A Study About How TAK-881 is Processed by the Body and Side Effects in People With Primary Immunodeficiency Diseases: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study About How TAK-881 is Processed by the Body and Side Effects in People With Primary Immunodeficiency Diseases (NCT05755035), a randomized phase 2, phase 3 study. The primary outcome is Area Under the Curve Over One Dosing Interval at Steady-State (AUC0-tau;ss) of Total IgG Levels With TAK-881 and HYQVIA Treatment in Participants >= 16 Years.

2. Clinical Question

The trial addresses a pharmacokinetic comparison rather than a direct test of whether one treatment prevents more infections or improves health more than the other. AUC0-tau;ss captures the total measured IgG concentration over a dosing interval at steady state. The registry reports geometric mean AUC values and a sponsor-reported equivalence analysis for the adult crossover comparison.

The adult design allows each participant to receive both treatments in different epochs, with participants assigned to one of two treatment sequences: TAK-881 followed by HYQVIA, or HYQVIA followed by TAK-881. This makes the treatment comparison within-person in design, although the posted primary analysis includes only participants who received both treatments and had evaluable pharmacokinetic profiles in both epochs without protocol violations that could affect the IgG time profiles.

The pediatric results answer a different, more limited question. Children aged 2 to under 16 received TAK-881 without a randomized HYQVIA treatment epoch. Consequently, the pediatric observations describe outcomes during TAK-881 treatment but do not provide a randomized treatment contrast with HYQVIA in that age group. The record lists infection outcomes for both age groups, but those groups differ in age and treatment design, so their estimates should not be read as a randomized comparison.

3. Trial Design

This was a multicenter, prospective, open-label, randomized crossover study of TAK-881 in people with primary immunodeficiency diseases. The registry lists Phase 2 and Phase 3 and an enrollment of 65. The study status is completed. Participants and investigators were not masked, and the allocation was randomized.

Adults aged 16 years and older entered one of two treatment sequences. One sequence received TAK-881 followed by HYQVIA; the other received HYQVIA followed by TAK-881. The study description says adult participants were treated with the same immunoglobulin dose and dosing interval across the treatment comparison. Adult treatment was planned for up to 51 weeks. The posted primary pharmacokinetic analysis uses participants who received all infusions in both crossover epochs and had evaluable profiles in each epoch, with no protocol violations judged to affect the reliability of the IgG profiles.

Pediatric participants aged 2 to under 16 were treated with TAK-881 in a single-arm treatment epoch, for up to 27 weeks. They did not contribute a HYQVIA comparison. The registry summary describes clinic visits every 3 or 4 weeks during the study. It also describes full-dose infusions after ramp-up; the exact protocol details beyond the information in the registry record are not reported in the registry record.

The primary outcome was assessed during the dosing interval after the last dose in each adult crossover epoch. The measurement schedule differed by dosing interval: the registry describes sampling through day 21 for a 3-week interval and through day 28 for a 4-week interval. The primary analysis population was the Pharmacokinetic Per-Protocol Analysis Set. The registry record does not report the rationale for the enrollment target, the planned statistical analysis details beyond the posted outcome descriptions, or whether interim analyses were conducted.

Although randomization applies to the adult treatment sequence, it does not make the pediatric single-arm results a randomized comparison. The study also was open-label, which is relevant when interpreting outcomes that involve reporting or clinical assessment. The registry record does not report blinding of outcome assessment.

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 aged greater than or equal to \[\>=\]16 years were randomized at a 1:1 ratio in the crossover part to one of the following treatment sequences: TAK-881 followed by HYQVIA (Sequence 1 \[AB\]) or HYQVIA followed by TAK-881 (Sequence 2 \[BA\]). Pediatric participants aged 2 to less than \[\<\] 16 years received treatment with the study drug (TAK-881 only) in a single-arm part.

Treatment Period 1: Week 1 to Week 25

Reasons for not completing this period:

Treatment Period 2: Week 25 to Week 49

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Per-Protocol Analysis Set (PKPPAS) included all participants who received all TAK-881 and HYQVIA infusions with evaluable PK profiles in both crossover epochs and who had no protocol violations that may affect the reliability of the IgG level time profiles.

