This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies (NCT03103542), a na phase 4 study. The primary outcome is ITI Success.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03103542 |
| Phase | Phase 4 |
| Condition | Hemophilia A |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Swedish Orphan Biovitrum |
| Results posted | Yes |
2. Clinical Question
Population
Participants had severe haemophilia A with inhibitors and had failed previous immune tolerance induction therapies. The registry record lists haemophilia A as the condition and reports enrollment of 16 participants. It does not give further participant characteristics in the primary endpoint population field.
Intervention
The study evaluated recombinant coagulation factor VIII Fc, abbreviated rFVIIIFc, as immune tolerance induction treatment. The arm description states a dose of 200 international units per kilogram, administered once daily or divided across several injections per day at the investigator’s discretion, for up to 60 weeks. The registry record does not report the treatment actually received by each participant.
Comparator
There was no control group. This was an open-label, non-controlled, single-group study, so the registry record does not present a concurrent comparison with another treatment or with no treatment. The listed allocation is not applicable.
Primary question
The primary question was how many participants achieved ITI success within up to 60 weeks of treatment. Success required meeting all of the registry’s inhibitor-titer, incremental-recovery, and factor VIII half-life criteria. The primary success count and an estimate of its precision are not reported in the registry record. Consequently, the record describes the question and its definition but does not establish the observed frequency of success.
3. Trial Design
This was a phase 4, open-label, multicenter, single-group study, with no randomized allocation and no control group. Its official title describes immune tolerance induction with rFVIIIFc within a timeframe of 60 weeks in severe haemophilia A patients with inhibitors who had failed previous ITI therapies. The registry lists enrollment of 16 and identifies Swedish Orphan Biovitrum as the sponsor. The study is marked completed; its recorded start date is 2017-08-29 and its primary completion date is 2019-09-04.
Participants received rFVIIIFc. The arm description specifies 200 international units per kilogram as once-daily injections or divided injections, at the investigator’s discretion, for up to 60 weeks during the ITI period. The available arm description is truncated after its reference to participants who meet criteria, so further details about treatment after ITI success are not reported in the registry record.
Because there was no control group, the design can describe outcomes among treated participants but cannot directly compare those outcomes with a concurrent alternative. Open-label treatment also means participants and investigators were not masked to the intervention. The registry record does not report a protocol-based statistical analysis plan, a sample-size justification, or details of enrollment and follow-up beyond the stated timeframes.
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: After informed consent was provided, patients underwent study specific screening procedures. During the 4- to 6-week screening period, patients continued with their usual treatment regimen in accordance with the local standard of care. Patients who met all inclusion and no exclusion criteria specified by the protocol were enrolled into the study. The 2 screening failures did not meet inclusion criteria 1 (signed informed consent) and 5 (inhibitor titer ≥0.6 BU at screening) respectively.
Overall Study
| Stage | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|
| STARTED | 16 |
| COMPLETED | 9 |
| NOT COMPLETED | 7 |
Reasons for not completing this period:
| Reason | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|
| Physician Decision | 2 |
| Adverse Event | 2 |
| Other | 2 |
| Withdrawal by Subject | 1 |
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: All enrolled patients
| Characteristic | Unit | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|---|
| Participants analysed | 16 | |
| Age, Categorical: <=18 years | Participants | 15 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 |
| Age, Categorical: >=65 years | Participants | 0 |
| Age, Continuous | years | 7.5 (3 to 46) |
| Sex: Female, Male: Female | Participants | 0 |
| Sex: Female, Male: Male | Participants | 16 |
| Race/Ethnicity, Customized: Race – White | Participants | 15 |
| Race/Ethnicity, Customized: Race – Asian | Participants | 0 |
| Race/Ethnicity, Customized: Race – Black or African American | Participants | 1 |
| Race/Ethnicity, Customized: Race – American Indian or Alaska Native | Participants | 0 |
| Region of Enrollment: Canada | participants | 3 |
| Region of Enrollment: Sweden | participants | 1 |
| Region of Enrollment: United States | participants | 1 |
| Region of Enrollment: Ireland | participants | 3 |
| Region of Enrollment: United Kingdom | participants | 3 |
| Region of Enrollment: Slovenia | participants | 1 |
| Region of Enrollment: Germany | participants | 4 |
| Hemophilia history - severity: Mild | Participants | 0 |
| Hemophilia history - severity: Moderate | Participants | 0 |
| Hemophilia history - severity: Severe | Participants | 16 |
| Hemophilia history - Family history of Inhibitors: Yes | Participants | 7 |
