Alphanate in Immune Tolerance Induction Therapy

A Multicenter Phase 2 Open-Label, Single-Arm, Prospective, Interventional Study of Plasma-Derived Factor VIII/VWF (Alphanate®) in Immune Tolerance Induction Therapy in Subjects With Congenital Hemophilia A

This is a multicenter, multinational, prospective, single-arm, nonrandomized, open-label study, planned in of approximately 25 male participants with congenital hemophilia A who will receive their first (primary) immune tolerance induction (ITI) treatment with alphanate.

The study consists of 2 phases:

• An ITI Treatment Phase in which all eligible participants will receive ITI treatment with alphanate for a period of up to 33 months. Upon confirmation of complete immune tolerization, participants will then enter a 12-month Prophylactic Phase. If, after 33 months of ITI, a participants has achieved partial immune tolerance, the participants will enter a 12-month Prophylactic Phase.
• A 12-month Prophylactic Phase for all participants who meet the criteria for complete or partial success to continue on a prophylactic dosing regimen of alphanate. Due to limited enrollment, this study was early terminated.

Study Overview

• Status: Terminated
• Conditions: Hemophilia A, Congenital
• Intervention / Treatment: Biological: Alphanate

Detailed Description

Male participants <12 years of age with an inhibitor titer >0.6 to <10 Bethesda Units (BU) will be screened before the planned start of ITI treatment. Participants continuing to meet the entrance criteria will enter the ITI Treatment Phase and receive daily doses of alphanate 100 IU/kg/day for up to 33 months, with a one-time option to increase to a dosing regimen of 200 IU/kg/day at any time after 90 days of ITI treatment.

Participants will continue to receive their daily alphanate dose for up to 33 months until the titer is negative (<0.6 BU) on 2 consecutive assessments and treatment success is confirmed by FVIII:C pharmacokinetic assessments, at which time they will enter the 12-month Prophylactic Phase.

In addition, participants who have achieved partial immune tolerance at the completion of 33 months of ITI treatment will enter the 12-month Prophylactic Phase. Participants who do not achieve partial immune tolerance at the completion of 33 months of ITI treatment will be discontinued as treatment failures.

The Prophylactic Phase begins with an 8-week taper period for participants tolerized with 100 IU/kg/day or with a 12-week taper period for participants tolerized with 200 IU/kg/day to bring the dose down in a step-wise manner to a prophylactic dose of alphanate 50 IU/kg every other day or 3 times per week, at the investigator's discretion. During the Prophylactic Phase, participants will be monitored monthly for the first 4 months and then every 2 months for the remaining 8 months to assess sustainability of immune tolerance. Due to limited enrollment, this study was early terminated.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N-3Z5
      • McMaster Children's Hospital
• India
  • Pune, India, 411001
    • B. J. Govt. Medical College & Sassoon Hospital
  • Maharashtra
    • Mumbai, Maharashtra, India, 400022
      • Lokmanya Tilak Municipal Medical College & General Hospital
• Italy
  • Firenze, Italy, 50134
    • Azienda Ospedaliera Universitaria Careggi
  • Roma, Italy, 00161
    • Università degli Studi di Roma La Sapienza
  • Umbria
    • Perugia, Umbria, Italy, 6132
      • A.O.U. Santa Maria della Misericordia Perugia
• Russian Federation
  • Kemerovo, Russian Federation, 650061
    • Kemerovo Regional Clinical Hospital
  • Kirov, Russian Federation, 610027
    • FGUs Hospital - Kirov Scientific Research Institute
  • Saint Petersburg, Russian Federation, 191186
    • Center for Hemophilia Treatment St.-Petersburg
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Autonomous Community Of Valencia
    • Valencia, Autonomous Community Of Valencia, Spain, 46026
      • Hospital Universitari i Politecnic La Fe
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Childrens Hospital and Clinics of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson Medical Group
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center & Children's Hospital of New Jersey
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University of North Carolina at Chapel Hill, Hemophilia and Thrombosis Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's Hospital, Seattle Children's Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• The subject has a documented diagnosis of severe congenital hemophilia A with FVIII:C <1% of normal.
• The subject is a male <12 years (and at least 2 years of age if in India) at the Baseline Visit.
• The subject's documented historical peak inhibitor titer is ≥5 BU and ≤200 BU.
• The subject has an inhibitor titer >0.6 BU and <10 BU at Screening.
• The subject has had a delay ≤24 months from the date of diagnosis of the inhibitor to the start of the subject's ITI treatment.