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: The safety analysis set (SAS) included all participants who received any amount of TAK-881 or HYQVIA. As pre-specified in the statistical analysis plan (SAP), baseline characteristics data were summarized by age group.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Curve Over One Dosing Interval at Steady-State (AUC0-tau;ss) of Total IgG Levels With TAK-881 and HYQVIA Treatment in Participants >= 16 Years, measured over During the dosing interval of 8th dose (3-week) or 6th dose (4-week): 3-week dosing - Day 1 (pre & post-infusion), 24,48,72 hours, 7,14,21 days (post-infusion); 4-week dosing - Day 1 (pre & post-infusion), 24,48,72 hours, 7,14,21,28 days (post-infusion).

The primary endpoint, AUC0-tau;ss, measures the area under the total IgG concentration-time curve over one dosing interval at steady state. In practical terms, it combines the concentrations measured at the scheduled time points across the interval into a summary of overall IgG exposure, rather than focusing on one concentration measurement alone. The registry specifies that the measure was calculated after the last dose in each adult crossover epoch using non-compartmental analysis.

This endpoint is useful for comparing pharmacokinetic exposure between treatments. A geometric mean is used because exposure values are commonly summarized on a multiplicative scale; the reported confidence intervals describe uncertainty around the treatment-specific geometric means. The adult results are 326.0 day*g/L for TAK-881, with a 95% confidence interval from 296.0 to 359.0, and 327.0 day*g/L for HYQVIA, with a 95% confidence interval from 297.0 to 360.0.

These estimates describe IgG exposure in the analysis population, not clinical benefit. The endpoint does not by itself establish whether infection rates, symptoms, tolerability, or other patient outcomes differ between treatments. The registry record reports the endpoint for participants aged 16 years and older; it does not report a corresponding primary endpoint comparison for the pediatric single-arm cohort.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: A crossover study assigns participants to treatment sequences and measures outcomes during more than one treatment epoch. The adult design compares TAK-881 and HYQVIA within participants, which can reduce the influence of stable participant characteristics on a treatment contrast. Interpretation still depends on the planned analysis and on whether treatment sequence, period effects, or carryover were addressed. Those analysis details are not reported in the registry record, so no claim can be made about how they were handled.

The primary outcome is a pharmacokinetic summary. AUC0-tau;ss is the area under the concentration-time curve across one dosing interval at steady state. The registry says that it was calculated by non-compartmental analysis using total IgG levels after the last dose in each crossover epoch. This approach summarizes exposure over the interval rather than treating each sampled concentration as an independent endpoint. The reported treatment-specific summaries are geometric means, with 95% confidence intervals. In general, a confidence interval expresses uncertainty around an estimate under the assumptions of the analysis; it is not a guarantee that the true value lies within the interval.

The sponsor’s primary comparison is reported as a geometric mean ratio with a 90% confidence interval and classified as an equivalence analysis. For a ratio, the no-difference reference is the value at which the two treatments have equal estimated exposure. An equivalence conclusion normally depends on whether the confidence interval lies within prespecified equivalence bounds. The record includes the ratio analysis but does not report those bounds or the decision rule. It is therefore possible to describe the reported analysis and its interval, but not to verify the formal equivalence criterion from the registry record alone.

For annualized rates, the posted outcome summaries give mean events per participant year with 95% confidence intervals. Recalculated rate comparisons use the arm-level summaries and are unadjusted. A rate ratio compares the estimated event rates in two groups; a value at the no-difference reference indicates equal rates, while values on either side indicate the direction of the contrast. These recalculations are not the sponsor’s reported inferential analyses. The registry lists no sponsor-reported analyses for the secondary outcomes.

General statistical explanation: Count outcomes are often analyzed with Poisson methods, which relate event counts to time at risk. The recalculations use a Poisson basis. Such methods rely on assumptions about the relationship between the mean and variability of event counts. Over-dispersion, meaning more variation than the Poisson model expects, can make standard uncertainty estimates too small if not addressed. The registry record does not report whether over-dispersion was assessed or whether an alternative variance method was used in the trial’s own analysis.

