Weight-based Dosing in Hemophilia A: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Weight-based Dosing in Hemophilia A (NCT02586012), a randomized phase 2 study. The primary outcome is Proportion of Subjects Dosed Based on LBM (Lean Body Mass) and TBW (Total Body Weight) Achieving Desired Peak FVIII Recovery..

2. Clinical Question

3. Trial Design

This was a randomized, controlled, open-label, crossover trial listed as phase 2. The registry records enrollment of 30 and a terminated status. Its start is recorded as 2015-09, and primary completion as 2020-01-10. The reason for termination is not reported in the registry record.

Participants were assigned to different sequences of dosing based on total body weight, lean body mass, and ideal body weight. Each sequence description specifies three weeks of dosing, with a different weight basis used in each week. A crossover design means that an individual can receive more than one of the approaches, so results from different dosing conditions may involve the same participants. The outcome counts for each approach should not be read as counts from separate, unrelated groups.

The trial was open label, meaning masking was not used according to the registry. The registry identifies recombinant factor VIII as the intervention. It does not report a washout period, details of adherence, a sequence-specific analysis, or whether the analysis accounted for period or sequence effects. Those aspects should not be inferred from the crossover label alone.

The intended population is described in the study summary as overweight and obese patients with hemophilia, but detailed eligibility criteria and baseline characteristics are not reported in the registry record. The registry also does not explain why enrollment is 30 while the outcome rows list 20 participants for each dosing approach. Since a crossover can have repeated measurements from participants, those row counts cannot be added to infer a number of unique participants.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Subjects receiving rFVIII based on LBM and TBW.

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.

6. Primary Endpoint

The registry lists the primary outcome as Proportion of Subjects Dosed Based on LBM (Lean Body Mass) and TBW (Total Body Weight) Achieving Desired Peak FVIII Recovery., measured over 3 weeks.

The primary endpoint is the count of participants achieving the desired peak factor VIII recovery after dosing based on lean body mass or total body weight. The registry specifies a target recovery value of 2 +/- 0.2 IU/dl per IU/kg, equivalent in its description to 100 +/- 10%, measured at 10 minutes following infusion. Recovery is calculated from weight, observed factor VIII recovery, and dose, then expressed relative to IU/kg.

This is a binary endpoint: each participant's measurement is classified according to whether it meets the stated target. Such an endpoint can make a threshold-based study question easy to interpret, because the result describes how many participants reached a prespecified range. It also loses information: two measurements on opposite sides of the threshold may be close, while two measurements on the same side may be far apart. The registry does not provide the underlying continuous recovery measurements, so the degree by which individual measurements missed or met the target cannot be assessed.

The endpoint concerns a laboratory recovery measurement soon after infusion. It is not itself a measure of bleeding, longer-term factor VIII control, or quality of life. The registry lists those clinical outcomes neither as the primary endpoint nor as results in this record. The target and timing explain what the outcome was intended to measure; they do not establish how well the result predicts longer-term clinical outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study has a binary primary outcome: a participant either met the specified factor VIII recovery target or did not. The registry reports counts rather than a continuous summary of recovery values. A count is directly interpretable as the number meeting the target, but a comparison of counts must also account for how observations were collected and for uncertainty in the estimated difference.

Why the crossover design matters

In a parallel-group trial, each participant generally receives one assigned approach, and groups consist of different people. In a crossover trial, participants receive multiple approaches in sequence. This can help compare conditions within the same person, because stable participant characteristics are shared across the conditions. The trade-off is that measurements from the same person are related rather than independent. A valid analysis may need to account for that pairing, as well as possible period or sequence effects. These are general considerations for crossover studies; the registry does not report the model specification or whether period and sequence were included.

The primary registry analysis is described as a mixed models analysis, and its reported p-value is p < 0.05. Mixed models can represent relationships among repeated observations and can include participant-level structure, depending on the specified model. The model terms, estimation method, assumptions, and treatment of missing observations are not reported in the registry record. A model name alone is not enough to reproduce or fully evaluate the analysis.

What a confidence interval means

In general, a confidence interval describes uncertainty around an estimated effect under a statistical method and its assumptions. A narrow interval indicates greater precision than a wide interval, while an interval that includes no difference is compatible with no difference as well as with effects on either side, subject to the method's assumptions. A p-value and a confidence interval are related summaries, but they are not interchangeable: the p-value does not quantify the size of an effect, and the interval displays a range of estimates compatible with the data and method.

The registry does not provide an estimate or confidence interval for the primary mixed-model comparison. The secondary unadjusted recalculation reports a risk difference of 0.05, a 95% confidence interval from -0.259 to 0.359, and p = 0.752. That recalculation uses posted summary counts and does not reproduce the mixed-model analysis. In a crossover study, an unadjusted comparison that does not use the participant-level pairing may not reflect the same information as an analysis of repeated observations.

