A Global Phase 3 Double-Blind, Placebo-Controlled study to assess Efficacy and Safety of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects with Light Chain (AL) Amyloidosis

• Register: EUCTR
• Last refreshed on: 16 December 2024
• Main ID: EUCTR2021-000037-14-IT
• Date of registration: 26/11/2021
• Prospective Registration: Yes
• Primary sponsor: Prothena Biosciences Limited
• Public title: A Global Phase 3 Double-Blind, Placebo-Controlled study to assess Efficacy and Safety of Birtamimab Plus Standard of Care vs. Placebo Plus Standard of Care in Mayo Stage IV Subjects with Light Chain (AL) Amyloidosis
• Scientific 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 - NA
• Date of first enrolment: 21/01/2022
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-000037-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Regulatory Affairs
• Affiliation: Prothena Biosciences Limited

• Name: Regulatory Affairs
• Affiliation: Prothena Biosciences Limited

Key inclusion & exclusion criteria

Inclusion criteria:
1.Aged =18 years
2.Newly diagnosed and AL amyloidosis treatment naive
3.Bone marrow demonstrating clonal plasma cells
4.Confirmed diagnosis of AL amyloidosis by the following:
-Histochemical diagnosis of amyloidosis determined by polarizing light
microscopy of green birefringent material in Congo red-stained tissue
specimens OR characteristic electron microscopy appearance
AND
-Confirmatory immunohistochemistry OR mass spectroscopy of AL
amyloidosis
5.Confirmed diagnosis of AL amyloidosis by mass spectrometry or
immunoelectron microscopy of amyloid material in tissue biopsy if the
subject meets any of the following:
-Is black or African American
-Is over 75 years of age with concurrent monoclonal gammopathy
-Has a history of familial amyloidosis and has concurrent monoclonal
gammopathy
OR
-If the subject meets any of the above 3 conditions and has
echocardiographic evidence of amyloidosis, biopsy-proven amyloidosis
with a monoclonal gammopathy and no tissue is available for mass
spectrometry or immunoelectron microscopy, the subject must have
gene sequencing consistent with transthyretin (TTR) wild type (e.g., no
TTR mutation present) AND must score 0 in technetium-99m-3,3-
diphosphono-1,2 propanodicarboxylic acid (99mTc DPD),
hydroxymethylenediphosphonate (99mTc HMDP), or pyrophosphate
(99mTc PYP) scintigraphy
6.Cardiac involvement as defined by all of the following:
-Past documented or presently noted clinical signs and symptoms
supportive of a diagnosis of heart failure in the setting of a confirmed
diagnosis of AL amyloidosis in the absence of an alternative explanation
for heart failure
-Either an endomyocardial biopsy demonstrating AL amyloidosis or an
echocardiogram demonstrating a mean left ventricular wall thickness at
diastole >12 mm in the absence of other causes (e.g., severe
hypertension, aortic stenosis), which would adequately explain the
degree of wall thickening
7.Confirmed Mayo Stage IV as defined by:
-NT-proBNP =1800 pg/mL and
-Troponin-T >0.03 ng/mL and
-dFLC =18 mg/dL
8.Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly
9.Adequate bone marrow reserve, hepatic function, and renal function,
as demonstrated by:
-Absolute neutrophil count =1.0 × 10e9/L
-Platelet count =75 × 10e9/L
-Hemoglobin =9 g/dL
-Total bilirubin = 2 × the upper limit of normal (ULN)
-Aspartate aminotransferase (AST)/serum glutamic oxaloacetic
transaminase =3 × ULN
-Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase
=3 × ULN
-Alkaline phosphatase (ALP) =5 × ULN (except for subjects with
hepatomegaly and isozymes specific to liver, rather than bone)
-Estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 as
estimated by the Chronic Kidney Disease Epidemiology Collaboration equation
10.Seated systolic blood pressure (BP) 90 to 180 mmHg
11.Distance walked during each Screening 6MWT is >30 meters and
<550 meters
12.Women of childbearing potential (WOCBP) must have 2 negative
pregnancy tests during Screening, the second within 24 hours prior to
the first administration of study drug, and must agree to use highly
effective physician-approved contraception from Screening to 90 days
following the last study drug administration
13.Male subjects must be surgically sterile or must agree to use highly
effective physician approved contraception from Screening to 90 days
following the last study drug administration
14.Ability to understand and willingness to sign an informed consent
form prior to initi
Exclusion criteria:
1.Non-AL amyloidosis
2.NT-proBNP >8500 pg/mL
3.Meets the International Myeloma Working Group (IMWG) definition of
multiple myeloma
*Note that subjects who meet the IMWG definition of symptomatic
multiple myeloma with signs and/or symptoms attributable only to
associated amyloidosis are potentially eligible upon approval of the
Sponsor.
4.Subject is eligible for and plans to undergo ASCT or organ transplant
during the study
5.Symptomatic orthostatic hypotension that in the medical judgment of
the Investigator would interfere with the subject's ability to safely
receive treatment or complete study assessments
6.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
7.Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve
area <1.0 cm2) or severe congenital heart disease
8.ECG evidence of acute ischemia or active conduction system
abnormalities with the exception of any of the following:
-First degree AV-block
-Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type)
-Right or left bundle branch block
-Atrial fibrillation with a controlled ventricular rate (uncontrolled [>110
bpm] ventricular rate is not allowed [determined by an average of 3
beats in Lead II or 3 representative beats if Lead II is not representative
of the overall ECG])
9.Peripheral neuropathy assessed as National Cancer Institute-Common
Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 with pain,
Grade 3, or Grade 4
10.Subject is receiving oral or intravenous antibiotics, antifungals, or
antivirals within 1 week of Month 1-Day 1 with the exception of
prophylactic oral agents
11.Prior treatment with hematopoietic growth factors, transfusions of
blood or blood products within 1 week of Month 1-Day 1
12.Prior radiotherapy within 4 weeks of Month 1-Day 1
13.Major surgery within 4 weeks of Month 1-Day 1 or planned major
surgery during the study
14.Active malignancy with the exception of any of the following:
-Adequately treated basal cell carcinoma, squamous cell carcinoma, or in
situ cervical cancer
-Adequately treated Stage I cancer from which the subject is currently in
remission and has been in remission for 2 years
-Low-risk prostate cancer with Gleason score <7 and prostate specific
antigen <10 ng/mL
-Any other cancer from which the subject has been disease-free for =2
years
15.History of severe allergy to any of the components of birtamimab
such as histidine/L histidine hydrochloride monohydrate, trehalose
dehydrate, or polysorbate 20 or history of Grade =3 infusion-related AEs
or hypersensitivity to another monoclonal antibody, or known
hypersensitivity to diphenhydramine (or an equivalent H1 antihistamine)
or acetaminophen (or its equivalent, paracetamol)
16.Known or history of uncontrolled, active HIV, hepatitis B or hepatitis C, or SARS-CoV-2 infection
17.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
18.Treatment with another investigational agent within 30 days of
Month 1-Day 1
19.Women who are pregnant or lactating
20.Any condition which could interfere with, or the treatment for which
might interfere with, the conduct of the study or which would, in the
opinion of the Investigator, unacceptably increase the subject's risk by
participating in the study
21.Subject

