Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients (NCT03186677), a non-randomized phase 1 study. The primary outcome is Number of Adverse Events (AEs) After the Administration of Investigational Products (IP).

2. Clinical Question

The design addresses an early-stage safety, pharmacokinetic, and pharmacodynamic question in previously treated patients. The registry also lists maximum plasma concentration and factor IX inhibitor as secondary outcomes. Numerical results for those secondary outcomes are not reported in the registry record. The cohort sequence and the varying routes, doses, and observation periods are central to interpreting the safety information: the cohorts are not interchangeable groups, and repeated cohort participation means a cohort-level count is not necessarily a count of distinct people across the whole study.

3. Trial Design

This was a phase 1, open-label, multicenter, dose-escalation study with non-randomized allocation and a sequential model. It enrolled 11 participants who completed the study, while the registry separately reports 13 unique subjects overall, including 2 who failed screening. The study began on 2017-06-03, reached primary completion on 2018-10-10, and has a completed status.

The five cohorts followed different exposure sequences. Cohort 1 received a single intravenous administration of BeneFIX at 75 IU/kg, then a single intravenous administration of ISU304/CB2679d at 75 IU/kg; each administration was followed by 72 hours of observation. Cohort 2 received intravenous ISU304/CB2679d at 75 IU/kg and then subcutaneous ISU304/CB2679d at 75 IU/kg, each with 72 hours of observation. Cohort 3 received the same intravenous dose followed by a subcutaneous dose of 150 IU/kg, with observation periods of 72 hours and 120 hours, respectively.

Cohort 4 received subcutaneous ISU304/CB2679d at 150 IU/kg once daily for 6 days, followed by 240 hours of observation. Cohort 5 received intravenous ISU304/CB2679d at 75 IU/kg followed by subcutaneous ISU304/CB2679d at 150 IU/kg once daily for 9 days, with 312 hours of observation. This progression means that dose, route, schedule, and observation duration vary across cohorts. Cohort-level results therefore describe those particular exposure sequences, rather than a single uniform regimen. The protocol’s rationale for the sequence and the rules governing dose escalation are not reported in the registry record.

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: There were 11 unique subjects who completed the study; 2 failed screening. Of the 5 subjects in Cohort 4, 1 subject previously participated in Cohort 1 and 2 subjects in Cohort 2. Of the 2 subjects in Cohort 5, 2 subjects previously participated in Cohort 4. As a result, the Safety Analysis Set included 16 subjects. Cohorts were conducted in numerical order.

Period 1

Period 2

Analysis population for the primary outcome, as defined in the registry: There were 13 unique subjects in the study: 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. 16 subjects were included in the Safety Analysis Set across 5 cohorts.

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: There were 13 unique subjects in the study: 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. Baseline characteristics are reported according to the initial cohort to which subjects were assigned. The 2 subjects who participated in Cohort 5 were previously in Cohort 4.

6. Primary Endpoint

The registry lists the primary outcome as Number of Adverse Events (AEs) After the Administration of Investigational Products (IP), measured over Through study completion, an average of 8 days.

The primary endpoint counts adverse events after administration of investigational products, with reported events categorized as local, systemic, or other and calculated by cohort. The stated timeframe is through study completion, an average of 8 days. An adverse-event count is a safety description: it records reported events, rather than measuring whether a treatment improved a clinical outcome.

General statistical context: event counts can help describe the types and frequency of problems observed during early exposure, which is relevant in a phase 1 dose-escalation study. A count of events is not necessarily the same as a count of affected participants. One participant may have more than one event, and participants may differ in their duration of exposure or observation. For that reason, interpreting counts may require information about events per participant, exposure time, event severity, and recurrence. Those detailed endpoint results are not reported in the registry record.

The registry’s cohort-specific safety figures report how many subjects were affected by serious and other adverse events, but those affected-subject figures should not be mistaken for the primary endpoint’s total number of events. The actual cohort-level event totals for the primary endpoint are not reported in the registry record. The endpoint is therefore defined, but its reported count results cannot be reconstructed from the affected-subject figures alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What the endpoint counts. The primary outcome is defined as the number of adverse events after investigational product administration, calculated by cohort. The registry identifies local, systemic, and other events as part of its description and gives a timeframe through study completion, an average of 8 days. This is a count outcome, not a continuous measurement such as a laboratory concentration. The registry record does not report the observed event totals for this endpoint, so an event-count analysis cannot be reproduced from the posted safety figures alone.

Events and affected subjects are different quantities. General statistical context: the number of events may exceed the number of people affected when a person has recurrent events. Conversely, a participant-level indicator of whether someone had any event records affected people but not the number of events each person experienced. The registry’s serious and other safety figures are presented as subjects at risk and subjects affected. They do not reveal how many events occurred in each category. Treating those figures as event totals would conflate distinct outcomes.

Why counts may need context. General statistical context: count data are often unevenly distributed, because many participants may have no events while a smaller number experience multiple events. If variability exceeds what a simple count model expects, over-dispersion can make standard errors too small and confidence intervals too narrow unless the model accounts for it. Repeated events within a person may also be correlated rather than independent. Analyses may therefore need participant-level data and an appropriate model for recurrence, exposure, and clustering. The registry record does not report an event-count model, estimates, confidence intervals, or an inferential analysis.

