Early Prophylaxis Immunologic Challenge (EPIC) Study

NCT01376700 | Terminated Phase 3 Results DMC

• 2 other identifiers: 0610022011-000410-18
• Study Type: interventional
• Target: 22
• Locations: 12 countries
• Sites: 19

Brief Summary

The purpose of the study was to assess if a once-weekly prophylactic regimen of 25 IU/kg ADVATE started at or before 1 year of age and before the onset of a severe bleeding phenotype (ie, joint bleeding), together with the minimization of immunological danger signals, can reduce the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A.

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Severe and Moderately Severe Hemophilia A (FVIII ≤ 2%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE

  Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing. Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: - i. High FVIII inhibitor titer (\> 5 BU/mL) or - ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).

  50 exposure days to ADVATE

Secondary Outcomes (9)

• Number of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE

  50 exposure days to ADVATE

• Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment

  50 exposure days to ADVATE

• Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors

  50 exposure days to ADVATE

• Number, Type, and Severity of All Bleeds Experienced When Different Prophylactic Dosing Frequencies Are Used (Once or Twice Per Week and Unknown Frequency)

  50 exposure days to ADVATE

• Number and Type of Surgeries

  50 exposure days to ADVATE

Study Arms (1)

ADVATE - Prophylactic Regimen

EXPERIMENTAL

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)

Interventions

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM) BIOLOGICAL

Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Also known as: ADVATE

ADVATE - Prophylactic Regimen

Eligibility Criteria

• Age: Up to 1 Year
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Participants with severe and moderately severe hemophilia A (FVIII ≤ 2%)
• Participants \< 1 year of age
• Participants must have ≤ 3 exposure days (EDs) to any FVIII concentrate or FVIII-containing product used for treatment of minor bleeds (bleeds requiring no more than 2 infusions per event), or for preventative or precautionary infusions following possible injury
• Participants with prior circumcision are allowed to enroll only if bleeding issues related to circumcision were the cause for the original diagnosis of hemophilia A and no more than 2 EDs of FVIII treatment were required
• Adequate venous access (without need for central venous access device (CVAD)-placement) as determined by the physician
• Written informed consent from legally authorized representative(s)

You may not qualify if:

• Life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment
• Evidence of inhibitor ≥ 0.6 Bethesda Unit (BU) in Nijmegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitor test results)
• Inherited or acquired hemostatic defect other than hemophilia A
• Any clinically significant, chronic disease other than hemophilia A
• Known hypersensitivity to ADVATE or any of its constituents
• Any planned elective surgery that cannot be postponed until after the first 20 EDs
• Participation in the Hemophilia Inhibitor Previously Untreated Patient Study
• Application of red blood cell, platelet, or leukocyte concentrates, or plasma
• Administration of any medication affecting coagulation or platelet function
• Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids)
• Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this study

Sponsors & Collaborators

• Baxalta now part of Shire: lead
• Baxter Innovations GmbH: collaborator

Study Sites (19)

Unknown Facility

Indianapolis, Indiana, United States

Location

Unknown Facility

New Brunswick, New Jersey, United States

Location

Unknown Facility

Vienna, Austria

Location

Unknown Facility

Sofia, Bulgaria

Location

Unknown Facility

Kingston, Ontario, Canada

Location

Unknown Facility

Brno, Czechia

Location

Unknown Facility

Bonn, Germany

Location

Unknown Facility

Bremen, Germany

Location

Unknown Facility

Giessen, Germany

Location

Unknown Facility

Munich, Germany

Location

Unknown Facility

Vilnius, Lithuania

Location

Unknown Facility

Nijmegen, Netherlands

Location

Unknown Facility

Lublin, Poland

Location

Unknown Facility

Olsztyn, Poland

Location

Unknown Facility

Chelyabinsk, Russia

Location

Unknown Facility

Krasnodar, Russia

Location

Unknown Facility

Saint Petersburg, Russia

Location

Unknown Facility

Belgrade, Serbia

Location

Unknown Facility

A Coruña, Spain

Location

Related Publications (1)

• Auerswald G, Kurnik K, Aledort LM, Chehadeh H, Loew-Baselli A, Steinitz K, Reininger AJ; EPIC clinical study group. The EPIC study: a lesson to learn. Haemophilia. 2015 Sep;21(5):622-8. doi: 10.1111/hae.12666. Epub 2015 Apr 23.

  PMID: 25912619 RESULT

MeSH Terms

Conditions

Hemophilia A

Interventions

Factor VIII

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Limitations and Caveats

Early termination lead to: -No statistical tests done on risk factors \& inhibitor formation. -FVIII consumption by participant not calculated due to large variation in # of EDs. -FVIII-Specific Antibody Isotypes summary statistics not done.

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2011
• First Posted: June 20, 2011
• Study Start: August 26, 2011
• Primary Completion: November 16, 2012
• Study Completion: November 16, 2012
• Last Updated: May 24, 2021
• Results First Posted: October 9, 2014

Record last verified: 2021-04

Locations

AU (1); RU (3); CA (1); DE (4); CZ (1); NL (1); LI (1); US (2); PL (2); BU (1); SE (1); ES (1)