Hemophilia APhase 4ReITIrateNCT03103542
Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies
A Phase 4 study testing Recombinant coagulation factor (rFVIIIFc) in people with Hemophilia A, run by Swedish Orphan Biovitrum at 12 sites in 7 countries.
Trial summary
The primary purpose of this study is to describe the outcome of Immune Tolerance Induction (ITI) treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients with haemophilia A who have failed previous attempts at tolerization. Read more about this study
- Who is it for?
- Any age, men only
- Conditions the study is for
- Hemophilia A
- What is being tested?
- Recombinant coagulation factor (rFVIIIFc)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 12 sitesin 7 countries
- Study dates
- 29 Aug 2017to 31 Aug 2020
- Phase
- Phase 4
- 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 Any age
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations
- Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record
- Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII
- Diagnosed with high titer inhibitors (historical peak ≥5 Bethesda units (BU)/mL according to medical records)
- Inhibitor titer >0.6 BU at screening
- Failed previous ITI attempt(s) with any plasma-derived or recombinant conventional or extended half-life FVIII including the use of immunosuppressant The attempt should be documented in the medical records and have the following characteristics:
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- A minimum FVIII dose equivalent to the low dose arm of the International ITI study (50 IU/kg, 3 times/week)
- A minimum ITI treatment period of 33 months or
- Shorter than 33 months if no downward trend of at least 20% in the inhibitor titer in a 6-month period after the initial 3 months of the ITI treatment
- All patients must practice effective contraception during the study and for 3 months after their last dose of study treatment
Who cannot join
- Other coagulation disorder(s) in addition to haemophilia A
- History of hypersensitivity reactions associated with any rFVIIIFc administration
- High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator
- Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed.
- Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of Hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids
- Abnormal renal function (serum creatinine >2.0 mg/dL) as assessed by local lab
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- Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) as assessed by local lab
- Serum total bilirubin >3 × ULN as assessed by local lab
- Cluster of differentiation 4 (CD4) lymphocytes ≤200 mm3 if known as HIV antibody positive at Screening
- Viral load of ≥400 copies/mL if known HIV antibody positive at Screening
- Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization
- Previous inclusion in this study
- Participation in another concurrent clinical interventional study within 30 days of screening or intake of an investigational drug within five half-lives of that investigational drug has passed
- Foreseeable inability to cooperate with given instructions or study procedures
- Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with rFVIIIFc
Trial locations and contacts
12 sites in 7 countries.
12 sites in 7 countries
Germany3 sites
Swedish Orphan Biovitrum Research Site
Bonn
Swedish Orphan Biovitrum Research Site
Frankfurt am Main
Swedish Orphan Biovitrum Research Site
Mörfelden-Walldorf
United Kingdom3 sites
Swedish Orphan Biovitrum Research Site
Birmingham
Swedish Orphan Biovitrum Research Site
Liverpool
Swedish Orphan Biovitrum Research Site
London, WC1N 3JH
Canada2 sites
Swedish Orphan Biovitrum Research Site
Hamilton
Swedish Orphan Biovitrum Research Site
Vancouver
United States1 site
Swedish Orphan Biovitrum Research Site
Washington D.C., District of Columbia, 20010-2970
About this study
Official title: A Non-Controlled, Open-Label, Multicenter, Study of Immune Tolerance Induction Performed With rFVIIIFc Within a Timeframe of 60 Weeks in Severe Haemophilia A Patients With Inhibitors Who Have Failed Previous Immune Tolerance Induction Therapies
The primary purpose of this study is to describe the outcome of Immune Tolerance Induction (ITI) treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients with haemophilia A who have failed previous attempts at tolerization.
Read the detailed description
This is an open-label, single-arm, interventional multi-center study designed to explore ITI performed with recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc) within a timeframe of 60 weeks in patients with severe haemophilia A, who have failed previous attempts at tolerization including use of immunosuppressants.
- Conditions
- Hemophilia A
- Being tested
- Recombinant coagulation factor (rFVIIIFc)
- Keywords
- ITI, rFVIIIFc, Immune Tolerance Induction
- 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 coagulation factor (rFVIIIFc)Biological
Also called ELOCTA, ELOCTATE
rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement
administered intravenously.
| Study group | Role | What they receive |
|---|---|---|
| Recombinant coagulation factor VIII Fc (rFVIIIFc) | Experimental | Participants will receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 60 Weeks during the ITI Period. Participants who meet the criteria for ITI success will enter a tapering period of 16 weeks where the dose will be tapered down until a prophylactic dose, as judged by the Investigator, is achieved and thereafter a follow-up period of 32 weeks where the patient will continue to receive prophylactic treatment with rFVIIIFc. Receives: Biological: Recombinant coagulation factor (rFVIIIFc) |
What is being measured
The primary outcome is the main question the study is designed to answer.
ITI Success
Number of patients who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria:
- Negative titer for inhibitor (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits
- FVIII incremental recovery (IR) >66% of the expected IR at 2 consecutive visits
- FVIII half-life (t½) ≥7 hours
Measured: up to 60 weeks
Secondary outcomes (11)
Time to ITI Success
Time to the patient reaches ITI success according to the pre-defined criteria
For the subset of patients who were classified as partial success at the end of the ITI period, the time to fulfillment of the criteria for partial success was also analyzed descriptively.
Measured: up to 60 weeks
Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment
Relapse was defined as a positive inhibitor (≥0.6 BU/mL) on 2 consecutive assessments and incremental recovery ≤66 % of the expected incremental recovery on 2 consecutive assessments
Measured: Up to 48 weeks
Number of Bleedings During ITI Treatment
Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode.
Measured: up to 60 weeks
Bleeding Rate During a 48-week Period Following Successful ITI Treatment
Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode.
Measured: up to 48 weeks
Adverse Events (AEs)
All observed adverse events as a measure of tolerability. (AE=adverse event, SAE=serious adverse event, TEAE=treatment emergent adverse event)
Measured: SAEs - approx 166 weeks AEs - approx 110 weeks
Consumption of rFVIIIFc
Consumption will be assessed based on amount of administered study treatment during the ITI period.
Measured: Up to 60 weeks
Number of Days Missed School or Work During ITI Treatment
Days missed school or work will be registered by the patients in an electronic diary
Measured: up to 60 weeks
Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment
Days missed school or work will be registered by the patients in an electronic diary
Measured: up to 48 weeks
Number of Hospitalizations During ITI Treatment
Days of hospitalization will be collected by the Investigator at the study visits
Measured: up to 60 weeks
Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment
Days of hospitalization will be collected by the Investigator at the study visits
Measured: Up to 48 weeks
Adherence
Defined as percentage of administered doses versus planned doses
Measured: up to 108 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2017
- Study start29 Aug 2017
- Primary completion4 Sep 2019
- Study completion31 Aug 2020
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.
- More trials run by Swedish Orphan BiovitrumThe sponsor's other registered studies.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swedish Orphan Biovitrum
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Bioverativ Therapeutics Inc.
- Responsible party
- Sponsor
- Investigators
- Study Physician, Study director, Study Medical Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03103542
- Sponsor's protocol ID
- Sobi.Elocta-003
- Other IDs
- 2017-000065-73, 2017
- Acronym
- ReITIrate
- Status last verified
- Sep 2024
- First submitted
- 31 Mar 2017
- Last updated
- 19 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: According to Sobi's data sharing policy Sobi may share anonymized clinical study data with qualified researchers. Sobi commits to sharing clinical study data on participant level and summary data for medicines and indications approved by EMA and/or FDA. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross functional panel of experts within Sobi.
Publications
Konigs C, Meeks SL, Nolan B, Schmidt A, Lofqvist M, Dumont J, Leickt L, Nayak S, Lethagen S. Rescue immune tolerance induction with a recombinant factor Fc-fused VIII: prospective ReITIrate study of clinical, humoral and cellular immune responses. Ther Adv Hematol. 2024 Nov 23;15:20406207241300809. doi: 10.1177/20406207241300809. eCollection 2024.
PubMed 39583653
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Non-Controlled, Open-Label, Multicenter, Study of Immune Tolerance Induction Performed With rFVIIIFc Within a Timeframe of 60 Weeks in Severe Haemophilia A Patients With Inhibitors Who Have Failed Previous Immune Tolerance Induction Therapies
- ClinicalTrials.gov ID
- NCT03103542
- Acronym / sponsor ID
- ReITIrate / Sobi.Elocta-003
- Conditions
- Hemophilia A
- Keywords
- ITI, rFVIIIFc, Immune Tolerance Induction
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Swedish Orphan BiovitrumIndustry (pharma, biotech, devices)
- Collaborators
- Bioverativ Therapeutics Inc.