| Hemophilia history - Family history of Inhibitors: No | Participants | 5 |
| Hemophilia history - Family history of Inhibitors: Unknown | Participants | 4 |
| Number of previous ITI Treatments: 1 Treatment | Participants | 10 |
| Number of previous ITI Treatments: 2 Treatments | Participants | 4 |
| Number of previous ITI Treatments: 3 Treatments | Participants | 2 |
| Inhibitor History - Historical Peak Titre Level | BU/ml | 127.4 (8 to 3000) |
| Inhibitor history - Age at Inhibitor development | years | 1.9 (SD 3.6) |
6. Primary Endpoint
The registry lists the primary outcome as ITI Success, measured over up to 60 weeks.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint was the number of participants achieving ITI success, assessed within up to 60 weeks. It is a count outcome: it records how many participants met the success definition, rather than measuring a continuous change in a laboratory value. The definition required all of the following: a negative inhibitor titer at two consecutive visits, with the threshold stated as <0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay; factor VIII incremental recovery greater than 66% of expected at two consecutive visits; and factor VIII half-life of at least 7 hours.
Using a combined definition can represent success across several aspects of inhibitor status and factor VIII response, rather than relying on a single measurement. Requiring repeated findings for the titer and incremental-recovery criteria makes those components dependent on results at consecutive visits. The endpoint is therefore a threshold-based, composite definition: a participant must satisfy every listed criterion to count as a success.
The registry record does not report the number meeting this definition, the analysis population used for the endpoint, or an uncertainty interval around the count or a corresponding proportion. Without those results, the endpoint’s observed frequency and precision cannot be described.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clinically defined primary endpoint and a treatment timeframe, but it does not report the primary outcome result. Although enrollment is listed as 16, the number of those participants who achieved ITI success is not reported in the registry record. The record also reports no analyses. Therefore, the observed success frequency, its uncertainty, and any statistical comparison cannot be established from the posted results described in the record.
The distinction between enrollment and outcome information is important. Enrollment tells readers how many participants entered the study as recorded; it does not by itself establish how many completed treatment, had endpoint assessments, or met the endpoint definition. Those details are not reported in the registry record. It would not be appropriate to treat the enrollment count as the endpoint denominator or to infer that unreported outcomes were failures or successes.
This was a single-group, open-label study without a randomized comparator. Any outcome reported for the treated participants would describe what occurred in this study group over the stated timeframe. Without a concurrent control group, such a result would not isolate the effect of rFVIIIFc from other explanations, including the course of the condition, participant selection, or differences in follow-up and assessment. The registry record does not report an adjusted or comparative estimate.
Precision is also not assessable from the primary outcome information in the record. In general, a confidence interval communicates the range of values compatible with an estimate under a specified statistical model; it is not a guarantee that the true value falls within that interval. No primary-outcome confidence interval or other measure of uncertainty is reported. A count without its result and denominator cannot be interpreted as an estimate of the probability of success.
The record describes several secondary outcomes, including time to ITI success, relapse during a 48-week period after successful treatment, bleeding outcomes, adverse events, factor consumption, and missed school or work. Listing an outcome does not show that it was analyzed or what the result was. The registry reports no analyses, so those outcomes cannot be interpreted as evidence of benefit, harm, or change. The safety information is separately described under adverse events, but it does not fill the gap in the primary efficacy result.
The record’s sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are not the study’s design: this trial had a single group. The record does not provide the observed primary effect needed to interpret an effect-based planning illustration. Such planning values, when available, would be hypothetical design calculations rather than observed power or a substitute for the trial’s outcome.
9. Statistical Methods Explained
What the design permits. In general, a single-group study measures outcomes among participants receiving an intervention without a concurrent comparison group. It can describe the observed experience of that group, but it cannot make a randomized between-group estimate. This study is listed as non-controlled, open-label, and single-group. The registry record does not report a comparator or an allocation procedure. As a result, causal attribution is more limited than it would be in a randomized controlled comparison, even if a primary outcome count were available.
