A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis

NCT ID: NCT04973137

Last Updated: 2025-12-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 208 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-30
• Study Completion Date: 2025-06-20

Brief Summary

A Phase 3 study to evaluate the efficacy and safety of birtamimab plus standard of care compared to placebo plus standard of care in Mayo Stage IV patients with AL amyloidosis.

Detailed Description

This is a Phase 3 multicenter, global, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of birtamimab in Mayo Stage IV patients with AL amyloidosis (i.e., Double-blind Phase), followed by a long-term, open-label extension (i.e., Open-label Extension [OLE] Phase). The primary objective of the Double-blind Phase is to evaluate the efficacy of birtamimab by assessing time to all-cause mortality. All patients will receive bortezomib-containing chemotherapy regimen as standard of care.

For the Double-blind Phase of the study, approximately 220 newly diagnosed Mayo Stage IV patients with AL amyloidosis will be enrolled and randomized in a 2:1 ratio to birtamimab or placebo. Subjects will remain on study until study completion, when the pre-defined number of events (all-cause mortality) have been reached.

After completion of the Double-blind Phase, eligible subjects may enter the optional OLE Phase, in which all subjects will receive open-label birtamimab treatment, regardless of Double-blind Phase randomized treatment assignment. Treatment in the OLE Phase will continue for an additional 24 months or until birtamimab is commercially available in a subject's country of residence, whichever occurs first (in accordance with country-specific regulations). The primary objective of the OLE Phase is to evaluate the long-term safety of birtamimab plus standard of care in Mayo Stage IV subjects with AL amyloidosis.

Conditions

Light Chain (AL) Amyloidosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Birtamimab plus Standard of Care Chemotherapy- For Double-blind Phase and OLE Phase of study

Intravenous administration of 24 mg/kg birtamimab every 28 days.

Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care.

The initiation of daratumumab treatment at randomization is allowed at the discretion of the Investigator; initiation at any other time during the Double-blind Phase is prohibited. For subjects who did not initiate daratumumab at randomization during the Double-blind Phase, daratumumab may be initiated at any time during the OLE Phase at the Investigator's discretion.

Group Type: EXPERIMENTAL

Standard of Care Chemotherapy

Intervention Type: DRUG

Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care

Birtamimab

Intervention Type: DRUG

Intravenous administration of 24 mg/kg birtamimab every 28 days

Placebo plus Standard of Care Chemotherapy- For Double-blind Phase of study

Intravenous 0.9% Saline administration as a placebo every 28 days.

Drug: Standard of Care Chemotherapy. Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care. Initiation of daratumumab at randomization allowed at the discretion of the investigator.

Group Type: PLACEBO_COMPARATOR

Standard of Care Chemotherapy

Intervention Type: DRUG

Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care

Placebo

Intervention Type: OTHER

Intravenous 0.9% Saline administration as a placebo every 28 days

Interventions

Standard of Care Chemotherapy

Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care

Intervention Type: DRUG

Birtamimab

Intravenous administration of 24 mg/kg birtamimab every 28 days

Intervention Type: DRUG

Placebo

Intravenous 0.9% Saline administration as a placebo every 28 days

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Aged ≥18 years and legal age of consent according to local regulations
• Newly diagnosed and AL amyloidosis treatment-naïve with cardiac involvement
• Confirmed diagnosis of AL amyloidosis
• Confirmed Mayo Stage IV AL Amyloidosis as defined by NT-proBNP ≥1800 pg/mL and Troponin-T ≥0.025 ng/mL or high sensitivity cardiac troponin T≥40ng/L and dFLC ≥18 mg/dL
• Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly

• Must not have discontinued treatment in Double-blind Phase
• WOCBP must have a negative pregnancy test and must agree to use highly effective contraception through 90 days following last study drug administration
• Male subjects must be surgically sterile or agree to use highly effective contraception through 90 days following last study drug administration
• Ability to understand and willingness to sign an ICF prior to initiating the OLE Phase

Exclusion Criteria

• Non-AL amyloidosis
• NT-proBNP >8500 pg/mL
• Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma except for malignancy biomarker of involved/uninvolved serum free light chain ratio ≥100
• Subject is eligible for and plans to undergo ASCT or organ transplant during the study
• Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit
• Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease
• ECG evidence of acute ischemia or active conduction system abnormalities
• Prior treatment with hematopoietic growth factors, transfusions of blood or blood products within 1 week of Month 1-Day 1
• Prior radiotherapy within 4 weeks of Month 1-Day 1
• Prior treatment with plasma cell-directed chemotherapy, birtamimab, daratumumab, 11- 1F4, anti-serum amyloid P antibody, doxycycline for amyloid, or other investigational treatment directed at amyloid
• Waldenström's macroglobulinemia and/or immunoglobulin M monoclonal gammopathy

• Any medical condition or clinically significant abnormality on physical, neurological, laboratory, vital signs, or ECG examination that precludes treatment with birtamimab or participation in the study, in the medical judgment of the Investigator
• Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject's ability to safely receive treatment or complete study assessments
• History of Grade ≥3 infusion-related AEs during the Double-blind Phase or hypersensitivity to birtamimab
• Unable or unwilling to adhere to the study-specified procedures and restrictions
• Planning to use any other investigational treatment during the study

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Prothena Biosciences Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Yale Cancer Center

North Haven, Connecticut, United States

Smilow Cancer Hospital Care Center at Trumbull

Trumbull, Connecticut, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

Cleveland Clinic Florida

Weston, Florida, United States

Johns Hopkins University

Bethesda, Maryland, United States

Boston University School of Med.

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Roswell Park Comprehensive Cancer Center

Buffalo, New York, United States

Perlmutter Cancer Center - 38th Street

New York, New York, United States

Columbia University Irving Medical Center

New York, New York, United States

New York University Langone Hospital - Long Island

New York, New York, United States

Duke Clinical Research Institute

Durham, North Carolina, United States

Cleveland Clinic Main Campus

Cleveland, Ohio, United States

The Ohio State University College of Medicine

Columbus, Ohio, United States

University of Tennessee Medical Center

Knoxville, Tennessee, United States

Vanderbilt - Ingram Cancer Center - Henry-Joyce Cancer Clinic

Nashville, Tennessee, United States

University of Washington

Seattle, Washington, United States

Froedtert and Medical College of Wisconsin

Milwaukee, Wisconsin, United States

SESLHD: St George Hospital

Kogarah, New South Wales, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Paracelsus Medical University

Salzburg, Salzburg, Austria

Paracelsus Medical University

Salzburg, , Austria

Medizinische Universität Wien

Vienna, , Austria

Medizinische Universität

Vienna, , Austria

Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan

Ostend, Oostende, Belgium

Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne

Yvoir, Yvoir, Belgium

AZ Sint-Jan Brugge-Oostende AV

Ostend, , Belgium

CHU UCL Namur (Site Godinne)

