A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

NCT03191799 | Completed Phase 3 Results DMC

• 2 other identifiers: MO391292016-004366-25
• Study Type: interventional
• Target: 195
• Locations: 24 countries
• Sites: 72

Brief Summary

This is a phase IIIb, single arm, open-label, multi-center study to evaluate the safety and tolerability of emicizumab in participants with congenital hemophilia A who have documented inhibitors against Factor VIII (FVIII) at enrollment. Approximately 200 participants, aged 12 or older, will be enrolled in this study and are expected to be enrolled at approximately 85 sites globally. Participants will receive an initial weekly dose of prophylactic emicizumab subcutaneously for 4 weeks, followed by a weekly maintenance dose subcutaneously for the remainder of the 2-year treatment period.

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (9)

• Overall Summary of the Number of Participants With Adverse Events, Severity Assessed According to the World Health Organization (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. aPCC = activated prothrombin complex concentrate

  From Baseline until study completion (up to 2 years)

• Adverse Events (AEs) Rates Per 100 Patient-Years for All-Grade AEs, Serious AEs, and Grade ≥3 AEs

  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. The AE rate per 100 patient-years was computed as follows: AE Rate = (Number of AEs observed/ Total patient-years at risk)\*100. Total patient-years at risk is the sum over all patients of the time intervals (in years) between start of study therapy (study day 1) and the end of follow up.

  From Baseline until study completion (up to 2 years)

• Number of Participants by Hematology and Biochemistry Laboratory Parameter Test Results as Shifts From the WHO Toxicity Grade at Baseline to the Worst WHO Toxicity Grade Post-Baseline

  The World Health Organization (WHO) toxicity grading scale was used for determining the severity of laboratory abnormalities (i.e., test results outside of the reference range) for hematology and biochemistry parameters; Grade 0 is normal and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). Not every laboratory abnormality qualified as an adverse event (AE). A laboratory test result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. Baseline was defined as the last available assessment prior to first receipt of study drug. Abs = absolute count; SGOT/AST = aspartate aminotransferase; SGPT/ALT = alanine aminotransferase

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Body Temperature at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Systolic Blood Pressure at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Diastolic Blood Pressure at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Pulse Rate at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Respiratory Rate at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

• Change From Baseline in Body Weight at Specified Timepoints

  Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

  Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Secondary Outcomes (39)

• Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds

  From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)

• Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds

  From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)

• Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds

  From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)

• Percentage of Participants by the Categorized Number of Bleeds for Treated Bleeds

  From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)

• Percentage of Participants by the Categorized Number of Bleeds for All Bleeds

  From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks)

Study Arms (1)

1.5 mg/kg Emicizumab QW

EXPERIMENTAL

Participants will receive initial weekly doses of prophylactic emicizumab subcutaneously for 4 weeks, followed by maintenance doses consisting of half the initial dose, administered subcutaneously for the remainder of the 2-year treatment period

Drug: Emicizumab

Interventions

Emicizumab DRUG

Initial dosing will be 3 mg/kg/week subcutaneously for 4 weeks; Maintenance dosing will follow at 1.5 mg/kg/week subcutaneously for the remainder of the 2-year treatment period

Also known as: Hemlibra, RO5534262, ACE910

1.5 mg/kg Emicizumab QW

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• As per investigator's judgement, a willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the patient-reported outcome (PRO) questionnaires and bleed diaries through the use of an electronic device or paper
• Aged 12 years or older at the time of informed consent
• Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII
• Documented treatment with bypassing agents or FVIII concentrates in the last 6 months (on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day before starting emicizumab
• Adequate hematologic, hepatic, and renal function
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of \<1% per year during the treatment period and for at least five elimination half-lives (24 weeks) after the last dose of emicizumab

You may not qualify if:

• Inherited or acquired bleeding disorder other than hemophilia A
• Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy (prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-hour washout period prior to the first emicizumab administration
• History of illicit drug or alcohol abuse within 12 months prior to screening, as per the investigator's judgment
• High risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA), as per the investigator's judgment
• 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
• Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
• History of clinically significant hypersensitivity reaction associated with monoclonal antibody therapies or components of the emicizumab injection
• Known human immunodeficiency virus (HIV) infection with CD4 count \<200 cells/μL within 6 months prior to screening
• Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of antiretroviral therapy
• 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 patient's safe participation in and completion of the study or interpretation of the study results
• Receipt of: Emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within five half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or five half-lives, whichever is shorter; or, Any concurrent investigational drug.
• Pregnancy or lactation, or intent to become pregnant during the study
• Positive serum pregnancy test result within 7 days prior to initiation of emicizumab (females only)

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (72)

Royal Prince Alfred Hospital; Haematology

Camperdown, New South Wales, 2050, Australia

Location

Alfred Hospital

Melbourne, Victoria, 3004, Australia

Location

Fiona Stanley Hospital

Murdoch, Western Australia, 6150, Australia

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Centro de Hematologia E Hemoterapia Do Parana - Hemepar

Curitiba, Paraná, 80045-145, Brazil

Location

Instituto Estadual de Hema

Rio de Janeiro, Rio de Janeiro, 20211-030, Brazil

Location

Hospital das Clinicas - UNICAMP

Campinas, São Paulo, 13083-888, Brazil

Location

Faculdade de Medicina de Ribeirão Preto - Universidade de Sao Paulo

Ribeirão Preto, São Paulo, 14051-140, Brazil

Location

Kaye Edmonton Clinic

Edmonton, Alberta, T6G 2V2, Canada

Location

CancerCare Manitoba; Neuro-Oncology

Winnipeg, Manitoba, R2H 2A6, Canada

Location

McMaster University Health Sciences Center

Hamilton, Ontario, L8N 3Z5, Canada

Location

St. Michael's Hospital

Toronto, Ontario, M5B 1W8, Canada

Location

Centro de Atención e Investigación Médica CAIMED S.A.S

Localidad Puente Aranda, 111611, Colombia

Location

Hospital Pablo Tobon Uribe

Medellín, 050034, Colombia

Location

Helsingin yliopistollinen keskussairaala, Meilahden sairaala

Helsinki, 00290, Finland

Location

Vivantes Klinikum im Friedrichshain - Landsberger Allee, Angiologie und Hämostaseologie

Berlin, 10249, Germany

Location

Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin

Bonn, 53127, Germany

Location

Hämophiliezentrum Med. Klinik III/Institut für Transfusionsmedizin; Johann Wolfgang Goethe-Univers.

Frankfurt/M., 60590, Germany

Location

Universitätsklinikum Leipzig, Innere Medizin, Neurologie, Dermatologie; Zentrum für Hämostaseologie

Leipzig, 04103, Germany

Location

Hämophilie-Zentrum Rhein Main GmbH

Mörfelden-Walldorf, 64546, Germany

Location

Klinikum der Universität München, Campus Innenstadt; Hämostaseologische Ambulanz/Hämophiliezentrum

München, 80336, Germany

Location

Oncomedica

Guatemala City, 01010, Guatemala

Location

Magyar Honvédség Egészségügyi Központ; Országos Haemophilia Központ

Budapest, 1134, Hungary

Location

Országos Vérellátó Szolgálat - Győri Regionális Vérellátó Központ

Győr, 9023, Hungary

Location

University of Pecs, I st Dept of Internal Medicine

Pécs, 7624, Hungary

Location

St. John's Medical College & Hospital; Department of Medicine

Bengaluru, Karnataka, 560034, India

Location

King Edward Memorial Hospital and Seth G.S. Medical College; Department of Hematology

Mumbai, Maharashtra, 400012, India

Location

Fortis Hospitals Limited

Mumbai, Maharashtra, 400078, India

Location

Sahyadri Speciality Hospital; Hematology & Bone Marrow Unit

Pune, Maharashtra, 411004, India

Location

Christian Medical College & Hospital; Department of Haematology

Vellore, Maharashtra, 632004, India

Location

Nil Ratan Sircar Medical College and Hospital; Department of Hematology

Kolkata, West Bengal, 700014, India

Location

Grant Medical Foundation, Ruby Hall Clinic

Pune, 411001, India

Location

Sheba Medical Center - National Hemophilia Center

Tel Litwinsky, 5262100, Israel

Location

AOU Federico II; Medicina Clinica Chirurgia Centro Emocoaugulopatie e Emofilia

Napoli, Campania, 80131, Italy

Location

AOU Policlinico S. Orsola Malpighi; U.O. Angiologia e Malattie della Coagulazione Marino Golinelli

Bologna, Emilia-Romagna, 40138, Italy

Location

AOU di Parma; Dip Emergenza-Urgenza Centro Riferimento Regionale per l'emofilia

Parma, Emilia-Romagna, 43126, Italy

Location

Universita' Degli Studi La Sapienza-Ist.Di Ematologia; Dip Biot Cel e Ematol

Rome, Lazio, 00161, Italy

Location

IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi"

Milan, Lombardy, 20122, Italy

Location

AO Città Salute e Scienza D-Osp S. G. Battista Molinette; SSCVD Malattie Tromboti e Emorragiche

Turin, Piedmont, 10126, Italy

Location

Azienda Uni Ria Policlinico P. Giaccone ; Divisione Di Ematologia E Trapianto

Palermo, Sicily, 90127, Italy

Location

AOU Careggi; SOD Malattie Emorragiche

Florence, Tuscany, 50134, Italy

Location

Azienda Ospedaliera di Padova; Centro Emofilia

Padua, Veneto, 35128, Italy

Location

Hospital General de México

Distrito Federal, Mexico CITY (federal District), 06726, Mexico

Location

CENTRO MEDICO NACIONAL SIGLO XXI; Banco de Sangre

Mexico City, Mexico CITY (federal District), 06720, Mexico

Location

Hospital de Especialidades Centro Medico Nacional La Raza; Haematology

Mexico City, 02990, Mexico

Location

Erasmus MC / location Sophia Kinderziekenhuis

Rotterdam, 3015 GJ, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

Complejo Hospitalario Arnulfo Arias Madrid; Servicio de Hematología

Panama City, 0824, Panama

Location

Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, 02-776, Poland

Location

Hospital Geral; Servico de Imuno-Hemoterapia

Coimbra, 3041-853, Portugal

Location

Hospital de Santa Maria; Servico de Imuno-Hemoterapia; Servico de Imuno-Hemoterapia

Lisbon, 1649-035, Portugal

Location

Hospital de Sao Joao; Servico de Imuno-Hemoterapia; Servico de Imuno-Hemoterapia

Porto, 4200-319, Portugal

Location

Louis Turcanu Emergency Clinical Hospital for Children; First Pediatric Clinic

Timișoara, 300011, Romania

Location

Regional State Budgetary Institution of Healthcare "Regional Cinilcal Hospital"; Pulmonology

Barnaul, Altayskiy Kray, 656024, Russia

Location

Morozov Children's Municipal Clinical Hospital. Haematology department

Moscow, 119049, Russia

Location

"Hematological Scientific Center

Moscow, 125167, Russia

Location

City Outpatient Clinic #37, City Hemophilia Treatment Center

Saint Petersburg, 191186, Russia

Location

Samara State Medical University

Samara, 443099, Russia

Location

King Faisal Specialist Hospital & Research Centre; Oncology

Riyadh, 11211, Saudi Arabia

Location

Hospital Universitario Vall de Hebron; Unidad de Hemofília

Barcelona, 08035, Spain

Location

Hospital Universitario la Paz; Servicio de Hematologia

Madrid, 28046, Spain

Location

Hospital Regional Universitario Carlos Haya; Servicio de Hematologia

Málaga, 29010, Spain

Location

Hospital Universitario Virgen del Rocio; Servicio de Hematologia

Seville, 41013, Spain

Location

Hospital Universitario la Fe; Servicio de Hematologia

Valencia, 46026, Spain

Location

Sahlgrenska Universitetssjukhuset; Koagulationscentrum

Gothenburg, 413 45, Sweden

Location

Karolinska Universitetssjukhuset; Koagulationsmottagningen

Solna, 171 64, Sweden

Location

Inselspital Bern; Hämatologie und Hämatologisches Zentrallabor

Bern, 3010, Switzerland

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, B15 2TH, United Kingdom

Location

The Royal London Hospital

London, E1 2ES, United Kingdom

Location

Royal Free Hospital

London, NW3 2QS, United Kingdom

Location

Royal Victoria Infirmary; Non-Malignant Haematology Research

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

Royal Hallamshire Hospital Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, S10 2JF, United Kingdom

Location

Related Publications (1)

• Castaman G, Peyvandi F, Kremer Hovinga JA, Schutgens REG, Robson S, Moreno K, Jimenez-Yuste V. Surgical Experience from the STASEY Study of Emicizumab Prophylaxis in People with Hemophilia A with Factor VIII Inhibitors. TH Open. 2024 Jan 12;8(1):e42-e54. doi: 10.1055/s-0043-1777766. eCollection 2024 Jan.

  PMID: 38222041 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: June 15, 2017
• First Posted: June 19, 2017
• Study Start: September 5, 2017
• Primary Completion: November 19, 2020
• Study Completion: November 19, 2020
• Last Updated: June 11, 2021
• Results First Posted: June 11, 2021

Record last verified: 2021-05

Locations

PA (1); BR (4); SA (1); ES (5); CH (1); SE (2); GB (5); ME (3); HU (3); PL (1); GU (1); CO (2); BE (1); AU (3); FI (1); DE (6); CA (4); IN (7); NL (2); PT (3); RU (5); RO (1); IT (9); IL (1)