How to understand the endpoint. The primary outcome is a count of participants meeting a composite definition. The criteria combine inhibitor titer, factor VIII incremental recovery, and factor VIII half-life. The first two criteria require results at two consecutive visits, and the stated thresholds are part of the endpoint definition. In general, a composite endpoint treats the listed components as jointly necessary when success is defined as meeting all of them. That makes the result straightforward to classify against the protocol definition, but it can conceal which component most often determines whether a participant qualifies. Component-specific results are not reported in the registry record.
Counts and proportions. A count is the number of participants who meet a condition. A proportion relates that count to a defined analysis denominator. The record gives enrollment of 16, but does not report the primary success count, the endpoint denominator, or the analysis population. Enrollment cannot be assumed to equal the number assessed for the endpoint. Without both a result and a defined denominator, readers cannot determine the observed proportion or its precision.
Uncertainty. In general, estimates from a study are subject to sampling uncertainty. A confidence interval gives a range of values that are reasonably compatible with an estimate under the chosen method and assumptions. It does not prove that the true value lies within the range, and its interpretation depends on the analysis. No primary outcome estimate or confidence interval is reported in the registry record. Therefore, the precision of the primary result cannot be assessed. A missing interval should not be read as evidence of either high or low precision.
Repeated measurements and timing. The success definition uses consecutive visits for the inhibitor and incremental-recovery criteria, and the primary timeframe is up to 60 weeks. In general, repeated assessments can help distinguish a finding observed at a single visit from one that persists across visits. They also make completeness and timing of assessments relevant to endpoint classification. The registry record does not report visit-level results, assessment schedules, or rules for handling measurements that were unavailable or outside the stated timing.
Over-dispersion and event counts. In general, over-dispersion occurs when count data vary more than a statistical model expects. It can make standard errors too small if the model assumes less variability than the data contain. This concept may matter for some count outcomes, such as bleeding counts, depending on the analysis and distribution of the observations. The registry record does not report the outcome distributions, model specifications, or analyses for these secondary outcomes. No conclusion about over-dispersion or its handling can be drawn for this study.
Planning calculations. In general, a sample-size calculation asks how many observations would be needed under stated assumptions to detect a specified effect with a chosen level of statistical evidence and power. It is a planning exercise, not a finding about what a completed study demonstrated. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; they also state that the effect to detect is a fraction of the observed effect. Those assumptions do not describe this single-group design. The registry record does not report the trial’s own sample-size justification, and the observed primary effect needed to interpret an effect-based illustration is not reported. Such calculations must not be described as observed power.
Multiplicity. When many outcomes or comparisons are tested, the chance of at least one nominally positive result can increase. General approaches include designating a primary endpoint in advance, using a testing hierarchy, or adjusting significance thresholds. The registry lists a primary endpoint and several secondary outcomes, but does not report a multiplicity procedure or statistical testing results. It is therefore not possible to assess how multiple outcomes were handled or whether any reported statistical findings were adjusted.
Analysis populations and missing observations. In general, an analysis population specifies which participants are included in a particular result; missing-data methods specify how unavailable measurements are treated. These choices can affect endpoint counts and their interpretation. The registry record does not report the primary analysis population, participant disposition, missing-data handling, or sensitivity analyses. Since the primary result itself is not reported, it is not possible to evaluate whether incomplete follow-up or missing assessments affected the endpoint estimate.
10. Multiplicity, Missing Data and Analysis Populations
The registry identifies ITI success as the primary outcome and lists secondary outcomes involving time to success, relapse, bleeding, adverse events, factor consumption, and missed school or work. It does not report a multiplicity strategy, such as a testing hierarchy or adjustment for testing multiple outcomes. It also reports no statistical analyses. Consequently, there are no reported inferential results from which to assess the handling of multiple testing.
The primary endpoint’s analysis population is not reported in the registry record. Enrollment is listed as 16, but the record does not state how many participants had evaluable endpoint data, completed the ITI period, or contributed to any particular analysis. The enrollment count should not be treated as an endpoint denominator without that information.
Missing-data methods, reasons for missing assessments, and sensitivity analyses are not reported in the registry record. This matters because the endpoint requires specified laboratory and recovery findings, including results at consecutive visits. In general, absent measurements can affect whether a participant can be classified against such a definition. The record does not say how unobserved or incomplete criteria were handled, so it is not possible to determine their influence on the reported outcome.
The registry also does not report interim analyses, a detailed statistical analysis plan, or a sample-size justification for this study. Those details should not be inferred from the list of outcomes or from the separate planning assumptions. Without the primary result and its analysis details, neither the completeness of endpoint assessment nor the robustness of any estimate can be evaluated.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | 7 | 16 | 43.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | 0 of 16 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | 16 of 16 |
Most frequent serious adverse event terms
| Event term | Organ system | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|---|
| Tonsillitis | Infections and infestations | 2 of 16 |
| Brachiocephalic vein thrombosis | Vascular disorders | 1 of 16 |
| Vena cava thrombosis | Vascular disorders | 1 of 16 |
| Thrombosis | Vascular disorders | 1 of 16 |
| Cough | Respiratory, thoracic and mediastinal disorders | 1 of 16 |
| Immune thrombocytopenic purpura | Blood and lymphatic system disorders | 1 of 16 |
| Spontaneous haemorrhage | Blood and lymphatic system disorders | 1 of 16 |
| Headache | Nervous system disorders | 1 of 16 |
| Pyrexia | General disorders | 1 of 16 |
| Haematuria | Renal and urinary disorders | 1 of 16 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|---|
| Headache | Nervous system disorders | 5 of 16 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 5 of 16 |
| Nasopharyngitis | Infections and infestations | 5 of 16 |
| Cough | Respiratory, thoracic and mediastinal disorders | 4 of 16 |
| Fall | Injury, poisoning and procedural complications | 3 of 16 |
| Vomiting | Gastrointestinal disorders | 3 of 16 |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | 3 of 16 |
| Pain in extremity | Musculoskeletal and connective tissue disorders | 3 of 16 |
| Upper respiratory tract infection | Infections and infestations | 3 of 16 |
| Viral infection | Infections and infestations | 3 of 16 |
Serious events with the highest arm-level rate: tonsillitis (12.5%), brachiocephalic vein thrombosis (6.2%), vena cava thrombosis (6.2%), thrombosis (6.2%), cough (6.2%).
The registry lists 16 participants at risk for adverse events in the rFVIIIFc group. It reports 7 participants with serious adverse events and 16 participants with other adverse events; deaths are reported as 0. These categories describe participants with events in the registry entry. They do not, by themselves, establish that an event was caused by the study treatment.
The listed serious adverse event terms include tonsillitis at 12.5%, brachiocephalic vein thrombosis at 6.2%, vena cava thrombosis at 6.2%, thrombosis at 6.2%, cough at 6.2%, and immune thrombocytopenic purpura at 6.2%. These are reported term percentages, not a full account of each participant’s clinical course. The registry record does not provide further detail about event timing, duration, severity beyond the serious classification, treatment, or causal assessment.
Counts of participants and event terms are not necessarily interchangeable: a participant may experience more than one event, and the listed terms do not show the total number of events. The figures also have no concurrent control group for comparison. They describe the recorded safety experience in this study group and should not be interpreted as comparative risk estimates.
12. What the Result Does, and Does Not, Mean
The study addresses a focused question: how many participants with severe haemophilia A and inhibitors, after failing previous ITI therapies, achieved a defined ITI success endpoint during up to 60 weeks of rFVIIIFc treatment. The registry record specifies the endpoint criteria and describes the study population and treatment approach. It does not report the primary success count, a proportion, or an uncertainty interval. Thus, the central outcome cannot be quantified from the record.
The record does report adverse-event figures for the study group, including serious adverse events in 7 of 16 participants, other adverse events in 16 of 16 participants, and 0 deaths. These are descriptive safety counts. They do not establish whether treatment caused an event, how the rates compare with another option, or whether the observed events are more or less common than they would be in a different population. The serious-event terms and percentages add detail but do not supply a controlled comparison.