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

AL amyloidosis involves a hematologic disorder caused by clonal plasma cells that produce misfolded immunoglobulin light chains. Overproduction of misfolded light chains results in both soluble, aggregated forms of light chains and insoluble, fibrillar deposits of abnormal AL protein (amyloid), in the tissues and organs. This can cause a range of symptoms and organ dysfunction including cardiac, renal, and hepatic dysfunction, gastrointestinal involvement and neuropathy and macroglossia
MedDRA version: 20.0 Level: PT Classification code 10036673 Term: Primary amyloidosis System Organ Class: 10021428 - Immune system disorders

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: Birtamimab
Product Code: [Birtamimab]
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: BIRTAMIMAB
CAS Number: 1608108-91-3
Current Sponsor code: birtamimab
Other descriptive name: Humanized IgG1 kappa antiamyloid
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Product Name: paracetamolo Zentiva Italia
Product Code: [NA]
Pharmaceutical Form: Tablet
INN or Proposed INN: PARACETAMOLO
Current Sponsor code: NA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Bortezomib Accord
Product Name: Bortezomib Accord
Product Code: [Bortezomib Accord]
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: BORTEZOMIB
Current Sponsor code: NA
Other descriptive name: Bortezomib D-mannitol
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 3500-

Product Name: Zirtec
Product Code: [NA]
Pharmaceutical Form: Tablet
INN or Proposed INN: CETIRIZINA DICLORIDRATO
Current Sponsor code: NA
Other descriptive name: NA
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Product Name: Aciclin
Product Code: [NA]
Pharmaceutical Form: Tablet
INN or Proposed INN: ACICLOVIR
Current Sponsor code: NA
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 200-400

Primary Outcome(s)

Main Objective: To evaluate the efficacy of birtamimab plus standard of care compared to placebo plus standard of care when administered intravenously in Mayo
Stage IV subjects with AL amyloidosis by assessing time to all-cause mortality.

Primary end point(s): Time to all-cause mortality

Secondary Objective: To evaluate birtamimab plus standard of care compared to placebo plus standard of care on the following:
• Change from baseline to Month 9 in health-related quality of life using the Short Form-36 questionnaire Version 2 (SF-36v2)
• Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance

Timepoint(s) of evaluation of this end point: -Interim Efficacy Analysis will be conducted when approximately 50%
(or 24) of the events have occurred
-Primary Analysis - for all-cause mortality, all deaths occurring after the
first infusion of study drug (i.e., Study Day 1) through the study's last
subject last visit will be included.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: from baseline until Month 9

Secondary end point(s): •Change from baseline to Month 9 in the Physical Component Summary
(PCS) score of the SF-36v2
•Change from baseline to Month 9 in the 6MWT distance (meters)

Secondary ID(s)

NCT04973137

146070

2021-000037-14-DK

NEOD001-301

Source(s) of Monetary Support

Prothena Biosciences Limited

Ethics review

Status: Approved
Approval date: 15/12/2021
Contact: