Immune Tolerance Induction in Hemophilia A Patients Using Wilate® —a Canadian 10 Year Study (PREVAIL)
Bibliographic record
Abstract
Abstract Introduction: Hemophilia A patients with inhibitors experience a higher morbidity, a worse orthopedic condition and a decreased quality of life. In children with severe hemophilia A, attempting to eliminate inhibitors with immune tolerance induction (ITI) is standard of care; however, in adults with longstanding inhibitors ITI has been less extensively studied. Although practical guidelines in adults are scarce there has been an increase in case reports highlighting the success of ITI in patients with long-standing inhibitors. The possibility that the type of factor VIII (FVIII) product used for ITI could influence the likelihood of successful tolerization is the subject of intense debate. It has been postulated that FVIII products containing von Willebrand factor (VWF) may improve the ITI success rate in some patients with inhibitors, especially those with poor prognostic characteristics, i.e., a historical peak inhibitor level >200 BU/mL, an inhibitor level >10 BU/mL at the start of ITI, age >5 years, or >24 months between inhibitor detection and start of ITI. Study Rationale Wilate® is the most extensively used plasma-derived FVIII/VWF concentrate for hemophilia A in Canada. Wilate® has been successful in eliminating inhibitors and reducing bleeding in Canadian children and adults who had developed inhibitors during treatment with other FVIII concentrates, including poor-prognosis patients. Wilate® was well tolerated at the high doses required for ITI. Furthermore, anecdotal clinical experience with Wilate® ITI therapy suggest that patients may have less bleeding, which may limit the need for bypassing agents. This research study was designed to evaluate the efficacy of Wilate® in achieving complete or partial ITI success in severe and moderate hemophilia A patients with inhibitors. Secondary objectives are to determine: the time to achieve immune tolerance; bleeding frequency while on Wilate® ITI treatment; quality of life while on Wilate® ITI treatment; joint health while on Wilate® ITI treatment; relapse rate; and time to relapse following successful ITI using Wilate® . Additional optional sub-studies have been incorporated into this study to gain insight into the biology of ITI, including biomarkers that might predict ITI success or failure: genotyping, anti-FVIII antibody characterization including epitope mapping, and thrombin generation. Study Procedures This 10-year Canadian study is an open-label, uncontrolled, multi-centre observational trial with both prospective and retrospective cohorts. A total of at least 80 hemophilia A patients with inhibitors will be enrolled into this study. The dose and frequency of ITI treatment will be at the discretion of the treating physician. However, use of risk-determined treatment protocols is recommended. Patients with high-titre inhibitors (defined as one with historical peak titre ≥5 BU/m) who have inhibitor titre ≤10 BU/mL at the start of ITI are “good-risk” for ITI success, and those who have inhibitor titre >10 BU/mL at the start of ITI are “poor-risk”. Patients with high-titre inhibitors who are good-risk should receive 50 IU FVIII/kg BW every other day or 3 times per week; daily treatment may also be considered. Patients with high-titre inhibitors who are poor-risk should receive 100-200 IU FVIII/kg BW daily. Patients with low-titre inhibitors (defined as one with historical peak titre For complete success, an individual must achieve the following three criteria: inhibitor titre Conclusion This research study aims to evaluate and document data on the success of Wilate ® ITI in hemophilia patients with FVIII-inhibitors. It is the first 10-year study of its kind in a Canadian setting. The results of this study will provide further insights into addressing one of the most serious complications of hemophilia A treatment. Disclosures Moorehead: Bioverativ: Honoraria; Pfizer: Speakers Bureau; Octapharma: Honoraria; Bayer: Honoraria; Baxalta: Honoraria, Speakers Bureau. Klaassen: Baxalta: Honoraria; Agios Pharmaceuticals: Consultancy; Hoffman-La Roche LTD: Consultancy; Biogen Canada LTD: Consultancy; Amgen: Consultancy; Octapharma: Honoraria. Carcao: Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Biotest: Honoraria.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".