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Alphanate in Immune Tolerance Induction Therapy

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ClinicalTrials.gov Identifier: NCT03095287
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : November 5, 2018
Sponsor:
Information provided by (Responsible Party):
Grifols Therapeutics LLC

Brief Summary:

This is a multicenter, multinational, prospective, single-arm, nonrandomized, open-label study of approximately 25 male subjects 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 subjects will receive ITI treatment with Alphanate for a period of up to 33 months. Upon confirmation of complete immune tolerization, subjects will then enter a 12-month Prophylactic Phase. If, after 33 months of ITI, a subject has achieved partial immune tolerance, the subject will enter a 12-month Prophylactic Phase.
  • A 12-month Prophylactic Phase for all subjects who meet the criteria for complete or partial success to continue on a prophylactic dosing regimen of Alphanate.

Condition or disease Intervention/treatment Phase
Hemophilia A, Congenital Biological: Alphanate Phase 2

Detailed Description:

Male subjects <8 years of age presenting with an inhibitor titer >0.6 to <10 Bethesda Units (BU) will be screened before the planned start of ITI treatment. Subjects 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.

Subjects 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, subjects who have achieved partial immune tolerance at the completion of 33 months of ITI treatment will enter the 12-month Prophylactic Phase. Subjects 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 subjects tolerized with 100 IU/kg/day or with a 12-week taper period for subjects 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, subjects 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 3, 2018
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2022


Arm Intervention/treatment
Experimental: Alphanate
Daily intravenous infusion of Alphanate 100 IU/kg/day
Biological: Alphanate
Daily intravenous infusion of Alphanate 100 IU/kg/day
Other Name: Factor VIII/von Willebrand Factor




Primary Outcome Measures :
  1. Complete immune tolerance [ Time Frame: Up to 33 months of treatment ]
    Proportion of subjects achieving complete immune tolerance within 33 months of initiation of ITI treatment. Complete immune tolerance is defined as achieving undetectable inhibitor, FVIII:C plasma recovery of at least 66% of the predicted normal value, and FVIII-C half-life of at least 6 hours.


Secondary Outcome Measures :
  1. Complete or partial immune tolerance [ Time Frame: Up to 33 months of treatment ]
    Proportion of subjects who achieve either complete or partial immune tolerance within 33 months of initiation of ITI. Partial immune tolerance is defined as achieving inhibitor level <5 BU or FVIII:C plasma recovery <66% of the predicted normal value or FVIII:C half-life of <6 hours and having a clinical response to FVIII therapy.

  2. Complete or partial immune tolerance without relapse [ Time Frame: Up to 12 months ]
    Proportion of subjects who maintain complete immune tolerance or partial immune tolerance without relapse during the Prophylactic Phase. For subjects who have achieved complete immune tolerance, relapse is defined as a return of FVIII inhibitor titer to detectable levels or FVIII:C recovery <66% of the predicted normal value or FVIII:C half-life <6 hours. For subjects who have achieved partial immune tolerance, relapse is defined as an increase of FVIII inhibitor titer to at least 5 BU.

  3. Frequency of bleeding events [ Time Frame: Up to 45 months ]
    Annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase


Other Outcome Measures:
  1. Treatment-emergent adverse events [ Time Frame: Up to 45 months ]
    Incidence of treatment-emergent adverse events during the ITI Treatment Phase and Prophylactic Phase



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Ages Eligible for Study:   up to 8 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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 up to 8 years (and at least 2 years of age if in India) at the Baseline Visit.
  • The subject's documented historical peak inhibitor titer is ≥10 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03095287


Contacts
Contact: Donna Babiar +1 919-316-2098 donna.babiar@grifols.com
Contact: Michael Woodward +34 938008784 michael.woodward@grifols.com

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

Responsible Party: Grifols Therapeutics LLC
ClinicalTrials.gov Identifier: NCT03095287     History of Changes
Other Study ID Numbers: GBI1406
First Posted: March 29, 2017    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Grifols Therapeutics LLC:
Factor VIII
von Willebrand Factor
Plasma-derived
Inhibitors
Immune tolerance induction
ITI
Antibodies
Hemophilia A

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants