A Phase I- Sequential Cohort Dosing to Determine Maximum Tolerated Dose in Healthy Male Volunteers.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase I- Sequential Cohort Dosing to Determine Maximum Tolerated Dose in Healthy Male Volunteers. (NCT01955564), a randomized phase 1 study. The primary outcome is Physical Examination Shift Table.

2. Clinical Question

The registry describes a prospective, randomized, double-blind, placebo-controlled, sequential-cohort study lasting 8 days. The central statistical challenge is that doses were examined in separate cohorts rather than as one simple two-arm comparison. The primary outcome is a count of participants reported abnormal at the end of the study, while adverse-event data are also reported by cohort and for placebo.

The record reports a trial enrollment of 54 and describes six independent cohorts. However, the available primary outcome is presented as counts by placebo and cohort, not as an adjusted dose-response analysis. No inferential result or formal estimate comparing NW-3509A with placebo is reported in the registry record.

3. Trial Design

This was a Phase I, randomized, triple-masked, parallel-design study. Its official description characterizes it as prospective, double-blind, placebo-controlled, sequential-cohort, escalating, and single-dose. The study was designed to evaluate safety and tolerability and to determine the maximum tolerated oral dose of NW-3509A in healthy male volunteers. The registry reports that the study is completed.

Six independent cohorts were described, with planned dose levels of 1mg, 2mg, 5mg, 10 mg, 20 mg, and 30 mg of NW-3509A, each against placebo. The brief summary says that each cohort included 12 volunteers, with the first 9 volunteers to qualify randomized to study medication and the remaining 3 used as backups or alternates. It also describes an allocation of 6 to NW-3509A and 3 to placebo within each cohort. The outcome records, however, report placebo as a group and report the six dose cohorts separately.

The record lists enrollment as 54. Study dates are reported as 2013-06 for start and 2014-09 for primary completion. The planned study duration is described as 8 days, with physical examinations spanning Day -1 (pre-dose) through Day 8 (discharge). The record does not give a detailed account of the randomization procedure, masking roles, or how escalation decisions were made. Those details are not reported in the registry record.

Because each dose is associated with its own cohort, comparisons across dose levels are not interchangeable with a single pooled treatment-versus-placebo contrast. The posted outcome groups retain the cohort structure, and the data do not include an analysis that models dose as an ordered exposure. The registry lists two secondary outcomes concerning maximum plasma concentration and total drug exposure over time, but it does not post their results in the outcome data.

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.

Only the first 6 of 7 groups are shown.

Overall 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: 9 healthy volunteers were assigned per cohort, within which 6 subjects received NW-3509A and 3 subjects received placebo by randomised selection.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Physical Examination Shift Table, measured over Day -1(pre-dose) through Day 8 (Discharge).

The primary outcome is titled “Physical Examination Shift Table” and is measured as the number of participants abnormal at the end of the study. Physical examinations covered lymph nodes, mouth, neck, nervous system, nose, skin, and throat, with the stated timeframe running from Day -1 (pre-dose) through Day 8 (discharge).

Physical examination findings can be used in an early-phase safety assessment to describe whether abnormalities were recorded during the observation period. A count of participants abnormal at the end of the study is a categorical, count-based summary: it reports how many participants in each group met the stated abnormality condition at that assessment. It is different from a continuous measure such as a laboratory value, and it does not directly quantify the severity, duration, or clinical importance of a finding.

Although the endpoint title uses the term “shift table,” the posted outcome description specifies the number abnormal at end of study. The record does not provide the underlying categories, the individual transitions from pre-dose status to end-of-study status, or definitions for classifying an examination as abnormal. Those details are not reported in the registry record. Therefore, the posted endpoint supports a descriptive reading of the end-of-study counts, but not a reconstruction of participant-level changes over time.

The endpoint was selected within a study whose stated aim was safety and tolerability after a single escalating dose. It is only one part of that assessment. Its counts should be read alongside the adverse-event information and the study’s limited observation window, rather than as a complete account of safety or as a measure of efficacy.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a count: participants classified as abnormal at the end of the study. Counts and proportions are commonly used for binary outcomes, where each participant is classified into one of two outcome states. In this record, only the number abnormal and the group size are available. No model-based estimate or inferential comparison is posted.

What does a count show?

A count conveys the number of participants meeting the endpoint definition in each group. Its interpretation depends on both the count and the group size. A count alone does not show the uncertainty around the underlying proportion, nor does it describe the timing, severity, or cause of an abnormal finding. The endpoint description names the physical examination areas and assessment timeframe, but the criteria for abnormality and the transition details are not reported in the registry record.

In general, an interval estimate can express the range of values compatible with observed data under a stated statistical method. For a count outcome, an interval around a proportion may help communicate uncertainty more clearly than a point estimate alone, especially when groups are small. No confidence interval is reported for this endpoint, and no interval should be inferred from the posted counts as though it were part of the registry result.

Why are the cohorts kept separate?

The trial uses sequential cohorts at distinct dose levels. Keeping the cohort results separate preserves the structure of the study and makes clear which dose level each group represents. Combining all dose cohorts into one treatment group would discard dose distinctions and could obscure a pattern that might be relevant to dose escalation. Conversely, comparing each cohort individually with the placebo group creates several possible comparisons and does not by itself provide a single overall treatment effect.

There is no posted statistical analysis that accounts for the cohort structure or estimates a dose-response relationship. The record does not report the statistical method used to assess escalation, nor does it report a formal maximum-tolerated-dose decision rule. These details are not reported in the registry record. As a general point, a dose-response model requires a specified relationship between dose and outcome; simply listing counts at increasing doses does not establish such a relationship.

What does “not estimable” mean in this record?

The registry information indicates that values are missing or not estimable for a two-arm comparison of this count endpoint. That means the available record does not support presenting the requested two-group comparison as a calculated result. It does not mean that a difference has been demonstrated to be zero. No inferential analyses are posted, so a p-value or comparative confidence interval cannot be interpreted from this outcome record.

For orientation, general methods for binary outcomes include tests or regression models that compare group proportions. Such methods depend on design choices and assumptions, including how groups are defined and whether adjustment is needed. In studies with small counts, some methods may perform poorly or require exact approaches. The registry does not identify a chosen method for this endpoint; the statistical method is not reported in the registry record.

How should the planning illustration be read?

The registry describes the basis for planning illustrations: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a stated fraction of the observed effect. Such an illustration is a planning calculation, not an observed analysis and not a report of achieved power. Any sample-size values are not stated in the registry record described for this result, so no specific planning number can be interpreted.

More generally, a sample-size illustration based on an observed effect depends on that effect estimate and on the assumed fraction to be detected. It does not establish that the original study was designed with those assumptions, and it cannot substitute for a reported design justification. The registry record does not report the original sample-size justification. No observed power should be inferred from these data.

In sum, the principal statistical evidence available for the primary endpoint is descriptive: counts by placebo and dose cohort. General statistical principles explain why denominators, uncertainty, group structure, and analysis choices matter, but they do not create an inferential result that is absent from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry reports three outcome measures and identifies two secondary outcomes: maximum plasma concentration of NW-3509A at doses tested and total drug exposure over time (AUC0-t) at doses tested. Their results are not included in the posted outcome information. The primary outcome is the physical examination count. The record does not identify a hierarchy of outcomes, a prespecified testing sequence, or a multiplicity adjustment. These details are not reported in the registry record.

Multiplicity is a general statistical concern when several outcomes, groups, time points, or comparisons are examined. The more opportunities there are to identify an apparently notable result, the more important it is to state which analyses were planned and how interpretation accounts for multiple testing. In this trial, the separate dose cohorts make the choice of comparisons especially relevant, but no inferential comparisons are posted. It is not possible to determine from the record whether multiplicity was addressed in an analysis plan.

The registry record also does not report how missing endpoint information was handled, whether all randomized participants were included in each outcome, or the definitions of any analysis populations. The brief summary describes backup or alternate volunteers, but the outcome information does not explain how such participants were treated in analysis. These details are not reported in the registry record.

In general, missing-data methods should match the outcome and the reason information is missing. Excluding participants, carrying values forward, or using a model can lead to different interpretations, so the chosen approach matters. No missing-data method can be attributed to this trial from the reported details. The endpoint counts should therefore be read as the posted group summaries, without assuming a particular population definition or imputation method.

11. Safety Results

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

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 serious adverse-event data report 0 affected participants in the placebo group and 0 in each of Cohorts 1 through 6. The registry lists 18 participants at risk for serious adverse events in placebo and 6 in each cohort. These are the posted serious-event counts; they do not establish that no serious event occurred outside the information captured in this outcome record.

The “other” adverse-event counts are 6 for placebo and 3, 1, 3, 2, 5, and 3 for Cohorts 1 through 6. The at-risk group sizes are 18 for placebo and 6 for each cohort. These figures describe participants affected, not the total number of separate event episodes. The registry record does not provide event terms for these counts in the information.

Deaths are not reported as numeric values in the adverse-event record. Their status is therefore not reported in the registry record, and it should not be restated as a confirmed absence of deaths. Small cohort sizes and the study’s single-dose, 8-day design limit how much can be concluded from zero serious-event counts. As a general statistical point, observing no events in a small group does not rule out an underlying risk; the precision of any risk estimate would be limited.

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

The results describe the counts recorded for a short, single-dose study of NW-3509A in healthy male volunteers. The primary physical examination outcome reports some groups with participants classified as abnormal at the end of the study and some groups with none recorded. The adverse-event summary reports serious-event counts of zero across the listed groups and non-serious “other” adverse events in each group. Those descriptions are the extent of the reported findings; no comparative statistical analysis is posted.