The single-group, open-label design is suited to describing the experience of enrolled participants but does not provide a randomized estimate of treatment effect. Even if the primary success result were reported, the lack of a concurrent control would limit conclusions about what would have happened under another treatment or without the study intervention. Participant selection, follow-up, and assessment may also affect how well results apply beyond the enrolled group; relevant detail is not reported in the registry record.
The registry’s listing of secondary outcomes indicates topics the study intended to assess, not results for those outcomes. Time to success, relapse, bleeding, factor consumption, and missed school or work cannot be interpreted without reported data and analysis. The posted record therefore documents a completed study with a defined clinical endpoint and descriptive safety information, but does not establish the observed primary outcome or a comparative treatment effect.
13. Why This Trial Matters Statistically
This study is statistically notable for the gap between a specific endpoint definition and the absence of a reported primary endpoint result in the registry record. ITI success is defined using multiple laboratory and physiological criteria, including requirements for consecutive assessments. That precision in defining what counts as success does not, by itself, reveal how many participants met the definition or how uncertain the estimate would be.
The design also illustrates why outcome estimates must be interpreted in light of the comparison structure. A single-group study can describe outcomes within the enrolled group, but it cannot estimate a randomized contrast against a control group. The registry identifies the study as non-controlled and open-label, so any reported group outcome would need to be framed descriptively rather than as a controlled treatment effect.
Safety reporting raises a related issue: participant counts, event terms, and causal attribution answer different questions. The registry reports serious and other adverse-event counts, a set of serious-event terms, and no deaths. Those data describe recorded events, but do not establish comparative risk or treatment causality. Keeping these distinctions clear is essential when interpreting small, non-controlled studies.
Finally, the planning assumptions described in the record are not the trial design and are not evidence of observed power. A planning calculation relies on assumptions about a target effect and a proposed comparison; this study was single-group, and its primary outcome result is not reported. Recognizing the difference between design planning, observed outcomes, and uncertainty prevents hypothetical calculations from being mistaken for trial findings.
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 principal limitation for interpreting efficacy is that the primary ITI success count and its analysis are not reported in the registry record. The endpoint definition is detailed, but no observed result, denominator, or uncertainty estimate is available. Enrollment of 16 does not establish how many participants were evaluable for the primary endpoint.
The study was open-label, non-controlled, and single-group. It therefore has no concurrent comparator to support a direct treatment contrast, and observed outcomes cannot be separated from other influences through randomization. The registry record does not report adjustment methods or analyses that could address those limitations.
Further information needed to assess endpoint completeness is not reported in the registry record. This includes the analysis population, participant disposition, missing-data handling, visit-level endpoint measurements, and sensitivity analyses. These omissions are especially relevant because success depends on several criteria, some of which require measurements at consecutive visits.
The record lists safety counts and serious adverse event terms, but does not report additional details about timing, event-level counts, causality assessments, or comparative safety. The small enrolled group and absence of a control group also limit how broadly descriptive event frequencies can be interpreted. The listed secondary outcomes do not have reported analyses, and the record does not report multiplicity procedures, interim analyses, or the study’s sample-size justification.
The available arm description is truncated, limiting interpretation of treatment procedures beyond the stated dose, administration options, investigator discretion, and maximum ITI timeframe. These limitations do not show that unreported analyses or procedures were absent from the conduct of the study; they mean that they are not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies — NCT03103542.
- Registry record last updated 2024-09-19; status last verified 2024-09.
- Results first posted 2021-11-30.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT03103542 is a completed phase 4, open-label, multicenter, single-group study sponsored by Swedish Orphan Biovitrum. It enrolled 16 participants with haemophilia A and evaluated rFVIIIFc for ITI after previous ITI therapies had failed. The recorded start date is 2017-08-29, and the primary completion date is 2019-09-04.
The primary endpoint was the number of participants achieving ITI success within up to 60 weeks, using defined inhibitor, incremental-recovery, and half-life criteria. The registry record does not report the primary success count or statistical analyses. It reports serious adverse events in 7 participants, other adverse events in 16 participants, and 0 deaths. Because the study had no control group, the record describes a treated cohort rather than a randomized comparison.