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

• ClinicalTrials.gov Identifier: NCT04973137
• Recruitment Status: Recruiting
• First Posted: July 22, 2021
• Last Update Posted: April 16, 2024
• Sponsor: Prothena Biosciences Ltd.
• Information provided by (Responsible Party): Prothena Biosciences Ltd.

Tracking Information

• First Submitted Date: July 1, 2021
• First Posted Date: July 22, 2021
• Last Update Posted Date: April 16, 2024
• Actual Study Start Date: August 30, 2021
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 14, 2024)

Time to all-cause mortality for the Double Blind Phase [ Time Frame: Time from the first dose of study drug until the pre-defined number of events (all-cause mortality) have been reached. ]

Comparison of time to all-cause mortality for birtamimab and placebo control.

Original Primary Outcome Measures (submitted: July 21, 2021)

Time to all-cause mortality [ Time Frame: Time from the first dose of study drug until death or end of study over 9 months ]

Comparison of time to all-cause mortality for birtamimab and placebo control.

Current Secondary Outcome Measures (submitted: February 23, 2024)

• 6MWT distance for the Double Blind Phase [ Time Frame: Month 9 ]
  Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance
• Physical Component Summary score of the Short Form-36, version 2 for the Double Blind Phase [ Time Frame: Month 9 ]
  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.

Original Secondary Outcome Measures (submitted: July 21, 2021)

• Physical Component Summary (PCS) score of the The Short Form-36, version 2 (SF-36v2) [ Time Frame: Month 9 ]
  The Short Form-36, version 2 (SF-36v2) is a 36-item self-administered quality-of-life (QoL) questionnaire that measures health on functional status, well-being, and overall evaluation of health. Higher SF-36 scores represent better health. The Physical Component Summary (PCS) is derived primarily from questions regarding physical functioning, physical problems, bodily pain, and general health questions
• 6MWT distance [ Time Frame: Month 9 ]
  Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: 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

Study Arms

• 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.

  Interventions:

  • Drug: Birtamimab
  • Drug: Standard of Care Chemotherapy
• 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.

  Interventions:

  • Other: Placebo
  • Drug: Standard of Care Chemotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 12, 2024): 220
• Original Estimated Enrollment (submitted: July 21, 2021): 150
• Estimated Study Completion Date: June 2027
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sonia Romero; 650-837-8550; AFFIRM-ALClinicalTrial@prothena.com

Contact: Karen Lai; 650-837-8550; AFFIRM-ALClinicalTrial@prothena.com

• Listed Location Countries: 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

Administrative Information

• NCT Number: NCT04973137
• Other Study ID Numbers: NEOD001-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Prothena Biosciences Ltd.
• Original Responsible Party: Same as current
• Current Study Sponsor: Prothena Biosciences Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Prothena Biosciences Ltd.
• Verification Date: April 2024