Dynamics of the Anti-factor VIII Antibody Signature During Treatment With Emicizumab (NAVIGATE)

The goal of this observational study is to learn about the changes of antibodies and inhibitors against the coagulation factor VIII in patients with severe hemophilia A receiving emicizumab therapy. No additional visits or procedures are planned. Patients in this study will continue to receive their routine care and analysis will be done from left over samples from routine visits.

Study Overview

• Status: Recruiting
• Conditions: Severe Hemophilia A; Severe Hemophilia A With Inhibitor; Severe Hemophilia A Without Inhibitor
• Intervention / Treatment: Other: no interventions

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Stephan Schultze-Strasser, Dr.; Phone Number: +496963016998; Email: stephan.schultze-strasser@kgu.de
• Study Contact Backup: Name: Christoph Koenigs, PD Dr. Dr; Phone Number: +4969630183030; Email: christoph.koenigs@kgu.de

Study Locations

• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Recruiting
      • University Hospital Frankfurt, Goethe University
      • Contact: Stephan Schultze-Strasser, Dr.; Phone Number: 00496963016998; Email: stephan.schultze-strasser@kgu.de
      • Contact: Christoph Koenigs, PD Dr. Dr.; Phone Number: 004969630183030; Email: christoph.koenigs@kgu.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study aims to recruit 100 patients with severe hemophilia A from 15 study sites in germany.

Description

Inclusion Criteria:

• Severe congenital hemophilia A (CHA)
• Treatment with emicizumab irrespective of any other treatment
• Informed consent

Exclusion Criteria:

• No therapy with emicizumab
• Immunosuppressive therapy
• HIV-infection with CD4 (cluster of differentiation 4) cells <200/µl

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Inhibitor negative, FVIII on demand or regularly; Patients with severe hemophilia A receiving emicizumab therapy which are negative for factor VIII Inhibitor (including patients post ITI) and are receiving factor VIII therapy either on demand or regularly,	Other: no interventions; no intervention, only 3 different patients groups
Inhibitor positive, FVIII therapy regularly (ITI); Patients with severe hemophilia A receiving emicizumab therapy which are positive for factor VIII Inhibitor and are receiving regularly factor VIII therapy (ITI)	Other: no interventions; no intervention, only 3 different patients groups
Inhibitor positive, no FVIII therapy; Patients with severe hemophilia A receiving emicizumab therapy which are positive for factor VIII Inhibitor and are receiving no factor VIII therapy	Other: no interventions; no intervention, only 3 different patients groups

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FVIII inhibitor development in inhibitor negative subjects	Rate of FVIII inhibitor development during three years of emicizumab prophylaxis in inhibitor negative subjects. Assessed with Bethesda Assay (BU/ml). Number of patients who develop an FVIII inhibitor within the study period, but were FVIII inhibitor negative at start of the study.	3 years
FVIII antibody development in inhibitor negative subjects	Rate of FVIII antibody development during three years of emicizumab prophylaxis in inhibitor negative subjects. FVIII anti drug antibody (ADA) is assessed by FVIII specific ELISA (OD=Optical Density). Number of patients who develop an FVIII antibody (ADA) within the study period, but were FVIII inhibitor negative at start of the study.	3 years
FVIII inhibitor disappearance in inhibitor positive subjects	Rate of FVIII inhibitor disappearance during three years of emicizumab prophylaxis in inhibitor positive subjects. Assessed with Bethesda Assay (BU/ml). Number of patients who loose an FVIII inhibitor within the study period, but were FVIII inhibitor positive at start of the study.	3 years
FVIII antibody disappearance in inhibitor positive subjects	Rate of FVIII antibody disappearance during three years of emicizumab prophylaxis in inhibitor positive subjects. FVIII anti drug antibody (ADA) is assessed by FVIII specific ELISA (OD=Optical Density). Number of patients who develop an FVIII antibody within the study period, but were FVIII inhibitor positive at start of the study.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-FVIII inhibitor development	Anti-FVIII inhibitor development (median BU/ml) over time. Assessed with Bethesda Assay (BU/ml). Description of inhibitor development in the different patient groups within the study period. Cut off is 0,6 BU/ml.	3 years
Anti-FVIII antibody development	Anti-FVIII antibody development (median arbitrary units, OD) over time. Description of antibody development in the different patient groups within the study period.	3 years
Time to negative inhibitor titers	Time to negative inhibitor titers. Assessed with Bethesda Assay (BU/ml). Description of the Time (days) observed for FVIII inhibitor disappearance within the study period in the patient groups. Cut off for inhibitor titer is 0,6 BU/ml.	3 years
Treatment of bleeds	Description of the use of FVIII and/or Bypassing agents treatment in addition to Emicizumab treatment in case of bleeds.	3 years
Response to treatment	Classification of bleeds as Effective, Partially Effective, Ineffective. Defined as: Effective: Bleeding episode responded to the usual number of injections or dose of FVIII as expected by the treating physician; Partially Effective: The bleeding episode responded with a higher number of injections and/or dose as expected by the treating physician; Ineffective: Routine failure to control hemostasis or hemostatic control required additional agents	3 years
Quality of the antibody response (FVIII epitopes)	Description of the location of FVIII epitopes over time, assessed by epitope mapping technique (ELISA)	3 years
Quality of the antibody response (IgG subclasses)	Description of a potential immune response over time, assessed by IgG subclass determination (ELISA).	3 years

Collaborators and Investigators

• Sponsor: Christoph Königs
• Collaborators: Roche Pharma AG; Chugai Pharma Germany GmbH
• Investigators: Principal Investigator: Christoph Koenigs, PD Dr. Dr, Goethe University

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: April 4, 2023
• First Posted (Actual): April 7, 2023

Study Record Updates

• Last Update Posted (Actual): July 10, 2023
• Last Update Submitted That Met QC Criteria: July 7, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: ML44394; DRKS00031196 (Registry Identifier: German Clinical Trials Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No