Exclusion Criteria:

• The subject has acquired factor VIII (FVIII) deficiency.
• The subject has previously received ITI treatment.
• The subject has a recent (within 1 month) history of central line infection at the time of Screening.
• The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event as judged by the investigator.
• The subject is currently undergoing treatment with immunosuppressive drugs (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin, interferon, or the use of a protein A column or plasmapheresis and is unwilling to discontinue these treatments starting at the screening visit.
• The subject has a known infection with human immunodeficiency virus (HIV) or has clinical signs and symptoms consistent with current HIV infection.
• The subject has a known previous infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or has clinical signs and symptoms consistent with current HBV or HCV infection.
• The subject has significant proteinuria, has a history of acute renal failure or severe renal impairment (blood urea nitrogen or creatinine >2 times the upper limit of normal), or is receiving dialysis at Screening.
• The subject has a value of aspartate transaminase or alanine aminotransferase >2 times the upper limit of normal at Screening.
• The subject has clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the subject at undue medical risk.
• The subject has a history of anaphylaxis or severe systemic reaction to any plasma derived or other blood products.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Alphanate; Participants were to receive alphanate 100 International Units (IU/kg/day) for up to 33 months in Immune tolerance induction (ITI) Treatment Phase. The dose could be increased up to 200 IU/kg/day based on Investigator's discretion. Following ITI Treatment Phase, participants were to enter the Prophylactic Phase where alphanate dose was to be tapered down in a step wise manner to reach a final prophylactic dose of 50 IU/kg every other day or 3 times per week, at the investigator's discretion.

Biological: Alphanate; Bolus IV injection.; Other Names: Factor VIII/von Willebrand Factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase	Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period.	Up to 32.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase	Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period. Partial immune tolerance was defined as participants achieving reduction of inhibitor titer to <5 BU confirmed at 2 consecutive assessments within 2 weeks of each other, FVIII:C in vivo plasma recovery of <66% of the predicted normal value or FVIII:C half-life of <6 hours after a 72-hour FVIII treatment-free period and clinical response to FVIII therapy.	Up to 32.5 months
Percentage of Participants Who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase	Relapse during the prophylactic phase for participants who have achieved complete immune tolerance was defined as a return of FVIII inhibitor titer to detectable levels (≥0.6 BU) or FVIII:C recovery <66% of the predicted normal value or FVIII:C half-life <6 hours, confirmed by repeat assessment within approximately 2 weeks. Relapse for participants who have achieved partial immune tolerance was defined as an increase of FVIII inhibitor titer to ≥5 BU, confirmed by repeat assessment within approximately 2 weeks.	12 months during prophylactic phase
Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase	Annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase	Up to 32.5 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-emergent Adverse Events	Incidence of treatment-emergent adverse events during the ITI Treatment Phase and Prophylactic Phase	Up to 32.5 months

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Collaborators: Grifols Biologicals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2018
• Primary Completion (Actual): September 18, 2020
• Study Completion (Actual): September 18, 2020

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 23, 2017
• First Posted (Actual): March 29, 2017

Study Record Updates

• Last Update Posted (Actual): November 23, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Factor VIII; Antibodies; Hemophilia A; Inhibitors; von Willebrand Factor; Plasma-derived; Immune tolerance induction (ITI)
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: GBI1406; 2015-005524-26 (EudraCT Number)

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