Clinical trial NCT03095287: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hemophilia A, Congenital
Keywords: Factor VIII
von Willebrand Factor
Plasma-derived
Inhibitors
Immune tolerance induction (ITI)
Antibodies
Hemophilia A
Lead sponsor: Grifols Therapeutics LLC
Sponsor class: INDUSTRY
Collaborators: name: Grifols Biologicals, LLC
First posted: 2017-03-29
Enrollment: 2
Sex: MALE
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants Who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase
timeFrame: Up to 32.5 months
Secondary outcomes:
measure: Percentage of Participants Who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase
timeFrame: Up to 32.5 months
measure: Percentage of Participants Who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase
timeFrame: 12 months during prophylactic phase
measure: Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase
timeFrame: Up to 32.5 months
Other outcomes:
measure: Treatment-emergent Adverse Events
timeFrame: Up to 32.5 months
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Minneapolis
country: United States
facility: Childrens Hospital and Clinics of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: New Brunswick
country: United States
facility: Robert Wood Johnson Medical Group
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center & Children's Hospital of New Jersey
state: New Jersey
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill, Hemophilia and Thrombosis Center
state: North Carolina
city: Seattle
country: United States
facility: Seattle Children's Hospital, Seattle Children's Research Institute
state: Washington
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Mumbai
country: India
facility: Lokmanya Tilak Municipal Medical College & General Hospital
state: Maharashtra
city: Pune
country: India
facility: B. J. Govt. Medical College & Sassoon Hospital
city: Perugia
country: Italy
facility: A.O.U. Santa Maria della Misericordia Perugia
state: Umbria
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Roma
country: Italy
facility: Universita degli Studi di Roma La Sapienza
city: Kemerovo
country: Russian Federation
facility: Kemerovo Regional Clinical Hospital
city: Kirov
country: Russian Federation
facility: FGUs Hospital - Kirov Scientific Research Institute
city: Saint Petersburg
country: Russian Federation
facility: Center for Hemophilia Treatment St.-Petersburg
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
state: Autonomous Community Of Valencia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
Study officials:
References: