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Alphanate in Immune Tolerance Induction Therapy

Primary Purpose

Hemophilia A, Congenital

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Alphanate
Sponsored by
Grifols Therapeutics LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A, Congenital focused on measuring Factor VIII, von Willebrand Factor, Plasma-derived, Inhibitors, Immune tolerance induction (ITI), Antibodies, Hemophilia A

Eligibility Criteria

undefined - 12 Years (Child)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Emory University
  • University of Kentucky
  • Childrens Hospital and Clinics of Minnesota
  • The Childrens Mercy Hospital
  • Robert Wood Johnson Medical Group
  • Newark Beth Israel Medical Center & Children's Hospital of New Jersey
  • University of North Carolina at Chapel Hill, Hemophilia and Thrombosis Center
  • Seattle Children's Hospital, Seattle Children's Research Institute
  • McMaster Children's Hospital
  • Lokmanya Tilak Municipal Medical College & General Hospital
  • B. J. Govt. Medical College & Sassoon Hospital
  • A.O.U. Santa Maria della Misericordia Perugia
  • Azienda Ospedaliera Universitaria Careggi
  • Universita degli Studi di Roma La Sapienza
  • Kemerovo Regional Clinical Hospital
  • FGUs Hospital - Kirov Scientific Research Institute
  • Center for Hemophilia Treatment St.-Petersburg
  • Hospital Universitari i Politecnic La Fe
  • Hospital Universitario La Paz
  • Hospital Universitario Virgen del Rocio

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Alphanate

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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

Full Information

First Posted
March 23, 2017
Last Updated
October 27, 2021
Sponsor
Grifols Therapeutics LLC
Collaborators
Grifols Biologicals, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03095287
Brief Title
Alphanate in Immune Tolerance Induction Therapy
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
Terminated due to limited enrollment (non-safety related decision)
Study Start Date
January 3, 2018 (Actual)
Primary Completion Date
September 18, 2020 (Actual)
Study Completion Date
September 18, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grifols Therapeutics LLC
Collaborators
Grifols Biologicals, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A, Congenital
Keywords
Factor VIII, von Willebrand Factor, Plasma-derived, Inhibitors, Immune tolerance induction (ITI), Antibodies, Hemophilia A

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Alphanate
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Alphanate
Other Intervention Name(s)
Factor VIII/von Willebrand Factor
Intervention Description
Bolus IV injection.
Primary Outcome Measure Information:
Title
Percentage of Participants Who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase
Description
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.
Time Frame
Up to 32.5 months
Secondary Outcome Measure Information:
Title
Percentage of Participants Who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase
Description
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.
Time Frame
Up to 32.5 months
Title
Percentage of Participants Who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase
Description
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.
Time Frame
12 months during prophylactic phase
Title
Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase
Description
Annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase
Time Frame
Up to 32.5 months
Other Pre-specified Outcome Measures:
Title
Treatment-emergent Adverse Events
Description
Incidence of treatment-emergent adverse events during the ITI Treatment Phase and Prophylactic Phase
Time Frame
Up to 32.5 months

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Childrens Hospital and Clinics of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Facility Name
The Childrens Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Robert Wood Johnson Medical Group
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
Newark Beth Israel Medical Center & Children's Hospital of New Jersey
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07112
Country
United States
Facility Name
University of North Carolina at Chapel Hill, Hemophilia and Thrombosis Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27517
Country
United States
Facility Name
Seattle Children's Hospital, Seattle Children's Research Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States
Facility Name
McMaster Children's Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N-3Z5
Country
Canada
Facility Name
Lokmanya Tilak Municipal Medical College & General Hospital
City
Mumbai
State/Province
Maharashtra
ZIP/Postal Code
400022
Country
India
Facility Name
B. J. Govt. Medical College & Sassoon Hospital
City
Pune
ZIP/Postal Code
411001
Country
India
Facility Name
A.O.U. Santa Maria della Misericordia Perugia
City
Perugia
State/Province
Umbria
ZIP/Postal Code
6132
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Careggi
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Facility Name
Universita degli Studi di Roma La Sapienza
City
Roma
ZIP/Postal Code
00161
Country
Italy
Facility Name
Kemerovo Regional Clinical Hospital
City
Kemerovo
ZIP/Postal Code
650061
Country
Russian Federation
Facility Name
FGUs Hospital - Kirov Scientific Research Institute
City
Kirov
ZIP/Postal Code
610027
Country
Russian Federation
Facility Name
Center for Hemophilia Treatment St.-Petersburg
City
Saint Petersburg
ZIP/Postal Code
191186
Country
Russian Federation
Facility Name
Hospital Universitari i Politecnic La Fe
City
Valencia
State/Province
Autonomous Community Of Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

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Alphanate in Immune Tolerance Induction Therapy

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