Yvoir, , Belgium

Tom Baker Cancer Centre

Calgary, Alberta, Canada

Royal Victoria Hospital

Montreal, Quebec, Canada

Fakultni nemocnice ostrava

Ostrava-Poruba, Moravian-Silesian, Czechia

Všeobecná fakultní nemocnice v Praze

Prague, Prague, Czechia

Odense Universitetshospital

Odense, Region Syddanmark, Denmark

Hôpital Bretonneau

Tours, Centre-Val de Loire, France

Hôpitaux Universitaires Henri Mondor

Créteil, Créteil, France

Hôpital Haut-Lévêque

Pessac, Gironde, France

Pitie-Salpêtrière Hospital

Paris, Ill-de-France, France

Hopital Necker

Paris, Ill-de-France, France

Hôpitaux de Brabois

Vandœuvre-lès-Nancy, Lorraine, France

Hopital Rangueil

Toulouse, Midi-Pyrenees, France

Hôpital Claude Huriez

Lille, Nord, France

CHU Nantes

Nantes, Pays de la Loire Region, France

Centre Hospitalier Universitaire Poitiers

Poitiers, Vienne, France

CHU de Bordeaux

Bordeaux, , France

Hopital Henri Mondor, Creteil

Créteil, , France

Hôpital Necker-Enfants Malades

Paris, , France

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

Uniklinik Köln

Köln, Baden-Wurttemberg, Germany

University Medicine Mainz

Mainz, Rhineland-Palatinate, Germany

Alexandra General Hospital

Athens, Attica, Greece

Theagenio Anti-Cancer Hospital of Thessaloniki

Thessaloniki, Central Macedonia, Greece

University Hospital of Patras

Patra, Peloponnese, Greece

Semmelweis Egyetem - I. sz. Belgyógyászati Klinika

Budapest, Budapest, Hungary

Cork University Hospital

Cork, Munster, Ireland

Cancer Clinical Trials and Research Unit, Beaumont Hospital

Dublin, , Ireland

Bnai Zion Medical Center

Haifa, Haifa District, Israel

Rambam Medical Center

Haifa, Haifa District, Israel

Hadassah Medical Center

Jerusalem, Jerusalem, Israel

Rabin Medical Center - Beilinson Hospital

Ashkelon, Southern District, Israel

Barzilai Medical Center

Ashkelon, , Israel

Carmel Medical Center

Haifa, , Israel

Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi

Bologna, Bologna, Italy

Azienda Ospedaliero-Universitaria Pisana

Pisa, , Italy

Fukushima Medical University Hospital

Fukushima, Fukushima, Japan

Kyoto Kuramaguchi Medical Center

Kita, Kyoto, Japan

Shinshu University Hospital

Matsumoto, Nagano, Japan

Jichi medical university hospital

Shimotsuke, Tochigi, Japan

Red Cross Medical Center

Shibuya-ku, Tokyo, Japan

Nagoya City University Hospital

Aichi, , Japan

Maastricht Universitair Medisch Centrum

Maastricht, Limburg, Netherlands

Universitair Medisch Centrum Groningen

Groningen, Provincie Groningen, Netherlands

Klinika Hematologii i Transplantologii

Gdansk, Pomeranian Voivodeship, Poland

Hospital de Braga

Braga, Braga District, Portugal

Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria

Lisbon, Lisbon District, Portugal

Keimyung University Dongsan Hospital

Daegu, Gyeongsangbuk-do, South Korea

Chonnam National University Hwasun Hospital

Gwangju, Jeollanam-do, South Korea

Samsung Medical Center

Seoul, Seoul, South Korea

Severance Hospital

Seoul, Seoul Teugbyeols, South Korea

Pusan National University Hospital

Busan, , South Korea

Kosin University Gospel Hospital

Busan, , South Korea

Gachon University Gil Medical Center

Incheon, , South Korea

Seoul National University Hospital

Seoul, , South Korea

The Catholic University of Korea - Seoul St. Mary's Hospital

Seoul, , South Korea

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Institut Català d'Oncologia - Hospital Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Clinic of Barcelona

Barcelona, Barcelona, Spain

Institut Català d'Oncologia - Hospital Duran i Reynals

Barcelona, Barcelona, Spain

University Hospital Marqués de Valdecilla

Santander, Cantabria, Spain

Hospital Josep Trueta ICO Girona

Girona, Girona, Spain

Hospital Ramon y Cajal

Madrid, Madrid, Spain

Clinica Universidad de Navarra - Pamplona

Pamplona, Navarre, Spain

Clinica Universidad de Navarra -Madrid

Pamplona, Navarre, Spain

Complejo Asistencial Universitario de Salamanca - Hospital Clínico

Salamanca, Salamanca, Spain

Hospital Universitario de Canarias

Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain

Hospital Universitario 12 de Octubre

Vila-real, , Spain

Kaohsiung Chang Gung Memorial Hospital

Kaohsiung City, Kaohsiung, Taiwan

National Taiwan University Hospital

Taipei City, Taipei, Taiwan

Taipei Veterans General Hospital

Taipei, Taipei, Taiwan

Ankara UMF

Ankara, Ankara, Turkey (Türkiye)

Gazi University

Ankara, Ankara, Turkey (Türkiye)

Istanbul University Cerrahpasa Medical Faculty

Istanbul, Istanbul, Turkey (Türkiye)

Ege Universitesi Tip Fakultesi

Izmir, İzmir, Turkey (Türkiye)

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

High Heaton, England, United Kingdom

Barts Health NHS Trust

London, England, United Kingdom

University College London Hospitals

London, England, United Kingdom

Manchester University NHS Foundation Trust

Manchester, England, United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Czechia; Denmark; France; Germany; Greece; Hungary; Ireland; Israel; Italy; Japan; Netherlands; Poland; Portugal; South Korea; Spain; Taiwan; Turkey (Türkiye); United Kingdom

References

Gertz MA, Cohen AD, Comenzo RL, Kastritis E, Landau HJ, Libby EN, Liedtke M, Sanchorawala V, Schonland S, Wechalekar A, Zonder JA, Palladini G, Walling J, Guthrie S, Nie C, Karp C, Jin Y, Kinney GG, Merlini G. Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. Blood. 2023 Oct 5;142(14):1208-1218. doi: 10.1182/blood.2022019406.

Reference Type: DERIVED

PMID: 37366170 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NEOD001-301

Identifier Type: -

Identifier Source: org_study_id