Light Chain (AL) Amyloidosis
Conditions
Keywords
Light Chain (AL) Amyloidosis, Mayo Stage IV, birtamimab
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.
Interventions
DRUGBirtamimab
Intravenous administration of 24 mg/kg birtamimab every 28 days
OTHERPlacebo
Intravenous 0.9% Saline administration as a placebo every 28 days
Bortezomib-containing chemotherapy regimen (e.g. cyclophosphamide, bortezomib, and dexamethasone (CyBorD)) according to the institutional standard of care
Sponsors
Prothena Biosciences Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to All-cause Mortality for the Double Blind Phase | 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. | Comparison of time to all-cause mortality for birtamimab and placebo control. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6MWT Distance at Month 9 | 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. |
| Physical Component Summary Score of the Short Form-36, Version 2 at Month 9 | 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. |
Countries
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, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Birtamimab (24 mg/kg) + Standard of Care Birtamimab, 24 mg/kg IV every 4 weeks with Standard of Care | 139 |
| Placebo + Standard of Care Placebo 0.9% Saline IV every 4 weeks with Standard of Care | 68 |
| Total | 207 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Phase | Adverse Event | 4 | 0 |
| Double Blind Phase | Death | 25 | 15 |
| Double Blind Phase | Other | 2 | 2 |
| Double Blind Phase | Physician Decision | 5 | 1 |
| Double Blind Phase | Withdrawal by Subject | 6 | 1 |
| Open Label Extension Phase | Death | 3 | 0 |
| Open Label Extension Phase | Physician Decision | 0 | 1 |
| Open Label Extension Phase | Site Terminated by Sponsor | 5 | 0 |
| Open Label Extension Phase | Study Terminated by Sponsor | 83 | 43 |
| Open Label Extension Phase | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo + Standard of Care | Birtamimab (24 mg/kg) + Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 37 Participants | 86 Participants | 123 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 53 Participants | 84 Participants |
| Age, Continuous | 64.1 Years STANDARD_DEVIATION 8.88 | 65.7 Years STANDARD_DEVIATION 10.38 | 65.2 Years STANDARD_DEVIATION 9.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 121 Participants | 183 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 15 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 27 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 14 Participants |
| Race (NIH/OMB) White | 44 Participants | 99 Participants | 143 Participants |
| Region of Enrollment Australia | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Austria | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Belgium | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Canada | 1 participants | 7 participants | 8 participants |
| Region of Enrollment Czechia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment France | 8 participants | 21 participants | 29 participants |
| Region of Enrollment Germany | 3 participants | 7 participants | 10 participants |
| Region of Enrollment Greece | 4 participants | 10 participants | 14 participants |
| Region of Enrollment Hungary | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Israel | 1 participants | 5 participants | 6 participants |
| Region of Enrollment Italy | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Japan | 2 participants | 7 participants | 9 participants |
| Region of Enrollment Netherlands | 4 participants | 7 participants | 11 participants |
| Region of Enrollment Portugal | 0 participants | 1 participants | 1 participants |
| Region of Enrollment South Korea | 7 participants | 12 participants | 19 participants |
| Region of Enrollment Spain | 6 participants | 13 participants | 19 participants |
| Region of Enrollment Taiwan | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Turkey | 3 participants | 1 participants | 4 participants |
| Region of Enrollment United Kingdom | 3 participants | 3 participants | 6 participants |
| Region of Enrollment United States | 14 participants | 31 participants | 45 participants |
| Sex: Female, Male Female | 24 Participants | 53 Participants | 77 Participants |
| Sex: Female, Male Male | 44 Participants | 86 Participants | 130 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 32 / 139 | 17 / 68 | 3 / 136 |
| other Total, other adverse events | 136 / 139 | 66 / 68 | 53 / 136 |
| serious Total, serious adverse events | 83 / 139 | 39 / 68 | 17 / 136 |
Outcome results
Primary
Time to All-cause Mortality for the Double Blind Phase
Comparison of time to all-cause mortality for birtamimab and placebo control.
Time frame: 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.
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Birtamimab (24 mg/kg) + Standard of Care | Time to All-cause Mortality for the Double Blind Phase | Event (Death) Occurred | 32 Participants |
| Birtamimab (24 mg/kg) + Standard of Care | Time to All-cause Mortality for the Double Blind Phase | Number of Subjects Censored | 107 Participants |
| Placebo + Standard of Care | Time to All-cause Mortality for the Double Blind Phase | Event (Death) Occurred | 17 Participants |
| Placebo + Standard of Care | Time to All-cause Mortality for the Double Blind Phase | Number of Subjects Censored | 51 Participants |
p-value: 0.76895% CI: [0.508, 1.649]Log Rank
Secondary
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.
Time frame: Month 9
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Birtamimab (24 mg/kg) + Standard of Care | 6MWT Distance at Month 9 | 4.5 Meters |
| Placebo + Standard of Care | 6MWT Distance at Month 9 | 7.75 Meters |
p-value: 0.528895% CI: [-35.47, 18.46]Rank ANCOVA
Secondary
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.
Time frame: Month 9
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Birtamimab (24 mg/kg) + Standard of Care | Physical Component Summary Score of the Short Form-36, Version 2 at Month 9 | 1.710 Score |
| Placebo + Standard of Care | Physical Component Summary Score of the Short Form-36, Version 2 at Month 9 | 4.205 Score |
p-value: 0.959795% CI: [-2.68, 3.37]Rank ANCOVA