Hemophilia APhase 3HAVEN 1NCT02622321
A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors
A Phase 3 study testing Emicizumab, rFVIIa and aPCC in people with Hemophilia A, run by Hoffmann-La Roche at 44 sites in 14 countries.
Trial summary
This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Hemophilia A
- What is being tested?
- Emicizumab, rFVIIa and aPCC
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 113 participants
- Where
- 44 sitesin 14 countries
- Study dates
- 18 Nov 2015to 1 Dec 2020
- 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 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Body weight >/= 40 kilograms (kg) at the time of screening
- Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor ( that is [i.e.], >/= 5 Bethesda Units [BU])
- Documentation of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks
- >/= 6 bleeds in the last 24 weeks prior to screening (if on an episodic bypassing agent regimen) or >/=2 bleeds in the last 24 weeks prior to screening (if on a prophylactic bypassing agent regimen)
- Adequate hematologic, hepatic and renal function
- For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined highly effective contraceptive methods
Who cannot join
- Participants with inherited or acquired bleeding disorder other than hemophilia A
- Participants with ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with Factor VIII (FVIII), with the exception of participants who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis
- Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
- Participants with other conditions (for example [e.g.], certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
- History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
- Known human immunodeficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count < 200 cells per microliter (cells/mcL) within 24 weeks prior to screening
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- Use of systemic immunomodulators (e.g., interferon or rituximab) at enrolment or planned use during the study, with the exception of antiretroviral therapy
- Participants who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous medical or family history of TMA), in the investigator's judgment
- Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the participant's safe participation in and completion of the study or interpretation of the study results
- Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
- Receipt of emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; An investigational drug concurrently
- Unwillingness to use highly effective contraception methods for the specified duration in the protocol (females only, unless required otherwise by the local health authority)
- Clinically significant abnormality on screening evaluations or laboratory tests that, in the opinion of the investigator, may pose an additional risk in administering study drug to the participant
- Pregnancy or lactation, or intent to become pregnant during the study
Trial locations and contacts
44 sites in 14 countries.
44 sites in 14 countries
United States11 sites
Winship Cancer Institute
Atlanta, Georgia, 30322
University of Colorado Denver, Children's Hospital
Aurora, Colorado, 80045
Boston Childrens Hospital
Boston, Massachusetts, 02115
Children's Hospital of Michigan; Pediatrics
Detroit, Michigan, 48201
Pennsylvania State Hershey Medical Center; Division of Hematology/Oncology, H046
Hershey, Pennsylvania, 17033-0850
Univ of TX Health Science Ctr; Gulf States Hemo and Throm Ctr
Houston, Texas, 77030
Children's Hospital Los Angeles
Los Angeles, California, 90010
Cornell Univ Medical College; Hematology-Oncolog
New York, New York, 10021
Oregon Health & Science Uni ; Dept of Pediatrics
Portland, Oregon, 97201
Santa Monica Oncology Center
Santa Monica, California, 90403
Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia
Seattle, Washington, 98104
Japan7 sites
Nagoya University Hospital
Aichi, 466-8560
Hiroshima University Hospital
Hiroshima, 734-8551
Hyogo College of Medicine Hospital
Hyōgo, 663-8501
St. Marianna University School of Medicine Hospital
Kanagawa, 216-8511
Hospital of the University of Occupational and Environmental Health,Japan
Kitakyushu-shi, 807-8556
Nara Medical University Hospital
Nara, 634-8522
Tokyo Medical University Hospital
Tokyo, 160-0023
France4 sites
Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique
Bron, 69677
CH de Bicetre; Centre de Traitement d' Hemophilie
Le Kremlin-Bicêtre, 94275
Hopital Cardiologique; Hematologie B
Lille, 59037
Groupe Hospitalier Necker Enfants Malades
Paris, 75015
Poland4 sites
Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii
Gdansk, 80-952
SPSK Nr1 Klinika Hematoo&Transpl.Szpiku
Lublin, 20-081
ALVAMED Lekarskie Gabinety Specjalistyczne
Poznan, 60-549
Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych
Warsaw, 02-776
Germany3 sites
Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin
Bonn, 53127
CTC North GmbH & Co. KG am Universitätsklinikum Hamburg-Eppendorf
Hamburg, 20251
Hämophilie-Zentrum Rhein Main GmbH
Mörfelden-Walldorf, 64546
Spain3 sites