Why over-dispersion can matter

In general, over-dispersion means that observed variability is greater than a statistical model expects. When that happens, a model that assumes less variability can make uncertainty appear too small. For binary outcomes, differences in participant risk or clustering can contribute to variability beyond a simple binomial assumption. The registry does not report an over-dispersion assessment or a model specification from which to determine whether it was relevant to this trial. It should therefore be treated as a general analytical consideration, not as a finding about these data.

Secondary binary comparisons are also vulnerable to multiplicity. When multiple outcomes or contrasts are examined, the chance of observing at least one apparently unusual result can increase if tests are interpreted without adjustment. The registry lists multiple outcome measures and reports analyses, but does not report a multiplicity strategy. Unadjusted secondary p-values should consequently be read as exploratory evidence rather than as confirmatory results.

Planning illustrations are not observed power

Planning sample sizes can illustrate how many participants per arm might be needed under stated assumptions and for a chosen effect size. The registry's planning assumptions use a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects defined as fractions of the observed effect. These are planning illustrations, not a measure of the probability that this completed trial detected an effect. They are not observed power, and their relevance depends on whether the assumed effect and design match a future study. The registry does not report the trial's own sample-size justification, so the planning calculations should not be interpreted as the original design rationale.

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("Lean Body Mass")
n      <- c(20)
events <- c(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  Lean Body Mass  20  9  45.0  23.1  68.5  25.8  65.8  25.7  66.0

11. Analyses Reported by the Sponsor

The registry reports the sponsor's primary comparison as a mixed models analysis with p < 0.05. It does not report a model-based effect estimate, confidence interval, or exact p-value. The posted counts are 9 participants meeting the target under lean-body-mass dosing and 6 under total-body-weight dosing, with 20 listed in each condition; these counts do not reveal the within-participant pattern of responses.

The sponsor's analysis is not directly reproduced by the simple recalculation for the secondary comparison. That recalculation compares the posted lean-body-mass and ideal-body-weight counts as an unadjusted binary comparison and reports p = 0.752. It does not use the mixed model or the participant-level crossover structure. The two p-values concern different contrasts and methods, so they should not be treated as conflicting estimates of the same analysis.

For the primary comparison, a recalculated two-group estimate is not reported because the summary data are insufficient for a suitable paired or mixed-model reanalysis. The sponsor's reported mixed-model result is therefore the available registry analysis for that contrast. Since its estimate, uncertainty interval, and model details are absent, the direction and precision of the model-based effect cannot be independently assessed from the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and secondary endpoints, with analyses reported for more than one comparison. When multiple outcomes, contrasts, or analyses are considered, the chance of at least one apparently significant result can rise if each is interpreted using an unadjusted threshold. Statistical plans can address this through prespecified testing hierarchies or multiplicity adjustments. Such a strategy is not reported in the registry record, so the reported p-values should be interpreted without assuming that any correction was used.

Missing-data methods are also not reported. The outcome rows give 20 participants for each dosing condition, while total enrollment is 30. The crossover design means a participant may contribute measurements under more than one approach, but the record does not explain the relation between enrollment and these analysis counts, whether all randomized participants completed all periods, or how missing measurements were handled. It does not report a flow of participants through the study or reasons for any unavailable outcome data.

The analysis population is not described in sufficient detail to identify whether the sponsor used all randomized participants, only participants with observed outcomes, or another defined group. The registry also does not report whether participants were analyzed according to assigned sequence, whether protocol deviations affected inclusion, or how repeated measurements were modeled. These omissions matter because inclusion rules and missing-data assumptions can influence both the estimated effect and its uncertainty.

In general, missing outcomes can lead to bias when the probability that an outcome is observed is related to the outcome itself or to participant characteristics. Statistical methods may address some missingness patterns, but those methods require assumptions. No particular missingness pattern or method can be attributed to this trial from the registry record. Likewise, no interim analyses or stopping rules are reported. The terminated status is recorded, but the reason and any connection to the analysis are not reported in the registry record.

13. 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.

The safety record lists 20 participants at risk under each of the total-body-weight, ideal-body-weight, and lean-body-mass approaches. It reports zero serious adverse events, zero other adverse events, and zero deaths in each listed group. These are the recorded counts for the registry's safety entries; they do not establish that no events could occur or that the approaches have equivalent safety.

Because the trial uses a crossover design, the same participant may be represented under more than one dosing condition. The at-risk counts should not be added to infer the number of distinct people exposed. The registry does not report the exposure duration used for each safety summary, detailed event definitions, or participant-level attribution across periods. It also lists no top serious adverse-event terms.

Zero recorded events in these entries provide limited information about uncommon events, particularly in a study with 30 enrolled participants. The record does not describe additional safety monitoring or provide enough detail to compare risks between dosing approaches. These figures should be read as registry-reported counts, not as a guarantee of safety.

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

The results describe achievement of a laboratory recovery target after factor VIII infusion under different weight-based dosing approaches. The primary outcome is a threshold classification at 10 minutes following infusion. The registry reports the counts meeting that target and a mixed-model p-value for the primary comparison, but not the model-based effect estimate or confidence interval. As a result, the statistical evidence reported by the sponsor cannot be translated from this record into a precise estimate of how much recovery differed.