These data do not establish that a finding was caused by the study drug, nor do they demonstrate that the groups were equivalent. A lack of a reported inferential comparison is not evidence of no difference. Likewise, the separate cohort counts do not establish a dose trend. Any interpretation of a dose pattern would need to account for the small group sizes, cohort structure, outcome definitions, and uncertainty, none of which is resolved by the descriptive counts alone.

The study’s stated aim was safety, tolerability, and maximum tolerated dose assessment. However, the registry record does not report a maximum tolerated dose conclusion or the escalation decision process. The available values cannot be used to supply that conclusion. Other desired outcomes, including pharmacokinetic measures listed as secondary outcomes, are also not reported in the posted results.

The record applies to a specific setting: healthy male volunteers receiving a single oral dose, with examinations spanning Day -1 through Day 8. It does not provide evidence about longer treatment, other populations, or clinical effectiveness. Although schizophrenia is listed as a condition, the described study population is healthy male volunteers; the record does not describe a treatment-effect assessment among people with schizophrenia.

Overall, the posted counts are useful as a transparent descriptive record of what was reported by group. Their role should remain descriptive unless additional analysis methods, uncertainty estimates, outcome definitions, and participant-level context are available. They do not by themselves support broad conclusions about safety or treatment effects.

13. Why This Trial Matters Statistically

This trial illustrates a common challenge in early-phase studies: dose is organized through sequential cohorts, but readers may encounter outcome summaries that invite simple comparisons. A cohort-specific count is easy to describe, yet it is not automatically a dose-response estimate. The distinction matters because each cohort represents a separate dose level, while placebo is reported as a group in the posted outcome data.

The study also shows why a clear endpoint definition is important. A physical examination “shift table” title suggests change categories, but the posted measure is the count abnormal at the end of the study. Without the underlying transitions or abnormality criteria, the result has a narrower interpretation than the title alone might imply. Precise descriptions help prevent readers from treating an endpoint count as a measure of change, severity, or causation.

Small groups make uncertainty a central part of interpretation. A zero count in a cohort can be stated exactly, but it should not be mistaken for proof that the underlying event cannot occur. Likewise, differences between counts across dose groups are descriptive unless an analysis evaluates them with appropriate methods and uncertainty. The registry does not post such an analysis for this endpoint.

Finally, the record distinguishes study intent from reported evidence. It describes an aim to determine a maximum tolerated dose and lists pharmacokinetic secondary outcomes, but those conclusions and results are not present in the posted outcome information. For clinical researchers, this is a reminder to separate protocol objectives from analyses and outcomes actually reported. Clear reporting of populations, definitions, missing-data handling, methods, and uncertainty is essential to making early-phase results interpretable.

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 available primary outcome is a count of participants abnormal at the end of the study, but the registry does not provide the criteria for abnormality, participant-level shifts, or severity of findings. This limits interpretation of what the counts represent and whether they reflect newly observed findings or changes from pre-dose status.

The study has small dose-cohort groups, and the outcome data do not include confidence intervals or a formal comparison. The record also indicates that a two-arm comparison was not estimable for this count endpoint. As a result, the reported values support description, not a precise estimate of differences among doses or versus placebo.

The design is a single-dose study with a stated 8-day duration in healthy male volunteers. The results therefore do not describe longer exposure or populations beyond the described participants. Although schizophrenia is listed as a condition, the study description identifies healthy male volunteers as the population; the record does not report a clinical outcome assessment in people with schizophrenia.

The registry lists maximum plasma concentration and total drug exposure over time as secondary outcomes, but their results are not reported in the outcome information. It also does not report the maximum tolerated dose determination, the escalation rule, a statistical analysis plan, multiplicity handling, missing-data methods, or analysis population definitions. These gaps limit assessment of how the posted counts relate to the trial’s objectives and intended analyses.

Deaths are not given as numeric results, and no event-term detail is available for the “other” adverse-event counts. Those aspects cannot be interpreted beyond the information recorded. These are limitations of what is reported in the registry record, not evidence that unreported analyses or events did or did not occur.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase I- Sequential Cohort Dosing to Determine Maximum Tolerated Dose in Healthy Male Volunteers. — NCT01955564.
• Registry record last updated 2017-06-20; status last verified 2017-04.
• Results first posted 2017-06-20.
• 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

NCT01955564 is a completed Phase I randomized, triple-masked, parallel, placebo-controlled study of single escalating oral doses of NW-3509A in healthy male volunteers. The registry reports enrollment of 54 and describes six sequential dose cohorts. The study began in 2013-06, with primary completion in 2014-09, and the planned study duration was 8 days.

The primary outcome is the number of participants abnormal at the end of the study on physical examination, assessed from Day -1 (pre-dose) through Day 8 (discharge). The posted outcome counts are reported for placebo and each cohort. Serious adverse-event counts are 0 across the listed groups; other adverse events are also reported by group. No statistical analyses are posted, and a two-arm comparison for the primary count endpoint is not estimable in the registry outcome information. The registry lists pharmacokinetic secondary outcomes but does not report their results in the available outcome data.