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

Light Chain (AL) Amyloidosis Clinical Trial

— AFFIRM-AL  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04973137
• Other study ID #: NEOD001-301
• Status: Recruiting
• Phase: Phase 3
• Start date: August 30, 2021
• Est. completion date: June 2027

Study information

• Verified date: April 2024
• Source: Prothena Biosciences Ltd.
• Contact: Sonia Romero
• Phone: 650-837-8550
• Email: AFFIRM-ALClinicalTrial[@]prothena.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: June 2027
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyloidosis
• Light Chain (AL) Amyloidosis

Intervention

Drug:
• Birtamimab
Intravenous administration of 24 mg/kg birtamimab every 28 days

Other:
• Placebo
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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Icon Cancer Centre - Wesley	Auchenflower	Queensland
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	SESLHD: St George Hospital	Kogarah	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Icon Cancer Center	South Brisbane	Queensland
Austria	Paracelsus Medical University	Salzburg
Austria	Paracelsus Medical University	Salzburg
Austria	Medizinische Universität	Vienna
Austria	Medizinische Universität Wien	Wien
Belgium	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan	Oostende
Belgium	AZ Sint-Jan Brugge-Oostende AV	Oostende
Belgium	Centre Hospitalier Universitaire Universite Catholique de Louvain - Site Godinne	Yvoir
Belgium	CHU UCL Namur (Site Godinne)	Yvoir
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Royal Victoria Hospital	Montréal	Quebec
Czechia	Fakultní Nemocnice Brno	Brno	Jihormoravsky Kraj
Czechia	Fakultni nemocnice ostrava	Ostrava-Poruba	Moravian-Silesian
Czechia	Všeobecná fakultní nemocnice v Praze	Praha	Prague
Denmark	Odense Universitetshospital	Odense	Syddanmark
France	CHU de Bordeaux	Bordeaux
France	Hopital Henri Mondor, Creteil	Créteil
France	Hôpitaux Universitaires Henri Mondor	Créteil
France	Hôpital Claude Huriez	Lille	Nord
France	Centre Hospitalier Universitaire Limoges	Limoges
France	CHU Nantes	Nantes	Pays De La Loire
France	Hôpital Necker-Enfants Malades	Paris
France	Pitie-Salpêtrière Hospital	Paris	Ill-de-France
France	Hopital Necker	Paris Cedex 15	Ill-de-France
France	Hôpital Haut-Lévêque	Pessac	Gironde
France	Centre Hospitalier Universitaire Poitiers	Poitiers	Vienne
France	Hopital Rangueil	Toulouse Cedex 9	Midi-Pyrenees
France	Hôpital Bretonneau	Tours Cedex 9	Centre
France	Hôpitaux de Brabois	Vandœuvre-lès-Nancy	Lorraine
Germany	Charité Campus Mitte	Berlin
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Wuerttemberg
Germany	Uniklinik Köln	Köln	Baden-Württemberg
Germany	University Medicine Mainz	Mainz	Rheinland-Pfalz
Greece	Alexandra General Hospital	Athens	Attica
Greece	University Hospital of Patras	Patra	Peloponnese
Greece	Theagenio Anti-Cancer Hospital of Thessaloniki	Thessaloníki	Central Macedonia
Hungary	Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet	Budapest
Hungary	Semmelweis Egyetem - I. sz. Belgyógyászati Klinika	Budapest
Hungary	Debreceni Egyetem Klinikai Központ	Debrecen	Hajdu-Bihar County
Hungary	Pécsi Tudományegyetem Klinikai Központ	Pécs	Baranya
Hungary	Szent-Györgyi Albert Klinikai Központ	Szeged	Csongrad
Ireland	Cork University Hospital	Cork	Munster
Ireland	Cancer Clinical Trials and Research Unit, Beaumont Hospital	Dublin
Israel	Samson Assuta Ashdod Hospital	Ashdod
Israel	Barzilai Medical Center	Ashkelon
Israel	Rabin Medical Center - Beilinson Hospital	Ashkelon	Southern District
Israel	Bnai Zion Medical Center	Haifa	Haifa District
Israel	Carmel Medical Center	Haifa
Israel	Rambam Medical Center	Haifa	Haifa District
Israel	Hadassah Medical Center	Jerusalem	Jerusalem District
Italy	Azienda Ospedaliero Universitaria Ospedali Riuniti Di Ancona	Ancona
Italy	Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi	Bologna
Italy	ASST Spedali Civili	Brescia
Italy	Azienda Ospedaliero Universitaria Policlinico Gaspare Rodolico - San Marco	Catania
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Italy	Umberto I - Policlinico di Roma	Roma
Japan	Nagoya City University Hospital	Aichi
Japan	Fukushima Medical University Hospital	Fukushima
Japan	Kyoto Kuramaguchi Medical Center	Kita	Kyoto
Japan	Tokushima University Hospital	Kuramoto	Tokushima
Japan	Shinshu University Hospital	Matsumoto	Nagano
Japan	Red Cross Medical Center	Shibuya-ku	Tokyo
Japan	Jichi medical university hospital	Shimotsuke	Tochigi
Korea, Republic of	Kosin University Gospel Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Keimyung University Dongsan Hospital	Daegu	Gyeongsangbugdo
Korea, Republic of	Chonnam National University Hwasun Hospital	Gwangju	Jeollanam-do
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Hanyang University Seoul Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul	Seoul Teugbyeols
Korea, Republic of	The Catholic University of Korea - Seoul St. Mary's Hospital	Seoul
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Maastricht Universitair Medisch Centrum	Maastricht	Limburg
Poland	Klinika Hematologii i Transplantologii	Gdansk	Pomorskie
Portugal	Hospital de Braga	Braga
Portugal	Centro Hospitalar e Universitário de Coimbra	Coimbra
Portugal	Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria	Lisboa
Spain	Institut Català d'Oncologia - Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	Hospital Universitari Vall d'hebron	Barcelona
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals	Barcelona
Spain	Hospital Josep Trueta ICO Girona	Girona
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda	Madrid
Spain	Hospital Son Llatzer	Palma De Mallorca	Balearic Islands
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Balearic Islands
Spain	Clinica Universidad de Navarra - Pamplona	Pamplona	Navarre
Spain	Clinica Universidad de Navarra -Madrid	Pamplona	Navarra
Spain	Complejo Asistencial Universitario de Salamanca - Hospital Clínico	Salamanca
Spain	University Hospital Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario de Canarias	Tenerife	Santa Cruz De Tenerife
Spain	Hospital Universitari i Politècnic la Fe	Valencia
Spain	Hospital Universitario 12 de Octubre	Vila-real
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei City	Taipei
Turkey	Ankara UMF	Ankara
Turkey	Gazi University	Ankara
Turkey	Istanbul University Cerrahpasa Medical Faculty	Istanbul
Turkey	Ege Universitesi Tip Fakultesi	Izmir
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	University Hospitals Birmingham NHS Foundation Trust - Queen Elizabeth Hospital	Birmingham	England
United Kingdom	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	Nottingham University Hospitals NHS Trust	Nottingham	England
United States	University of Michigan Rogel Cancer Center	Ann Arbor	Michigan
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	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Cleveland Clinic Main Campus	Cleveland	Ohio
United States	The Ohio State University College of Medicine	Columbus	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Duke Clinical Research Institute	Durham	North Carolina
United States	Goshen Center for Cancer Care	Goshen	Indiana
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	St. Francis Hospital	Hartford	Connecticut
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Froedtert and Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilt - Ingram Cancer Center - Henry-Joyce Cancer Clinic	Nashville	Tennessee
United States	New York University Langone Hospital - Long Island	New York	New York
United States	Perlmutter Cancer Center - 38th Street	New York	New York
United States	Yale Cancer Center	North Haven	Connecticut
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of Washington	Seattle	Washington
United States	Smilow Cancer Hospital Care Center at Trumbull	Trumbull	Connecticut
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Cleveland Clinic Florida	Weston	Florida
United States	Wake Forest Baptist Health - Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Prothena Biosciences Ltd.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Secondary	6MWT distance for the Double Blind Phase	Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance	Month 9
Secondary	Physical Component Summary score of the Short Form-36, version 2 for the Double Blind Phase	The Short Form-36, version 2 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