Different exposure and observation. The cohorts used different doses, routes, schedules, and follow-up windows. General statistical context: raw event counts are difficult to compare when exposure opportunities differ. A participant observed for longer, or receiving more administrations, may have more opportunity for an event to be recorded. Exposure-adjusted rates or clearly defined participant-level summaries can address some of this issue, but the registry record does not report such rates or analyses. In addition, some completers participated in multiple cohorts, which creates within-person dependence across cohort observations. The record does not describe an analysis that accounts for that dependence.

Design and comparison. Non-randomized allocation and sequential dosing mean the cohorts are not exchangeable by design. General statistical context: randomization can balance measured and unmeasured characteristics on average, while sequential designs do not guarantee that comparability. Here, Cohort 1 received BeneFIX before ISU304/CB2679d; that order does not constitute random assignment to a concurrent control group. Comparisons between cohorts would also be complicated by different administration schedules and observation periods. The registry itself warns that the arms are not a like-for-like control comparison. An adjusted comparative analysis is not reported in the registry record.

Precision and uncertainty. A confidence interval, in general, describes a range of values compatible with an estimate under the assumptions of the statistical method. It can communicate uncertainty that a point estimate alone does not. No confidence interval for the primary adverse-event endpoint is reported in the registry record. Given the small cohort sizes, any cohort-specific proportion or rate would have substantial uncertainty; the posted counts should not be read as precise estimates of event risk in a broader population. No inferential tests or analysis estimates are reported.

Planning illustrations. The stated assumptions for planning illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the detectable effect set as a stated fraction of the observed effect. For time-to-event tables, the stated quantity is total events; for other tables, it is participants per arm. These are planning illustrations computed from the observed effect, not the trial’s own design or observed power. The record does not report a trial-specific sample-size justification, and the non-randomized sequential cohorts do not form a like-for-like two-arm comparison. No cohort-specific planning values are reported in the registry record.

Analysis details. The registry record reports no analyses. The statistical analysis plan, including the handling of recurrent events, censoring or incomplete observation, covariate adjustment, and prespecified subgroup analyses, is not reported in the registry record. Without those details and participant-level results, the endpoint definition and safety counts can be described, but not independently recalculated or used to establish a model-based estimate.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists the number of adverse events as the primary outcome and maximum plasma concentration and factor IX inhibitor as secondary outcomes. Numerical results for the secondary outcomes are not reported in the registry record. The registry record also reports no analyses, so it does not provide a statistical testing framework or estimates from which to assess whether any formal comparisons were made.

Multiplicity arises when several outcomes, time points, dose groups, or statistical comparisons are examined. General statistical context: conducting multiple tests can increase the chance of at least one apparently notable result even when no underlying effect exists. Prespecifying a primary outcome and a testing strategy can help readers distinguish confirmatory analyses from exploratory ones. The record identifies a primary outcome, but adjustment for multiple comparisons, outcome hierarchies, and any multiplicity strategy are not reported in the registry record. No claim about adjusted or unadjusted significance can be made from the available information.

The registry states that 13 unique subjects were in the study, 11 completed it, and 2 failed screening. Five completers participated in multiple cohorts, and 16 subjects were included in the Safety Analysis Set across the cohorts. The reasons for the difference between the unique-subject count and the Safety Analysis Set count are not detailed beyond the cohort participation information. The handling of missing endpoint observations, withdrawals after treatment, incomplete observation, or missing secondary-outcome measurements is not reported in the registry record. Nor is the analysis population for each secondary outcome described.

These omissions matter because missing outcome data can affect both event counts and the set of people contributing to a summary. General statistical context: interpretation depends on whether unavailable observations are related to participants’ health, exposure, or event experience, and on the assumptions used to handle them. No missing-data method or sensitivity analysis is reported in the registry record. The safety figures should therefore be understood as the posted cohort-specific descriptions, without assuming that unreported observations were absent or handled in a particular way.

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 non-serious adverse event terms

The serious adverse-event figures report 0 affected subjects in each cohort: Cohort 1 had 3 subjects at risk, Cohort 2 had 3, Cohort 3 had 3, Cohort 4 had 5, and Cohort 5 had 2. The record also reports 0 deaths. These numbers describe what was recorded in the study’s safety groups; they do not show that the risk of a serious event is zero outside the observed study experience.

The “other” adverse-event figures report 0 affected subjects in Cohort 1, 3 in Cohort 2, 3 in Cohort 3, 5 in Cohort 4, and 2 in Cohort 5. These are affected-subject counts, not total event counts. The registry does not list serious-event terms, and the actual number of events for the primary endpoint is not reported in the registry record.

General statistical context: when no event is observed in a small group, uncertainty about the underlying event risk remains. The cohort sizes are small, and participants could contribute to more than one cohort. Different exposure schedules and observation periods also affect how the counts should be interpreted. These figures are descriptive and should not be taken as a precise estimate of safety in a wider population or as a randomized comparison.

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

The registry describes a phase 1 study that collected safety information while examining the pharmacokinetics and pharmacodynamics of ISU304/CB2679d in previously treated patients with hemophilia B. Its posted serious adverse-event figures show no affected subjects in any cohort and no deaths. The other adverse-event category includes affected subjects in Cohorts 2 through 5, while Cohort 1 has none recorded in that category. Those are cohort-level affected-subject observations, not the primary endpoint’s total event counts.

The results do not establish that a product is safe or unsafe in general. General statistical context: absence of a recorded event in a small study is not evidence that the event cannot occur, and the precision of a risk estimate depends on the amount and structure of the observed data. Here, cohort sizes are small, exposures differ, and some completers appear in multiple cohorts. The record does not report confidence intervals or inferential analyses for the safety endpoint.

The design also does not support a causal comparison between BeneFIX and ISU304/CB2679d. BeneFIX was used before ISU304/CB2679d in Cohort 1, and allocation was non-randomized. The sequence is not a concurrent randomized comparison, and the record explicitly cautions against treating the arms as like-for-like controls. Cohort differences cannot be attributed to product differences on the basis of these figures alone.

The record lists maximum plasma concentration and factor IX inhibitor as secondary outcomes, but numerical results are not reported in the registry record. Nor are primary adverse-event totals, an analysis plan, or missing-data methods reported. The study therefore provides a limited descriptive account of safety observations and design, rather than a complete statistical basis for conclusions about comparative effects, precision, or outcomes beyond the recorded study experience.

13. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the interpretive limits of early-phase, sequential dose-escalation evidence. In phase 1 research, cohort-level safety observations can document what was reported during defined exposures. But small groups, different dosing schedules, and non-randomized allocation limit how far those observations can be generalized or compared. The registry’s warning that the arms are not a like-for-like control comparison is important when reading any cohort differences.

The study also distinguishes two kinds of safety summaries that are easy to confuse. The primary endpoint is the number of adverse events, while the safety figures report how many subjects were affected by serious and other events. Counts of events and counts of affected subjects answer different questions. Because the primary event totals are not reported in the registry record, the listed affected-subject counts cannot stand in for the defined endpoint.

Repeated participation is another relevant feature: 5 of the 11 completers were in multiple cohorts, while 16 subjects were included in the Safety Analysis Set across 5 cohorts. Cohort-level rows therefore do not necessarily represent separate sets of people. This complicates simple comparisons and any interpretation that assumes independent groups.

Finally, the record demonstrates why statistical conclusions depend not only on outcome labels but also on analysis details. The analysis plan, inferential results, confidence intervals, and handling of missing data are not reported in the registry record. The posted information supports a careful descriptive reading, while leaving important questions about precision and analysis methods unresolved.

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 main limitation is that the primary endpoint is defined but its actual cohort-level event counts are not reported in the registry record. The safety figures provide affected-subject counts for serious and other adverse events, which are not equivalent to the number of events. Serious-event terms are not listed. Numerical results for the secondary outcomes—maximum plasma concentration and factor IX inhibitor—are also not reported.

The cohort groups are small and have different exposure patterns. Dose, route, number of administrations, and observation duration vary among cohorts. In addition, 5 of the 11 completers participated in multiple cohorts, so cohort observations may include the same individual more than once. These features limit simple comparisons and make it inappropriate to treat cohort counts as independent observations from distinct groups.

Allocation was non-randomized and sequential, with no masking. BeneFIX was administered before ISU304/CB2679d in Cohort 1, rather than as a randomized concurrent control. The registry cautions that the arms are not a like-for-like comparison. Accordingly, differences between cohort observations cannot be interpreted as causal product effects from the posted information.

The registry reports no analyses. The statistical analysis plan, sample-size justification, handling of missing observations, exposure-adjusted event rates, confidence intervals, and methods for accounting for repeated events or repeated cohort participation are not reported in the registry record. The duration of follow-up is described for each schedule and as an average of 8 days for the primary endpoint timeframe, but detailed participant-level follow-up and event timing are not reported. These limitations leave uncertainty about the precision and completeness of the safety summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients — NCT03186677.
• Registry record last updated 2020-11-10; status last verified 2020-10.
• Results first posted 2020-11-10.
• 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

NCT03186677 is a completed phase 1, open-label, multicenter, non-randomized, sequential dose-escalation study of ISU304/CB2679d in previously treated patients with hemophilia B. The study began on 2017-06-03 and reached primary completion on 2018-10-10. It enrolled 11 participants who completed the study; the registry also reports 13 unique subjects overall, including 2 who failed screening. Five completers participated in multiple cohorts, and 16 subjects were included in the Safety Analysis Set across 5 cohorts.

The primary outcome was the number of adverse events by cohort through study completion, an average of 8 days. The posted safety figures report no subjects affected by serious adverse events and no deaths, alongside cohort-specific counts for other adverse events. The primary event totals, numerical secondary-outcome results, and statistical analyses are not reported in the registry record. Because exposure schedules differ and allocation was not randomized, the cohort figures are descriptive rather than a like-for-like comparative analysis.