Primary Systemic (AL) Amyloidosis
Conditions
Brief summary
This is a multi-center, international, randomized, double-blind, placebo-controlled, two-arm efficacy and safety study in subjects newly diagnosed with AL amyloidosis. Subjects will remain on-study until study completion, which will occur when all primary endpoint events (all-cause mortality or cardiac hospitalizations) have been reached.
Detailed description
This is a multi-center, international, randomized, double-blind, placebo-controlled, two-arm efficacy and safety study in subjects newly diagnosed with AL amyloidosis. Approximately 236 subjects will be enrolled in \ 60 centers, with approximately 118 subjects per arm. This is an event driven trial, therefore subjects will remain on-study until study completion, which will occur when all primary endpoint events (all-cause mortality or cardiac hospitalizations) have been reached. All subjects who discontinue will be followed until the last event is adjudicated. The estimated overall study duration is approximately 42 months, including the enrollment and treatment periods Study drug will be administered once every 28 days as a 60-120 minute IV infusion. First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered weekly. The number of cycles of first-line chemotherapy that are administered are at the discretion of the Investigator, and subsequent chemotherapy regimens may be prescribed as per standard of care at the Investigator's discretion. An independent Data Monitoring Committee (DMC) will review data on a regular basis.
Interventions
DRUGNEOD001
NEOD001, is a humanized immunoglobulin G1 monoclonal antibody, which specifically targets misfolded light chain aggregates and amyloid deposits. NEOD001 is proposed for use to target the misfolded light chain protein in subjects with AL amyloidosis.
OTHERPlacebo
Placebo
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: 1. Age ≥ 18 years 2. Newly diagnosed, AL amyloidosis treatment naïve 3. Bone marrow consistent with plasma cell dyscrasia 4. Confirmed diagnosis of AL amyloidosis 5. Cardiac involvement 6. Planned first-line chemotherapy contains a proteasome-inhibiting agent administered weekly 7. Adequate bone marrow reserve, hepatic and renal function Key
Exclusion criteria
1. Non-AL amyloidosis 2. Meets diagnostic criteria for symptomatic multiple myeloma 3. Subject is eligible for and plans to undergo ASCT 4. History of Grade ≥ 3 infusion-associated AEs or hypersensitivity to another monoclonal antibody, or known hypersensitivity to diphenhydramine or acetaminophen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Composite of All-cause Mortality or Cardiac Hospitalization | Randomization until the date of death or cardiac hospitalization, up to 32 months | Time to all-cause mortality death occurring after the first infusion of study drug or cardiac hospitalization as adjudicated by the CEC occurring at least 91 days after first infusion of study drug through last subject last visit, whichever came first |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Greece, Israel, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NEOD001 (24 mg/kg) + Standard of Care NEOD001, 24 mg/kg IV every 4 weeks on top of Standard of Care | 130 |
| Placebo + Standard of Care Placebo 0.9% Saline IV every 4 weeks on top of Standard of Care | 130 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Death | 31 | 36 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Patient progression and institution of a new therapy | 1 | 0 |
| Overall Study | Patient transferred to hospice | 0 | 1 |
| Overall Study | Physician Decision | 7 | 6 |
| Overall Study | Study Terminated by Sponsor | 81 | 74 |
| Overall Study | Subject missed three consecutive treatment visits | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | NEOD001 (24 mg/kg) + Standard of Care | Placebo + Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 61 Participants | 60 Participants | 121 Participants |
| Age, Categorical Between 18 and 65 years | 69 Participants | 70 Participants | 139 Participants |
| Age, Continuous | 63.69 years STANDARD_DEVIATION 9.478 | 63.24 years STANDARD_DEVIATION 9.708 | 63.46 years STANDARD_DEVIATION 9.578 |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black Or African American | 9 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Not Reported | 12 Participants | 6 Participants | 18 Participants |
| Race/Ethnicity, Customized Hispanic Or Latino | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino | 116 Participants | 122 Participants | 238 Participants |
| Race/Ethnicity, Customized Race not Reported | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 118 Participants | 120 Participants | 238 Participants |
| Sex: Female, Male Female | 48 Participants | 40 Participants | 88 Participants |
| Sex: Female, Male Male | 82 Participants | 90 Participants | 172 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 130 | 42 / 130 |
| other Total, other adverse events | 124 / 130 | 125 / 130 |
| serious Total, serious adverse events | 88 / 130 | 91 / 130 |
Outcome results
Primary
Time to Composite of All-cause Mortality or Cardiac Hospitalization
Time to all-cause mortality death occurring after the first infusion of study drug or cardiac hospitalization as adjudicated by the CEC occurring at least 91 days after first infusion of study drug through last subject last visit, whichever came first
Time frame: Randomization until the date of death or cardiac hospitalization, up to 32 months
Population: ITT Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NEOD001 (24 mg/kg) + Standard of Care | Time to Composite of All-cause Mortality or Cardiac Hospitalization | Number of Subjects Who Died or Experienced Cardiac Hospitalization | 56 Participants |
| NEOD001 (24 mg/kg) + Standard of Care | Time to Composite of All-cause Mortality or Cardiac Hospitalization | Number of Subjects Censored | 74 Participants |
| Placebo + Standard of Care | Time to Composite of All-cause Mortality or Cardiac Hospitalization | Number of Subjects Who Died or Experienced Cardiac Hospitalization | 62 Participants |
| Placebo + Standard of Care | Time to Composite of All-cause Mortality or Cardiac Hospitalization | Number of Subjects Censored | 68 Participants |
p-value: 0.302895% CI: [0.5735, 1.1889]Log Rank