the duration of an individual participant’s treatment or follow-up beyond the outcome timeframe.

The safety outcome was assessed in the safety analysis population, defined as participants who received at least one dose of study medication and had at least one safety assessment. Reported group sizes differ across dose and schedule groups, and some groups are small. Randomization procedures, allocation concealment, cohort progression rules, and the rationale for the selected group sizes are not reported in the registry record. The specific statistical analysis plan is also not reported.

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: Total n=31. SAD n=28 (Active treatment n=22 and placebo n=6). 21 participants continued on to the MAD phase of the study. 3 participants chose not to continue. MAD n=24. 3 participants were directly enrolled into the MAD phase of the study in addition to the 21 participants from the SAD phase.

Single Ascending Dose (SAD)

Multiple Ascending Dose (MAD)

Analysis population for the primary outcome, as defined in the registry: All safety analyses were based on the safety analysis population, which included all subjects that received at least one dose of study medication (RO7049389 or placebo), with at least one safety 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: Total n=31. SAD n=28. 21 participants continued and 3 new participants were directly enrolled in MAD (n=24). The 400/200 arm enrolled 2 new participants and the 600/400 arm enrolled 1. Baseline characteristics are split in to SAD and MAD to account for the 3 additional participants.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Adverse Events, measured over From the date of first administered dose through 28 days after the last administered dose..

The primary endpoint is the percentage of participants with adverse events during the period from the first administered dose through 28 days after the last administered dose. The registry defines an adverse event as an untoward medical occurrence after administration of a pharmaceutical product, whether or not it is considered causally related to that product. The definition includes unfavorable signs, symptoms, or diseases, abnormal laboratory findings, and preexisting conditions that worsen during the study.

This endpoint is used to describe the frequency of participants who experienced an adverse event during the specified observation period. It is a participant-level summary: the percentage concerns whether participants had an event, not the total number of event episodes. It therefore does not, by itself, describe how many events each affected participant experienced, their severity, duration, or suspected relationship to treatment.

The posted percentages are reported separately for each dose and dosing-schedule group. The registry also provides counts of participants at risk for serious adverse events, other adverse events, and deaths. Those counts add safety context, but the primary outcome is the percentage with adverse events, not a measure of pharmacokinetic exposure or a formal test of treatment differences. The registry record does not report confidence intervals for the primary percentages or a formal comparison estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level outcome: a participant either had at least one adverse event during the stated period or did not. Reporting the percentage with an event expresses that frequency relative to the number of participants assessed in a group. It is different from counting every event, because one participant may experience more than one event while still contributing only once to the percentage of participants with an event.

What does a percentage describe?

A percentage is an estimate of the event frequency in the particular group observed. Its interpretation depends on both the number of participants with the outcome and the number assessed. For this study, the reported group sizes range from 2.0 to 10.0, and the registry lists outcome percentages for each dose and schedule group. With such small groups, an individual participant’s outcome can have a noticeable effect on the group percentage. The percentage is therefore best read as a description of these participants, not as a highly precise estimate of what would occur in a much larger population.

A confidence interval is a statistical range expressing uncertainty around an estimate under a specified method. It helps distinguish a relatively precise estimate from one that is compatible with a broad range of underlying event frequencies. No confidence intervals for the primary percentages are reported in the registry record. Without them, the displayed point estimates do not communicate their statistical precision directly. No new interval should be inferred from the percentages alone.

Why keep the cohorts separate?

The study has both SAD and MAD cohorts, and each schedule has its own placebo group. A single-dose cohort and a multiple-dose cohort do not represent the same dosing schedule. Their placebo percentages also differ in the posted results. Describing each group separately avoids obscuring that structure. A valid combined estimate or a direct treatment contrast would require an analysis that accounts for the study design and the relevant comparison groups; such an estimate is not reported in the registry record.

The registry identifies the study as randomized and sequential, but the detailed randomization method and the rules governing progression through cohorts are not reported in the registry record. The word sequential describes the listed study model; it does not, on its own, establish the exact sequence of dose decisions, whether formal interim analyses occurred, or what decision thresholds were used. Those details are not reported in the registry record.

What can a formal comparison add?

A formal comparison can estimate a difference between groups and quantify uncertainty in that estimate. Depending on the plan and data, it may also adjust for design features or account for repeated measurements. The posted primary outcome results give group percentages, but no formal arm-comparison estimate or analysis is reported. The registry lists no analyses. Consequently, there is no posted inferential result supporting a claim that observed percentages are statistically distinguishable. This does not mean that the groups are equivalent; the registry record simply does not report an analysis establishing either a difference or equivalence.

