Hemophilia APhase 3EPICNCT01376700
Early Prophylaxis Immunologic Challenge (EPIC) Study
A Phase 3 study testing Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM) in people with Hemophilia A, run by Baxalta now part of Shire at 19 sites in 12 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages Up to 1 year, men only
- Conditions the study is for
- Hemophilia A
- What is being tested?
- Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 19 sitesin 12 countries
- Study dates
- 26 Aug 2011to 16 Nov 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 1 year
- Men only
- No healthy volunteers
- Child
Who may be able to join
- 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)
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
19 sites in 12 countries.
19 sites in 12 countries
Germany4 sites
Study site
Bonn
Study site
Bremen
Study site
Giessen
Study site
Munich
Russia3 sites
Study site
Chelyabinsk
Study site
Krasnodar
Study site
Saint Petersburg
United States2 sites
Study site
Indianapolis, Indiana
Study site
New Brunswick, New Jersey
About this study
Official title: A Phase 3b Clinical Study to Assess Whether Regular Administration of ADVATE in the Absence of Immunological Danger Signals Reduces the Incidence Rate of Inhibitors in Previously Untreated Patients With Hemophilia A
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
- Being tested
- Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)Biological
Also called ADVATE
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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
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).
Measured: 50 exposure days to ADVATE
Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment
Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 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).
Measured: 50 exposure days to ADVATE
Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors
- High FVIII inhibitor titer (> 5 Bethesda Unit (BU)/mL) - Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL)
Measured: 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)
Nominal Dosing Frequency: - 1 time per week - 2 times per week - Unknown dosing frequency (UK) Bleeding Type (BT): - Skin - Muscle and Soft Tissue - Mucosal - Joint - Other - Multiple - Total Bleeding severity: - Minor - Moderate - Severe - Total
Measured: 50 exposure days to ADVATE
Number and Type of Surgeries
- Elective surgery is not allowed during period of first 20 exposure days (EDs) - Peripherally inserted central catheter (PICC)
Measured: 50 exposure days to ADVATE
Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation
Measured: 50 exposure days to ADVATE
Total Factor VIII (FVIII) Consumption by Participant
Measured: 50 exposure days to ADVATE
FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)
Measured: 50 exposure days to ADVATE
Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE
Possibly or probably related adverse events
Measured: 50 exposure days to ADVATE
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2011 (estimated)
- Study start26 Aug 2011
- Primary completion16 Nov 2012
- Study completion16 Nov 2012
Why it stopped: It became unlikely to achieve the study objective of 50% reduction over published inhibitor rates. The Data Monitoring Committee supported this decision.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hemophilia AStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baxalta now part of Shire
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Baxter Innovations GmbH
- Responsible party
- Sponsor
- Investigators
- Study Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01376700
- Sponsor's protocol ID
- 061002
- Other IDs
- 2011-000410-18
- Acronym
- EPIC
- Status last verified
- Apr 2021
- First submitted
- 17 Jun 2011
- Last updated
- 24 May 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 25912619
Study at a glance
From the registry record, last updated by the sponsor on 24 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 3b Clinical Study to Assess Whether Regular Administration of ADVATE in the Absence of Immunological Danger Signals Reduces the Incidence Rate of Inhibitors in Previously Untreated Patients With Hemophilia A
- ClinicalTrials.gov ID
- NCT01376700
- Acronym / sponsor ID
- EPIC / 061002
- Conditions
- Hemophilia A
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: It became unlikely to achieve the study objective of 50% reduction over published inhibitor rates. The Data Monitoring Committee supported this decision.
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Baxalta now part of ShireIndustry (pharma, biotech, devices)
- Collaborators
- Baxter Innovations GmbH
- Study start
- 26 Aug 2011 (actual)
- Primary completion
- 16 Nov 2012 (actual)
- Study completion
- 16 Nov 2012 (actual)
- First posted
- 20 Jun 2011 (estimated)
- Results
- Posted 9 Oct 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ADVATE - Prophylactic Regimen | Experimental | Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)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. |
Who may qualify
- Ages
- Up to 1 year
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)Also: ADVATEIntravenous 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. | Biological | ADVATE - Prophylactic Regimen |
Primary outcome
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
Time frame: 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).
9 secondary outcomes
Number of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE
Time frame: 50 exposure days to ADVATE
Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment
Time frame: 50 exposure days to ADVATE
Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors
Time frame: 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)
Time frame: 50 exposure days to ADVATE
Number and Type of Surgeries
Time frame: 50 exposure days to ADVATE
Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation
Time frame: 50 exposure days to ADVATE
Total Factor VIII (FVIII) Consumption by Participant
Time frame: 50 exposure days to ADVATE
FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)
Time frame: 50 exposure days to ADVATE
Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE
Time frame: 50 exposure days to ADVATE
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 May 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 25912619Auerswald 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Director study director
Takeda
19 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM) in people with Hemophilia A, run by Baxalta now part of Shire at 19 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 24 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Germany, Russia, United States, Poland, Austria and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Oct 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: 50 exposure days to ADVATE). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01376700, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 May 2021.