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

A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects With Light Chain (AL) Amyloidosis

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.

Study Overview

• Status: Terminated
• Conditions: Light Chain (AL) Amyloidosis
• Intervention / Treatment: Drug: Birtamimab; Drug: Standard of Care Chemotherapy; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • SESLHD: St George Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Austria
  • Salzburg, Austria
    • Paracelsus Medical University
  • Vienna, Austria
    • Medizinische Universitat Wien
  • Vienna, Austria
    • Medizinische Universität
  • Salzburg
    • Salzburg, Salzburg, Austria, 5020
      • Paracelsus Medical University
• Belgium
  • Ostend, Belgium
    • AZ Sint-Jan Brugge-Oostende AV
  • Yvoir, Belgium
    • CHU UCL Namur (site Godinne)
  • Oostende
    • Ostend, Oostende, Belgium, 8400
      • Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan
  • Yvoir
    • Yvoir, Yvoir, Belgium, 5530
      • Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N4N2
      • Tom Baker Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H3A1A1
      • Royal Victoria Hospital
• Czechia
  • Moravian-Silesian
    • Ostrava-Poruba, Moravian-Silesian, Czechia, 70852
      • Fakultni Nemocnice Ostrava
  • Prague
    • Prague, Prague, Czechia, 12808
      • Vseobecna fakultni nemocnice v Praze
• Denmark
  • Region Syddanmark
    • Odense, Region Syddanmark, Denmark, 5000
      • Odense Universitetshospital
• France
  • Bordeaux, France
    • CHU de Bordeaux
  • Créteil, France
    • Hopital Henri Mondor, Creteil
  • Paris, France
    • Hôpital Necker-Enfants Malades
  • Centre-Val de Loire
    • Tours, Centre-Val de Loire, France, 37044
      • Hopital Bretonneau
  • Créteil
    • Créteil, Créteil, France, 94000
      • Hôpitaux Universitaires Henri Mondor
  • Gironde
    • Pessac, Gironde, France, 33604
      • Hôpital Haut-Lévêque
  • Ill-de-France
    • Paris, Ill-de-France, France, 75013
      • Pitié-Salpêtrière Hospital
    • Paris, Ill-de-France, France, 75743
      • Hopital Necker
  • Lorraine
    • Vandœuvre-lès-Nancy, Lorraine, France, 54511
      • Hopitaux de Brabois
  • Midi-Pyrenees
    • Toulouse, Midi-Pyrenees, France, 31059
      • Hopital Rangueil
  • Nord
    • Lille, Nord, France, 59037
      • Hopital Claude Huriez
  • Pays de la Loire Region
    • Nantes, Pays de la Loire Region, France, 44093
      • CHU Nantes
  • Vienne
    • Poitiers, Vienne, France, 86021
      • Centre Hospitalier Universitaire Poitiers
• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • UniversitatsKlinikum Heidelberg
    • Köln, Baden-Wurttemberg, Germany, 50937
      • Uniklinik Koln
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55131
      • University Medicine Mainz
• Greece
  • Attica
    • Athens, Attica, Greece, 11528
      • Alexandra General Hospital
  • Central Macedonia
    • Thessaloniki, Central Macedonia, Greece, 54007
      • Theagenio Anti-Cancer Hospital of Thessaloniki
  • Peloponnese
    • Patra, Peloponnese, Greece, 26504
      • University Hospital of Patras
• Hungary
  • Budapest
    • Budapest, Budapest, Hungary, 1087
      • Semmelweis Egyetem - I. sz. Belgyógyászati Klinika
• Ireland
  • Dublin, Ireland
    • Cancer Clinical Trials and Research Unit, Beaumont Hospital
  • Munster
    • Cork, Munster, Ireland, T12 DFK4
      • Cork University Hospital
• Israel
  • Ashkelon, Israel, 7830604
    • Barzilai Medical Center
  • Haifa, Israel, 3436212
    • Carmel Medical Center
  • Haifa District
    • Haifa, Haifa District, Israel, 31048
      • Bnai Zion Medical Center
    • Haifa, Haifa District, Israel, 3109601
      • Rambam Medical Center
  • Jerusalem
    • Jerusalem, Jerusalem, Israel, 9112001
      • Hadassah Medical Center
  • Southern District
    • Ashkelon, Southern District, Israel, 7830604
      • Rabin Medical Center - Beilinson Hospital
• Italy
  • Pisa, Italy, 56124
    • Azienda Ospedaliero-Universitaria Pisana
  • Bologna
    • Bologna, Bologna, Italy, 40138
      • Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
• Japan
  • Aichi, Japan
    • Nagoya City University Hospital
  • Fukushima
    • Fukushima, Fukushima, Japan, 960-1247
      • Fukushima Medical University Hospital
  • Kyoto
    • Kita, Kyoto, Japan
      • Kyoto Kuramaguchi Medical Center
  • Nagano
    • Matsumoto, Nagano, Japan, 390-0802
      • Shinshu University Hospital
  • Tochigi
    • Shimotsuke, Tochigi, Japan
      • Jichi Medical University Hospital
  • Tokyo
    • Shibuya-ku, Tokyo, Japan, 150-8935
      • Red Cross Medical Center
• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229HX
      • Maastricht Universitair Medisch Centrum
  • Provincie Groningen
    • Groningen, Provincie Groningen, Netherlands, 9713GZ
      • Universitair Medisch Centrum Groningen
• Poland
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-214
      • Klinika Hematologii i Transplantologii
• Portugal
  • Braga District
    • Braga, Braga District, Portugal, 4710-243
      • Hospital de Braga
  • Lisbon District
    • Lisbon, Lisbon District, Portugal, 1649-028
      • Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria
• South Korea
  • Busan, South Korea, 49241
    • Pusan National University Hospital
  • Busan, South Korea, 602702
    • Kosin University Gospel Hospital
  • Incheon, South Korea, 21565
    • Gachon University Gil Medical Center
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 06591
    • The Catholic University of Korea - Seoul St. Mary's Hospital
  • Gyeongsangbuk-do
    • Daegu, Gyeongsangbuk-do, South Korea, 42601
      • Keimyung University Dongsan Hospital
  • Jeollanam-do
    • Gwangju, Jeollanam-do, South Korea, 58128
      • Chonnam National University Hwasun Hospital
  • Seoul
    • Seoul, Seoul, South Korea, 06351
      • Samsung Medical Center
  • Seoul Teugbyeols
    • Seoul, Seoul Teugbyeols, South Korea, 120-752
      • Severance Hospital
• Spain
  • Vila-real, Spain, 1254
    • Hospital Universitario 12 de Octubre
  • Balearic Islands
    • Palma de Mallorca, Balearic Islands, Spain, 07120
      • Hospital Universitario Son Espases
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Institut Català d'Oncologia - Hospital Germans Trias i Pujol
    • Barcelona, Barcelona, Spain, 08036
      • Hospital Clinic of Barcelona
    • Barcelona, Barcelona, Spain, 08908
      • Institut Català d'Oncologia - Hospital Duran i Reynals
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • University Hospital Marqués de Valdecilla
  • Girona
    • Girona, Girona, Spain, 17007
      • Hospital Josep Trueta ICO Girona
  • Madrid
    • Madrid, Madrid, Spain, 28034
      • Hospital Ramon y Cajal
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Clinica Universidad de Navarra - Pamplona
    • Pamplona, Navarre, Spain
      • Clínica Universidad de Navarra -Madrid
  • Salamanca
    • Salamanca, Salamanca, Spain, 37007
      • Complejo Asistencial Universitario de Salamanca - Hospital Clínico
  • Santa Cruz de Tenerife
    • Santa Cruz de Tenerife, Santa Cruz de Tenerife, Spain, 38320
      • Hospital Universitario de Canarias
• Taiwan
  • Kaohsiung
    • Kaohsiung City, Kaohsiung, Taiwan, 833
      • Kaohsiung Chang Gung Memorial Hospital
  • Taipei
    • Taipei, Taipei, Taiwan, 11217
      • Taipei Veterans General Hospital
    • Taipei City, Taipei, Taiwan, 10047
      • National Taiwan University Hospital
• Turkey (Türkiye)
  • Ankara
    • Ankara, Ankara, Turkey (Türkiye), 06100
      • Ankara UMF
    • Ankara, Ankara, Turkey (Türkiye), 06500
      • Gazi University
  • Istanbul
    • Istanbul, Istanbul, Turkey (Türkiye), 34320
      • Istanbul University Cerrahpasa Medical Faculty
  • İzmir
    • Izmir, İzmir, Turkey (Türkiye), 35100
      • Ege Universitesi Tip Fakultesi
• United Kingdom
  • England
    • High Heaton, England, United Kingdom, NE77DN
      • The Newcastle upon Tyne Hospitals NHS Foundation Trust
    • London, England, United Kingdom, EC1A7BE
      • Barts Health NHS Trust
    • London, England, United Kingdom, NW12PG
      • University College London Hospitals
    • Manchester, England, United Kingdom, M139WL
      • Manchester University NHS Foundation Trust
• United States
  • Connecticut
    • North Haven, Connecticut, United States, 06473
      • Yale Cancer Center
    • Trumbull, Connecticut, United States, 06611
      • Smilow Cancer Hospital Care Center at Trumbull
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Maryland
    • Bethesda, Maryland, United States, 20814-1422
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Med.
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10016
      • Perlmutter Cancer Center - 38th Street
    • New York, New York, United States, 11501
      • New York University Langone Hospital - Long Island
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Clinical Research Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Main Campus
    • Columbus, Ohio, United States, 43210
      • The Ohio State University College of Medicine
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt - Ingram Cancer Center - Henry-Joyce Cancer Clinic
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert And Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria for Double-blind Phase:

• 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

Inclusion Criteria for Open-label (OLE) Phase:

• 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

Key Exclusion Criteria for Double-blind Phase:

• 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

Exclusion Criteria for OLE Phase:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Birtamimab; 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
Placebo Comparator: 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.	Drug: Standard of Care Chemotherapy; Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care; Other: Placebo; Intravenous 0.9% Saline administration as a placebo every 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to All-cause Mortality for the Double Blind Phase	Comparison of time to all-cause mortality for birtamimab and placebo control.	Time from the first dose of study drug until the pre-defined number of events (all-cause mortality) have been reached, assessed up to 39 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6MWT Distance at Month 9	Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance calculated as the value at 9 months minus the value at baseline.	Month 9
Physical Component Summary Score of the Short Form-36, Version 2 at Month 9	Change from baseline to Month 9 in the Short Form-36, version 2 (SF-36) calculated as the value at 9 months minus the value at baseline. SF-36 v2 is a 36-item self-administered quality-of-life questionnaire that measures health on functional status, well-being, and overall evaluation of health. The Physical Component Summary score ranges from 0 to 100 with higher scores indicating higher health-related quality of life. The Physical Component Summary is derived primarily from questions regarding physical functioning, physical problems, bodily pain, and general health questions.	Month 9

Collaborators and Investigators

• Sponsor: Prothena Biosciences Ltd.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2021
• Primary Completion (Actual): April 2, 2025
• Study Completion (Actual): June 20, 2025

Study Registration Dates

• First Submitted: July 1, 2021
• First Submitted That Met QC Criteria: July 21, 2021
• First Posted (Actual): July 22, 2021

Study Record Updates

• Last Update Posted (Estimated): December 16, 2025
• Last Update Submitted That Met QC Criteria: November 20, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Light Chain (AL) Amyloidosis; Mayo Stage IV; birtamimab
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Nutritional and Metabolic Diseases; Amyloidosis; birtamimab
• Other Study ID Numbers: NEOD001-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No