Hospital Universitario la Paz; Servicio de Hematologia
Madrid, 28046
Hospital Universitario Virgen del Rocio; Servicio de Hematologia
Seville, 41013
Hospital Universitario la Fe; Servicio de Hematologia
Valencia, 46026
United Kingdom3 sites
Cardiff and Vale NHS Trust
Cardiff, CF14 4XW
St Thomas' Hospital; Haemostasis & Thromboisis Centre
London, SE1 7EH
Oxford University Hospitals NHS Trust - Churchill Hospital
Oxford, OX3 7LE
Australia2 sites
Royal Prince Alfred Hospital; Haematology
Camperdown, New South Wales, 2050
The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit
Melbourne, Victoria, 3004
Italy2 sites
AOU Careggi; SOD Malattie Emorragiche
Florence, Tuscany, 50134
IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi"
Milan, Lombardy, 20122
New Zealand1 site
Auckland City Hospital; Auckland Haemophilia Centre
Auckland, 1023
South Africa1 site
Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center
Johannesburg, 2193
About this study
Official title: A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors
This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent participants will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than [<] 9 or greater than or equal to [>/=] 9 bleeds); Arm B participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Prophylactic bypassing agent participants will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last participant has enrolled in Arms A or B or until approximately 50 participants have enrolled in Arm C, whichever occurs first. Episodic bypassing agent participants who previously participated in the non-interventional study BH29768 (NCT02476942) who were unable to enroll in Arms A or B, or participants on prophylactic bypassing agents who were unable to enroll in Arm C, prior to their closure will have the opportunity to enroll in Arm D. Like participants in Arms A and C, Arm D participants will receive emicizumab prophylaxis from the start of the trial. All participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, preferably with recombinant activated factor VII (rFVIIa).
- Conditions
- Hemophilia A
- Being tested
- Emicizumab, rFVIIa, aPCC
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EmicizumabDrug
Also called Hemlibra, RO5534262, RG6013, ACE910
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.
rFVIIaDrug
Also called NovoSeven®
Participants will continue to receive rFVIIa.
aPCCDrug
Also called Factor Eight Inhibitor Bypassing Activity (FEIBA®)
Participants will continue to receive aPCC.
| Study group | Role | What they receive |
|---|---|---|
| Arm A: 1.5 mg/kg Emicizumab QW | Experimental | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Receives: Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC |
| Arm B (Control): No Prophylaxis, Then Emicizumab | Active comparator | Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Receives: Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC |
| Arm C: 1.5 mg/kg Emicizumab QW | Experimental | Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Receives: Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC |
| Arm D: 1.5 mg/kg Emicizumab QW | Experimental | Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Receives: Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Secondary outcomes (28)
Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of all bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
This was an intra-participant comparison of the ABRs for treated bleeds in Arm A participants who had previously received episodic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm A NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm A). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
Measured: Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of treated joint bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Bleeds due to surgery/procedure were excluded.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
This was an intra-participant comparison of the annualized bleed rates (ABRs) for all bleeds in Arm C participants who had previously received prophylactic bypassing agents during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of all bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
This was an intra-participant comparison of the ABRs for treated bleeds in Arm C participants who had previously received bypassing agent prophylaxis during the non-interventional study (NIS) BH29768 (NCT02476942) (Arm C NIS) prior to entry in this study versus emicizumab prophylaxis during this study (Arm C). The number of treated bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, efficacy period ended the day before the first day on the up-titrated dose.
Measured: Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of treated spontaneous bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of treated target joint bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health).
Measured: Week 25
Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life.
Measured: Week 25
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Measured: Week 25
EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed).
Measured: Week 25
Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old)
The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children's health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Baseline was defined as the last assessment prior to treatment. Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose; baseline for Arm B (Emi) is the same as Week 25 for Arm B (Control).
Measured: Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
The number of bleeds over the efficacy period was assessed as an ABR using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. All bleeds included both treated and non-treated bleeds. Treated spontaneous bleeds: treated bleeds with no known contributing factor (e.g., trauma, surgery). Treated joint bleeds: treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: swelling/warmth, pain/decreased range of motion (RoM), or difficulty moving the joint. Treated target joint bleeds: treated joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. For all types of bleeds: the 72-hour rule was implemented, and bleeds due to surgery/procedure and bleeds after up-titration were excluded.
Measured: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of treated bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: a bleed for which coagulation factors were administered. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of all bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds included both treated bleeds (with coagulation factors) and non-treated bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
The number of treated spontaneous bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
Measured: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale
Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. For participants whose emicizumab dose was up-titrated, only data before up-titration is included. aPCC = activated prothrombin complex concentrate; Hypersens.= hypersensitivity
Measured: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study
'Total ADA Negative' is the sum of all subjects who tested negative for ADA in the 2 following categories: 'ADA Negative', those who are pre-dose ADA negative or are missing pre-dose ADA data and who have all negative post-dose ADA results; and 'ADA Negative (Treatment Unaffected)', a subset who are pre-dose ADA positive but do not have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement. 'Total ADA Positive' is the sum of all subjects who tested positive for ADA in the 2 following categories: 'ADA Positive (Treatment Boosted)', those who are pre-dose ADA positive and have a ≥4-fold increase in post-dose ADA levels compared to baseline measurement; and 'ADA Positive (Treatment Induced)', those who are pre-dose ADA negative or missing data and who have at least one post-dose ADA positive sample. ADA-positive samples were further analyzed for neutralizing capacity using a modified FVIII chromogenic assay; if also positive, they were considered neutralizing ADAs.
Measured: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
Plasma Trough Concentrations of Emicizumab at Specified Timepoints
Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Because participants in Arm B switched from episodic bypassing agents to start receiving emicizumab prophylaxis after Week 24, the timepoints for Arm B (Emi) are expressed relative to first emicizumab dose.
Measured: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2015 (estimated)
- Study start18 Nov 2015
- Primary completion25 Oct 2016
- Study completion1 Dec 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 (2)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 Hoffmann-La RocheThe 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 113 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Chugai Pharmaceutical
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02622321
- Sponsor's protocol ID
- BH29884
- Other IDs
- 2015-002866-21, 2015
- Acronym
- HAVEN 1
- Status last verified
- May 2021
- First submitted
- 2 Dec 2015
- Last updated
- 24 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Expanded access
- Available
Publications
Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, Croteau SE, Lambert T, Kempton CL, Pipe SW, Ko RH, Trzaskoma B, Dhalluin C, Bienz NS, Niggli M, Lehle M, Paz-Priel I, Young G, Jimenez-Yuste V. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Adv. 2022 Dec 27;6(24):6140-6150. doi: 10.1182/bloodadvances.2022007458.
PubMed 35939785Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.
PubMed 28691557
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors
- ClinicalTrials.gov ID
- NCT02622321
- Acronym / sponsor ID
- HAVEN 1 / BH29884
- Conditions
- Hemophilia A
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 113 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Collaborators
- Chugai Pharmaceutical
- Study start
- 18 Nov 2015 (actual)
- Primary completion
- 25 Oct 2016 (actual)
- Study completion
- 1 Dec 2020 (actual)
- First posted
- 4 Dec 2015 (estimated)
- Results
- Posted 24 Nov 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent participants will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than [<] 9 or greater than or equal to [>/=] 9 bleeds); Arm B participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Prophylactic bypassing agent participants will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last participant has enrolled in Arms A or B or until approximately 50 participants have enrolled in Arm C, whichever occurs first. Episodic bypassing agent participants who previously participated in the non-interventional study BH29768 (NCT02476942) who were unable to enroll in Arms A or B, or participants on prophylactic bypassing agents who were unable to enroll in Arm C, prior to their closure will have the opportunity to enroll in Arm D. Like participants in Arms A and C, Arm D participants will receive emicizumab prophylaxis from the start of the trial. All participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, preferably with recombinant activated factor VII (rFVIIa).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm A: 1.5 mg/kg Emicizumab QW | Experimental | Drug: Emicizumab, Drug: rFVIIa, Drug: aPCCParticipants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Arm B (Control): No Prophylaxis, Then Emicizumab | Active comparator | Drug: Emicizumab, Drug: rFVIIa, Drug: aPCCParticipants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Arm C: 1.5 mg/kg Emicizumab QW | Experimental | Drug: Emicizumab, Drug: rFVIIa, Drug: aPCCParticipants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
| Arm D: 1.5 mg/kg Emicizumab QW | Experimental | Drug: Emicizumab, Drug: rFVIIa, Drug: aPCCParticipants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Body weight >/= 40 kilograms (kg) at the time of screening
- Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor ( that is [i.e.], >/= 5 Bethesda Units [BU])
- Documentation of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks
- >/= 6 bleeds in the last 24 weeks prior to screening (if on an episodic bypassing agent regimen) or >/=2 bleeds in the last 24 weeks prior to screening (if on a prophylactic bypassing agent regimen)
- Adequate hematologic, hepatic and renal function
Key exclusion criteria (14 listed)
- Participants with inherited or acquired bleeding disorder other than hemophilia A
- Participants with ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with Factor VIII (FVIII), with the exception of participants who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis
- Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
- Participants with other conditions (for example [e.g.], certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
- History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
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 |
|---|---|---|
| EmicizumabAlso: Hemlibra, RO5534262, RG6013, ACE910Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly. | Drug | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis, Then Emicizumab, Arm C: 1.5 mg/kg Emicizumab QW, Arm D: 1.5 mg/kg Emicizumab QW |
| rFVIIaAlso: NovoSeven®Participants will continue to receive rFVIIa. | Drug | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis, Then Emicizumab, Arm C: 1.5 mg/kg Emicizumab QW, Arm D: 1.5 mg/kg Emicizumab QW |
| aPCCAlso: Factor Eight Inhibitor Bypassing Activity (FEIBA®)Participants will continue to receive aPCC. | Drug | Arm A: 1.5 mg/kg Emicizumab QW, Arm B (Control): No Prophylaxis, Then Emicizumab, Arm C: 1.5 mg/kg Emicizumab QW, Arm D: 1.5 mg/kg Emicizumab QW |
Primary outcome
Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.
28 secondary outcomes
Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
Time frame: Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
Time frame: Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks
Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
Time frame: Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
Time frame: Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks
Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)
Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: Week 25
Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: Week 25
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: Week 25
EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
Time frame: Week 25
Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old)
Time frame: Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
Time frame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
Time frame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
Time frame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
Time frame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale
Time frame: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study
Time frame: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
Plasma Trough Concentrations of Emicizumab at Specified Timepoints
Time frame: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35939785Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, Croteau SE, Lambert T, Kempton CL, Pipe SW, Ko RH, Trzaskoma B, Dhalluin C, Bienz NS, Niggli M, Lehle M, Paz-Priel I, Young G, Jimenez-Yuste V. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Adv. 2022 Dec 27;6(24):6140-6150. doi: 10.1182/bloodadvances.2022007458.
- Derived from this study: PubMed 28691557Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.
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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.
Clinical Trials study director
Hoffmann-La Roche
44 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Emicizumab, rFVIIa and aPCC in people with Hemophilia A, run by Hoffmann-La Roche at 44 sites in 14 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 14 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 24 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 44 sites in United States, Japan, France, Poland, Germany and 9 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 24 Nov 2017). 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?
Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis (time frame: From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] 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 NCT02622321, which also lists 2 linked publications.
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 Jun 2021.