The record’s planning description refers to illustrations based on a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. That description explains the assumptions used for planning illustrations; it is not evidence of the study’s own design justification or an analysis of observed power. Specific sample-size illustration values and the trial’s sample-size justification are not reported in the registry record. Sample-size planning figures, when presented, are planning illustrations rather than a measure of the probability that this completed study detected an effect.

Why does over-dispersion matter?

Over-dispersion is a general issue for count outcomes when their variability is greater than a model expects. It can make standard errors too small if the analysis does not account for the extra variability. The primary outcome is a percentage of participants with at least one event, rather than a reported count of repeated event episodes, and the registry gives no model-based estimate or dispersion measure. The registry record does not report an over-dispersion assessment. This concept therefore does not supply a missing analysis or change the interpretation of the posted group percentages.

More broadly, the statistical analysis plan, any interim analysis plan, multiplicity procedures, and details of missing-data handling are not reported in the registry record. The registry’s outcome definitions and group results permit descriptive reading, but do not establish which statistical procedures were prespecified or how unobserved outcomes were handled.

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("SAD - Placebo", "SAD RO7049389 - 200 mg", "SAD RO7049389 - 400 mg", "SAD RO7049389 - 600 mg", "MAD - Placebo", "MAD RO7049389 - 200 mg")
n      <- c(6, 2, 10, 10, 4, 10)
events <- c(1, 0, 3, 1, 2, 9)
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  SAD - Placebo  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SAD RO7049389 - 200 mg  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  SAD RO7049389 - 400 mg  10  3  30.0  6.7  65.2  10.8  60.3  10.9  61.0
ARM  SAD RO7049389 - 600 mg  10  1  10.0  0.3  44.5  1.8  40.4  2.3  41.3
ARM  MAD - Placebo  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3
ARM  MAD RO7049389 - 200 mg  10  9  90.0  55.5  99.7  59.6  98.2  58.7  97.7

11. Multiplicity, Missing Data and Analysis Populations

The study lists a primary safety outcome and secondary pharmacokinetic outcomes. The secondary outcomes include maximum observed plasma concentration, time to maximum observed concentration, area under the plasma concentration-time curve to the last measurable concentration, area under the curve extrapolated to infinity, apparent half-life, clearance, trough concentration, and accumulation index. Nine secondary outcomes are reported as posted. Their numerical results are not reported in the registry record.

When a study assesses multiple outcomes or makes multiple comparisons, the chance of at least one apparently notable result can increase. Statistical methods may address this through a prespecified hierarchy, adjustment, or another strategy. The registry record does not report whether a multiplicity procedure was planned or used. It also does not report a prespecified hierarchy among the secondary outcomes or between dose groups.

The analysis population for safety is defined as participants who received at least one dose and had at least one safety assessment. This is the population specified for the safety analyses; the record does not provide the participant-level analysis details needed to assess exclusions or missing observations beyond that definition. The handling of missing safety assessments, missing outcome data, or participants with incomplete follow-up is not reported in the registry record. It is also not reported whether any imputation or sensitivity analysis was performed.

The record does not report an interim analysis plan or the details of a statistical analysis plan. Therefore, it is not possible to determine from the registry record whether outcome definitions, comparison procedures, or missing-data methods were prespecified in a protocol or analysis document. The posted results should be read as the reported descriptive safety findings, without assuming an unreported multiplicity adjustment or missing-data procedure.

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 non-serious adverse event terms

The adverse-event details distinguish serious adverse events, other adverse events, and deaths. The reported number of participants with serious adverse events is 0 in every listed group, and the reported number of deaths is 0 in every listed group. For other adverse events, the registry reports 1 participant in SAD placebo, 0 in SAD RO7049389 200 mg, 3 in SAD RO7049389 400 mg, 1 in SAD RO7049389 600 mg, 2 in MAD placebo, 9 in MAD RO7049389 200 mg, and 6 in MAD RO7049389 400 mg.

These are counts of participants, with the corresponding at-risk group sizes reported separately. A zero count means no participant in that group was recorded with the specified category in the posted results; it does not establish that the underlying risk is zero. The absence of serious adverse events or deaths in these groups should also be read in light of the small group sizes and the study’s limited observation period, which ran from the first dose through 28 days after the last dose for the primary outcome.

The registry does not report the serious-event terms, severity distributions, or event-level details in this record. Counts of other adverse events should not be confused with the percentage of participants experiencing any adverse event, which is the primary outcome. Neither the participant counts nor the primary percentages alone establish whether an event was caused by the study medication.

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

The posted results describe adverse-event percentages and participant counts for the dose and schedule groups in this phase 1 study. They show that reported adverse events occurred in some groups and not others, and that the observed percentages vary across SAD and MAD cohorts. The results also report no serious adverse events and no deaths in the listed groups. These findings describe the participants and observation period recorded in the registry.