Some secondary outcomes are uncommon. When few events occur, estimates can be unstable and confidence intervals can be wide. A group with no observed events does not establish that the underlying event rate is zero; the posted HYQVIA acute serious bacterial infection rate is 0.0, with a 95% confidence interval from 0.0 to 0.214. The interval indicates uncertainty despite the zero point estimate. Comparisons based on sparse counts should therefore be read with attention to the interval, not only the point estimate or p-value.

The recalculated p-values for secondary rate comparisons are unadjusted. A p-value assesses compatibility with a specified null hypothesis under the analysis assumptions; it does not measure the size or clinical importance of an effect. With several outcomes and comparisons, some small p-values may occur by chance. The registry record does not report a multiplicity strategy, so these results do not carry the same weight as a prespecified, multiplicity-controlled primary analysis.

The sample-size illustrations are planning calculations based on observed effects, not the trial’s enrollment rationale or observed power. They assume a two-sided significance level of 0.05, equal allocation, and a normal approximation, and consider effects set at stated portions of the observed effect. Such calculations can show how planning requirements change as an assumed effect becomes smaller, but they do not establish that the trial had a particular probability of success. The registry record does not report the trial’s own sample-size justification or the assumptions used when enrollment was planned.

The analysis population matters as well. The primary pharmacokinetic population excludes participants who did not meet the stated completion and evaluability criteria. The registry record does not report how missing concentrations, incomplete treatment epochs, or other missing outcome data were handled. It also does not report whether the secondary rate estimates were adjusted for baseline characteristics or differences in follow-up. Those omissions limit independent assessment of the analysis beyond the stated endpoints and posted summaries.

10. Analyses Reported by the Sponsor

The registry reports a sponsor analysis of the adult primary endpoint as a geometric mean ratio with a 90% confidence interval and labels it an equivalence analysis. The adult treatment-specific geometric mean AUC estimates are 326.0 day*g/L for TAK-881 and 327.0 day*g/L for HYQVIA. The sponsor’s ratio estimate is close to the no-difference reference, and its interval includes that reference. The registry record does not report the equivalence margins or the prespecified decision rule, so the reported interval cannot be checked against the formal criterion for equivalence.

The posted secondary rate comparisons are recalculated, unadjusted comparisons based on the registry’s arm-level summaries. They are not sponsor-reported analyses: the registry lists no reported analyses for these secondary outcomes. Where those recalculations differ in inferential approach or result from a sponsor analysis, the sponsor’s own analysis takes precedence; the registry record does not identify a discrepancy for the primary endpoint. The recalculated secondary results should not be read as replacements for the trial’s full analysis.

In particular, the primary result concerns IgG exposure in the adult pharmacokinetic per-protocol population, while the secondary outcomes concern infections and other events across treatment groups and follow-up periods. A close pharmacokinetic comparison and an infection-rate comparison answer different questions. The record does not provide enough information to determine whether the sponsor’s full statistical report included additional analyses, sensitivity checks, or decision criteria beyond those posted in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report whether the statistical plan controlled for multiplicity across the secondary outcomes, treatment comparisons, or repeated assessments. It lists multiple secondary outcomes, including infection rates, fever episodes, time to first acute serious bacterial infection, infection duration, days affected by illness or treatment, antibiotic days, and hospitalizations. The record does not state which outcomes were designated as confirmatory, whether any hierarchy was prespecified, or whether adjustments to significance thresholds were planned.

That omission matters because unadjusted p-values address each comparison separately. When many outcomes are considered, an apparently small p-value may arise even if none of the underlying effects is real. The recalculated secondary p-values are unadjusted and should not be treated as a family-wide test. The registry record lists a sponsor-reported analysis for the primary outcome but no sponsor-reported analyses for the posted secondary endpoints.

The primary endpoint population is explicitly defined as the Pharmacokinetic Per-Protocol Analysis Set. It includes participants who received all TAK-881 and HYQVIA infusions, had evaluable pharmacokinetic profiles in both crossover epochs, and had no protocol violations that could affect the reliability of the IgG profiles. The registry record does not report the number or characteristics of participants excluded from that set, or how exclusions affected the analysis.

Missing-data methods are not reported in the registry record. In particular, the record does not describe how missing pharmacokinetic samples, incomplete treatment epochs, withdrawals, or missing secondary outcome observations were handled. It does not report sensitivity analyses for missing data. The record also does not report whether the time-to-first-event outcome used a specific censoring approach or how participants without an event were handled.

Interim analyses and stopping rules are not reported in the registry record. Nor are detailed statistical model specifications, covariate adjustments, or sensitivity analyses for the posted outcomes. These omissions do not establish that the trial lacked such procedures; they mean the registry record does not document them. The posted results can be interpreted in light of the stated analysis population and endpoint descriptions, but a full assessment of multiplicity and missing-data handling would require information not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastritis viral (4.5%), influenza (4.5%), pneumonia aspiration (4.5%), ataxia (2.6%), chest discomfort (2.6%).

The registry reports serious adverse events for three treatment groups: the pediatric TAK-881 single-arm group, the adult TAK-881 crossover treatment group, and the adult HYQVIA crossover treatment group. Serious adverse events affected 3 of 22 participants in the pediatric group, 1 of 41 in the adult TAK-881 group, and 3 of 38 in the adult HYQVIA group. No deaths were reported in any of these groups.

These are participant counts over the reported study periods, not exposure-adjusted rates. The groups differ in age, treatment design, and the number at risk, so the counts should not be interpreted as a direct randomized safety comparison. The crossover treatment groups also reflect treatment epochs within a crossover study; the registry record does not provide additional detail about event attribution or exposure-adjusted comparisons.

The record lists gastritis viral, influenza, and aspiration pneumonia at 4.5% each among the top serious event terms, and ataxia, chest discomfort, and headache at 2.6% each. These percentages describe the listed terms in the registry record; they do not by themselves establish causation by a treatment. The record does not provide enough detail to infer comparative risk, timing, severity patterns beyond the serious-event classification, or whether events were judged treatment-related.

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

The primary result describes total IgG exposure over a dosing interval at steady state among adults who met the pharmacokinetic per-protocol criteria. The reported geometric mean estimates are similar in magnitude, and the sponsor reported an equivalence analysis. This is evidence about a pharmacokinetic measure in the analyzed adult population, not a direct demonstration of equivalent effects on infections, daily functioning, or other clinical outcomes.

Formal equivalence is a decision against prespecified bounds, not simply a judgment that two point estimates look close or that a confidence interval includes the no-difference reference. The registry record does not report the equivalence margins or decision rule. The sponsor’s equivalence label can be reported, but the registry record alone does not allow readers to verify the criterion used or the basis for that conclusion.

The secondary infection and fever findings describe event rates over follow-up and include recalculated, unadjusted comparisons. They are subject to uncertainty, sparse events for some outcomes, and the lack of a reported multiplicity plan. Contrasts involving children and adults are not randomized treatment comparisons. The pediatric group received TAK-881 only, while the adult participants entered a crossover comparison, and the age groups had different maximum treatment durations.

The serious adverse event counts and listed terms provide a registry-level account of events reported during the study. They do not establish that a treatment caused an event or that one treatment has a lower risk than another. The groups are not directly comparable from the counts alone, and the record does not provide exposure-adjusted safety analyses or detailed attribution information.

Overall, the posted evidence should be kept within the scope of the measured endpoints and analysis populations. The record does not support conclusions beyond the pharmacokinetic estimates, secondary outcome summaries, and reported safety counts. It does not establish clinical benefit, comparative effectiveness, or a complete characterization of safety.

14. Why This Trial Matters Statistically

This trial is statistically informative because its main adult comparison uses a randomized crossover structure for a pharmacokinetic endpoint. Each adult participant was assigned to a treatment sequence and the primary outcome was measured in both treatment epochs. That design targets a within-participant comparison of IgG exposure, while the primary analysis’s per-protocol definition makes clear that the result applies to participants with evaluable profiles in both epochs and no specified profile-affecting protocol violations.