- Study start
- 29 Aug 2017 (actual)
- Primary completion
- 4 Sep 2019 (actual)
- Study completion
- 31 Aug 2020 (actual)
- First posted
- 6 Apr 2017 (actual)
- Results
- Posted 30 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary purpose of this study is to describe the outcome of Immune Tolerance Induction (ITI) treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients with haemophilia A who have failed previous attempts at tolerization.
Detailed description
This is an open-label, single-arm, interventional multi-center study designed to explore ITI performed with recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc) within a timeframe of 60 weeks in patients with severe haemophilia A, who have failed previous attempts at tolerization including use of immunosuppressants.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Recombinant coagulation factor VIII Fc (rFVIIIFc) | Experimental | Biological: Recombinant coagulation factor (rFVIIIFc)Participants will receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 60 Weeks during the ITI Period. Participants who meet the criteria for ITI success will enter a tapering period of 16 weeks where the dose will be tapered down until a prophylactic dose, as judged by the Investigator, is achieved and thereafter a follow-up period of 32 weeks where the patient will continue to receive prophylactic treatment with rFVIIIFc. |
Who may qualify
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (10 listed)
- Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations
- Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record
- Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII
- Diagnosed with high titer inhibitors (historical peak ≥5 Bethesda units (BU)/mL according to medical records)
- Inhibitor titer >0.6 BU at screening
Key exclusion criteria (15 listed)
- Other coagulation disorder(s) in addition to haemophilia A
- History of hypersensitivity reactions associated with any rFVIIIFc administration
- High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator
- Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed.
- Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of Hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids
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 coagulation factor (rFVIIIFc)Also: ELOCTA, ELOCTATErFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement administered intravenously. | Biological | Recombinant coagulation factor VIII Fc (rFVIIIFc) |
Primary outcome
ITI Success
Time frame: up to 60 weeks
Number of patients who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: * Negative titer for inhibitor (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits * FVIII incremental recovery (IR) >66% of the expected IR at 2 consecutive visits * FVIII half-life (t½) ≥7 hours
11 secondary outcomes
Time to ITI Success
Time frame: up to 60 weeks
Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment
Time frame: Up to 48 weeks
Number of Bleedings During ITI Treatment
Time frame: up to 60 weeks
Bleeding Rate During a 48-week Period Following Successful ITI Treatment
Time frame: up to 48 weeks
Adverse Events (AEs)
Time frame: SAEs - approx 166 weeks AEs - approx 110 weeks
Consumption of rFVIIIFc
Time frame: Up to 60 weeks
Number of Days Missed School or Work During ITI Treatment
Time frame: up to 60 weeks
Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment
Time frame: up to 48 weeks
Number of Hospitalizations During ITI Treatment
Time frame: up to 60 weeks
Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment
Time frame: Up to 48 weeks
Adherence
Time frame: up to 108 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 39583653Konigs C, Meeks SL, Nolan B, Schmidt A, Lofqvist M, Dumont J, Leickt L, Nayak S, Lethagen S. Rescue immune tolerance induction with a recombinant factor Fc-fused VIII: prospective ReITIrate study of clinical, humoral and cellular immune responses. Ther Adv Hematol. 2024 Nov 23;15:20406207241300809. doi: 10.1177/20406207241300809. eCollection 2024.
- Individual participant dataSharing planned: Yes. According to Sobi's data sharing policy Sobi may share anonymized clinical study data with qualified researchers. Sobi commits to sharing clinical study data on participant level and summary data for medicines and indications approved by EMA and/or FDA. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross functional panel of experts within Sobi.
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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 Physician study director
Study Medical Director
12 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Recombinant coagulation factor (rFVIIIFc) in people with Hemophilia A, run by Swedish Orphan Biovitrum at 12 sites in 7 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 10 inclusion and 15 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: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Germany, United Kingdom, Canada, United States, Ireland and 2 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 30 Nov 2021). 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?
ITI Success (time frame: up to 60 weeks). 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 NCT03103542, 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 19 Sep 2024.