They do not establish a treatment effect. There is no reported formal comparison between RO7049389 and placebo, no confidence interval for the primary percentages, and no reported inferential analysis. The percentages alone cannot determine whether apparent differences between groups reflect a stable underlying difference or variation that could occur with small groups. Nor do the data establish equivalence between RO7049389 and placebo.

The results also do not establish a dose-response pattern. The reported percentages do not rise consistently across the SAD dose groups, and the MAD results are from a separate multiple-dose schedule with its own placebo group. Comparing percentages across these distinct cohorts is descriptive, not a substitute for a prespecified statistical analysis.

The primary endpoint records whether participants experienced at least one adverse event during the defined period. It does not fully characterize the number of events, duration, severity, clinical importance, or causal relationship to treatment. Although pharmacokinetic outcomes were listed, their numerical findings are not reported in the registry record, so no conclusion about drug exposure or pharmacokinetic behavior can be drawn from those listed outcomes alone.

Finally, the record does not report the sample-size justification, handling of missing data, multiplicity procedure, or detailed statistical analysis plan. Those omissions limit assessment of how precisely the results estimate event frequencies and how the study’s planned analyses relate to its posted descriptive findings.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the limits of interpreting early-phase safety percentages from small, separate cohorts. The study reports a randomized, placebo-controlled design, but its SAD and MAD groups have different dosing schedules and separate placebo groups. Keeping those comparisons distinct is important: a percentage in a single-dose cohort does not automatically serve as a direct comparator for a multiple-dose cohort.

The varying group sizes also make the denominator central to interpretation. A percentage may look substantial or small while still being based on few participants. Without confidence intervals or formal comparisons, readers cannot judge the precision of the percentages from the point estimates alone. The descriptive results are useful for seeing what was recorded in the enrolled groups, but not for establishing a statistically supported difference between regimens.

The study also illustrates the distinction between a safety endpoint and a complete account of safety. The primary endpoint summarizes participants with any adverse event, while separate counts address serious adverse events, other adverse events, and deaths. These measures answer related but non-identical questions. None alone conveys every aspect of event frequency, severity, timing, or attribution.

Finally, the registry lists pharmacokinetic outcomes alongside the safety assessment, but their numerical results are not reported in the registry record. This matters because outcome names indicate what was intended for assessment, not what the results were. Careful statistical reading separates prespecified or listed questions from the findings actually posted, and separates observed descriptive patterns from conclusions that require a reported analysis.

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 group sizes are small and differ across the dose and dosing-schedule cohorts. This limits the precision that can be expected from the reported percentages and makes them sensitive to individual outcomes. The registry does not report confidence intervals for the primary endpoint, so the uncertainty around each group percentage is not directly quantified.

The primary safety results are presented as group-level percentages, without a reported formal comparison between RO7049389 and placebo. The registry record does not report adjusted estimates, tests of treatment differences, or an equivalence analysis. Because the SAD and MAD cohorts have separate placebo groups, their results should not be treated as if they came from one common comparison.

The registry record does not report the randomization procedures, allocation concealment, cohort progression rules, detailed statistical analysis plan, sample-size justification, or interim analysis plan. It also does not report how missing assessments or incomplete follow-up were handled, or whether any multiplicity procedure was used. These omissions limit assessment of the planned inferential framework and the completeness of the posted outcomes.

The adverse-event definition includes events regardless of whether they are considered related to treatment. Event-level details, severity distributions, and the serious-event terms are not reported in this record. The results therefore do not describe every dimension needed to characterize adverse events. The listed secondary pharmacokinetic outcomes have no numerical results reported in the registry record, preventing interpretation of those endpoints from the posted information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Double-Blind Single-Ascending Dose (SAD) and Multiple-Ascending Dose (MAD) Study to Investigate the Safety, Tolerability, and Pharmacokinetics of RO7049389 in Healthy Chinese Participants — NCT03570658.
• Registry record last updated 2020-02-28; status last verified 2020-02.
• Results first posted 2020-02-28.
• 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

NCT03570658 is a completed randomized phase 1 study of RO7049389 and placebo in healthy Chinese participants. It used single-ascending-dose and multiple-ascending-dose cohorts and was described as double-blind, sponsor-open, investigator-blinded, and subject-blinded. Enrollment was 31. The recorded start date was 2018-08-24 and the primary completion date was 2019-01-28.

The primary outcome was the percentage of participants with adverse events from first dose through 28 days after the last dose. Percentages were reported for the separate SAD and MAD dose groups. The safety results also report no serious adverse events and no deaths in the listed groups. The registry lists pharmacokinetic secondary outcomes, but their numerical findings, formal arm-comparison analyses, confidence intervals, and detailed statistical methods are not reported in the registry record.