The endpoint also illustrates why statistical interpretation depends on the question being asked. AUC0-tau;ss summarizes exposure over time, while infection rates describe clinical events during follow-up. Similarity in one measure does not dictate the result for another. Keeping those questions separate helps avoid treating pharmacokinetic results as a substitute for outcomes that matter to participants.

The record also illustrates the importance of distinguishing randomized comparisons from descriptive cross-group contrasts. The pediatric cohort had no HYQVIA arm, so its results cannot be used as a randomized comparator for adults. Differences in age and study structure are entangled with any apparent difference in rates. This distinction is essential when reading the recalculated secondary comparisons.

Finally, the record demonstrates why confidence intervals, analysis populations, and multiplicity information matter alongside point estimates. The primary analysis has a defined population and a sponsor-reported equivalence analysis, but the formal margins are not posted. Secondary rate comparisons are unadjusted recalculations, and a multiplicity plan is not reported. Those details determine how strongly statistical evidence can support a conclusion, beyond whether estimates appear close or p-values appear small.

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 registry record gives limited detail about the statistical plan. It does not report the rationale for the enrollment target, formal equivalence margins, the planned analysis model for the primary endpoint, or whether treatment sequence and period effects were considered. Without those details, the primary result can be described but the full equivalence decision process cannot be independently assessed from the registry record.

The primary endpoint is analyzed in a per-protocol pharmacokinetic population of 28 participants per treatment estimate, rather than all 65 enrolled participants. The registry record does not report the number excluded from this analysis, their reasons for exclusion, or whether the exclusions could have affected the observed estimates. The record also does not describe missing-data handling or sensitivity analyses.

The secondary outcomes have several specific constraints. Pediatric participants received TAK-881 without a randomized HYQVIA comparator, and comparisons between that cohort and adult groups mix age and treatment-design differences. Follow-up also differed by cohort, with treatment described for up to 27 weeks in the pediatric group and up to 51 weeks in the crossover group. The recalculated rate comparisons are unadjusted; the registry record does not report whether the sponsor’s analyses adjusted for differences in exposure or other participant characteristics.

Several secondary outcomes involve relatively uncommon events, including acute serious bacterial infections. Sparse event data can yield imprecise estimates, as reflected by wide confidence intervals. The registry record does not report whether over-dispersion was assessed for rate analyses or whether sensitivity methods were used. A multiplicity strategy is also not reported, limiting the strength of interpretation for nominal secondary p-values.

The safety information is presented as participant counts and selected event terms, without exposure-adjusted comparisons or detailed treatment attribution in the registry record. These limitations are specific to the posted record; they do not establish that additional analyses were not conducted, only that the record does not report them.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study About How TAK-881 is Processed by the Body and Side Effects in People With Primary Immunodeficiency Diseases — NCT05755035.
• Registry record last updated 2026-09-30; status last verified 2026-09.
• Results first posted 2026-09-30.
• 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

NCT05755035 is a completed, multicenter, prospective, open-label, randomized crossover study of TAK-881 in people with primary immunodeficiency diseases. The registry lists Phase 2 and Phase 3 and enrollment of 65. Adults aged 16 years and older were assigned to TAK-881 followed by HYQVIA or the reverse sequence; pediatric participants aged 2 to under 16 received TAK-881 in a single-arm treatment epoch.

The primary endpoint was total IgG AUC0-tau;ss at steady state in the adult pharmacokinetic per-protocol population. The registry reports similar treatment-specific geometric mean estimates and a sponsor-reported equivalence analysis, but does not report the formal equivalence margins. Secondary infection and fever outcomes are presented as annualized rates, with recalculated comparisons that are unadjusted and not sponsor-reported analyses. Serious adverse event counts are reported for each treatment group, with no deaths listed. Important details, including missing-data methods and multiplicity control, are not reported in the registry record.