The endpoint does not directly measure bleeding prevention, treatment burden, longer-term factor VIII levels, or other clinical outcomes. The study summary explains that the research concerns dosing calculations in overweight and obese patients with hemophilia, but the posted primary outcome is recovery rather than a clinical event. No claim about longer-term benefit or comparative clinical effectiveness follows from the target counts alone.

The secondary unadjusted comparison is also uncertain: its confidence interval includes no difference and extends to estimates on either side. It is a recalculation from summary counts, not the crossover mixed-model analysis. The primary mixed-model result and secondary recalculation therefore have different scopes and should not be collapsed into one conclusion.

The record does not report detailed eligibility criteria, participant characteristics, missing-data handling, model specification, or a multiplicity plan. These gaps make it difficult to assess how broadly the result applies or how robust the reported analysis is. The trial's terminated status is recorded, but the reason is not reported. Overall, the registry supports a description of the measurements and analyses posted, while leaving important questions about magnitude, precision, and clinical relevance unresolved.

15. Why This Trial Matters Statistically

This trial presents a useful statistical distinction between the measurement of a biological response and the clinical outcome that a dosing strategy is ultimately intended to influence. The primary endpoint counts participants who meet a specified recovery target shortly after infusion. That may be an informative pharmacologic measure, but it is not the same as demonstrating a difference in bleeding outcomes or other longer-term consequences.

The crossover design also makes the analysis structure important. Since participants receive multiple dosing approaches, comparisons can draw on within-person information, but repeated measurements are correlated. A mixed model may be used to represent such data, yet the model's details are necessary to evaluate what was estimated and how uncertainty was handled. Reporting only a significance threshold leaves readers without the effect size and confidence interval that would convey magnitude and precision.

The comparison between the sponsor's mixed-model result and an unadjusted recalculation illustrates why methods cannot be separated from design. A simple calculation from counts may be useful as a check or descriptive comparison, but it does not recreate a paired analysis when participant-level data are unavailable. The same principle applies to secondary outcomes: multiple comparisons and missing multiplicity information affect how much weight to place on isolated results.

Finally, planning illustrations are distinct from the actual study design and from the evidence observed in the completed trial. Their assumptions can help researchers think about future sample sizes, but they do not establish that the trial was adequately powered or explain why it was designed as it was. This record is statistically instructive because it shows how outcome definition, repeated measurement, model reporting, and precision all shape interpretation.

16. 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.

Several limitations specific to this trial constrain interpretation. The outcome rows list 20 participants for each dosing approach, while enrollment is 30. Because the design is crossover, those rows may include repeated observations from the same people; the registry does not explain the relationship between enrollment, completed treatment periods, and analysis counts. This prevents a clear reconstruction of the participant flow or the number with complete data across all approaches.

The sponsor reports a mixed-model analysis, but the registry does not specify its terms, covariance structure, handling of period and sequence, or approach to missing observations. The primary model's estimated difference and confidence interval are also not reported. Thus, the reported p-value cannot convey the size or precision of the primary effect, and the analysis cannot be independently reproduced from the posted summary information.

The record does not report the trial's sample-size justification, multiplicity plan, interim analyses, or reason for termination. Detailed eligibility criteria and baseline participant characteristics are not reported in the registry record, limiting assessment of generalizability. The study is described as focused on overweight and obese patients with hemophilia, but the record does not provide enough detail to determine which participant characteristics were represented.

The outcome is a recovery target measured shortly after infusion, not a direct clinical endpoint. The registry does not report bleeding outcomes in the posted results. The secondary unadjusted recalculation cannot account for within-participant correlation, and its uncertainty should not be mistaken for the sponsor's mixed-model uncertainty. Finally, the safety entries report zero events in the listed groups but do not provide detailed exposure periods or enough information to assess uncommon harms.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Weight-based Dosing in Hemophilia A — NCT02586012.
• Registry record last updated 2020-09-25; status last verified 2020-09.
• Results first posted 2020-09-25.
• 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.

20. Record Summary

The registry identifies NCT02586012 as a randomized, open-label, phase 2 crossover trial of recombinant factor VIII dosing based on total body weight, lean body mass, and ideal body weight. It records enrollment of 30, a start of 2015-09, primary completion on 2020-01-10, and terminated status. The reason for termination is not reported in the registry record.

The primary endpoint is the count achieving a specified factor VIII recovery target at 10 minutes following infusion. The posted counts are 9 for lean-body-mass dosing and 6 for total-body-weight dosing, with 20 participants listed for each approach. The sponsor reports a mixed-model analysis with p < 0.05, but no effect estimate or confidence interval. Secondary comparisons include ideal-body-weight dosing; available recalculation results are unadjusted and should be interpreted with caution in light of the crossover design and unreported multiplicity and missing-data methods.