AL Amyloidosis
Conditions
Keywords
amyloidosis, ntprobnp, NEOD001, Prothena, PRONTO, amyloid, plasma cell dyscrasia, immunotherapy
Brief summary
This is a global, multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who had a hematologic response to previous treatment for their amyloidosis (e.g., chemotherapy, autologous stem cell transplant \[ASCT\]) and have persistent cardiac dysfunction.
Interventions
DRUGNEOD001
NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates
DRUGPlacebo
Saline Bag
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
1. Age ≥18 years 2. Confirmed diagnosis of systemic AL amyloidosis 3. ≥1 prior systemic plasma cell dyscrasia therapy with at least a partial hematologic response 4. Cardiac involvement 5. NT-proBNP ≥650
Exclusion criteria
1. Non-AL amyloidosis 2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma 3. NT-proBNP \>5000 4. Received Plasma cell directed chemotherapy within 6 months 5. Received autologous stem cell transplant (ASCT) within 12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Cardiac Response and Non-Response | Baseline through 12 months of treatment | N-terminal pro-brain natriuretic peptide (NT-proBNP ) best response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment. Cardiac best response, as assessed by NT-proBNP alone, is defined as the most favorable category among response (ie, decrease in NT-proBNP from baseline of \>30% and \>300 ng/L), stable (ie, neither response nor progression), and progression (ie, increase in NT-proBNP from baseline of \>30% and \>300 ng/L) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Non-response is defined as either stable or progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 6MWT Distance | Baseline to 12 months of treatment | Change in 6 Minute Walk Test (6MWT) Distance (meters) |
| Number of Participants With Renal Best Response and Non-Response | Baseline through 12 months of treatment | Proteinuria and estimated Glomerular Filtration Rate (eGFR) response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment in subjects with renal involvement. Renal best response, as assessed by proteinuria, is defined as the most favorable category among response (ie, ≥30% decrease from baseline or \<0.5 g/24 hours postbaseline result if subject does not meet criteria for progression), stable (ie, neither response nor progression), and progression (ie, ≥25% decrease in eGFR from baseline) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Assessments that qualify as both a response and progression are counted as progression. Non-response is defined as either stable or progression. |
| SF-36v2 PCS Score | Baseline to 12 months of treatment | Change in Short Form-36 (SF-36 version 2) questionnaire Physical Component Summary \[PCS\] Score. PCS scores are calculated based on responses to specific Short Form-36 (version 2) questions using a weight scoring method. The lower the PCS score the more disability, the higher the score the less disability. A score of 50 is the mean in the US General Population and the standard deviation is 10. Minimum is 0 and maximum value is 100. |
| NT-proBNP Slope | Baseline through 12 months of treatment | Rate of change in NT-proBNP (ng/L per infusion). Estimates of the intercept, slope, SE, and associated 95% CI for each treatment group, and the NEOD001 and placebo group difference comparisons are estimated using a general linear mixed effects model. The model fits a random intercept and slope for each subject and includes fixed effects for treatment group, time, treatment group by time interaction, IWRS stratification factors (hematologic response to first-line therapy: CR/VGPR, PR and NT-proBNP \<1800 ng/L, ≥1800 ng/L), and an unstructured covariance structure to model the within-subject errors. Time is represented in months as a continuous variable and includes all scheduled time points, including baseline. The p-value is associated with the visit by treatment group interaction term. |
| Hepatic Best Response | Baseline through 12 months of treatment | Alkaline Phosphatase response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment in subjects with hepatic involvement |
| NIS-LL Total Score | Baseline to 12 months of treatment | Change in Neuropathy Impairment Score-Lower Limb (NIS-LL) Total Score in subjects with peripheral nerve involvement. NIS-LL is a scoring system graduated from 0 points to a maximum of 88 points (the absence of all motor, sensory, and reflex activity in the lower extremities). The scale is an additive of all deficits (64 potential points for muscle strength, 8 points for reflexes, and 16 points for sensory function) in the lower extremities. A score of 0 is normal and score of 88 is total impairment. |
Countries
Australia, Austria, France, Germany, Greece, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NEOD001 24mg/kg NEOD001, 24 mg/kg IV every 4 weeks for 12 months | 66 |
| Placebo Placebo, 0.9% Saline IV every 4 weeks for 12 months | 63 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Physician Decision | 5 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | NEOD001 24mg/kg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 34 Participants | 59 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 29 Participants | 70 Participants |
| Age, Continuous | 62.09 years STANDARD_DEVIATION 9.188 | 63.90 years STANDARD_DEVIATION 8.332 | 62.98 years STANDARD_DEVIATION 8.794 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 61 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Multiple Races Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not reported | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Race White | 61 Participants | 56 Participants | 117 Participants |
| Sex: Female, Male Female | 27 Participants | 24 Participants | 51 Participants |
| Sex: Female, Male Male | 39 Participants | 39 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 66 | 6 / 63 |
| other Total, other adverse events | 58 / 66 | 52 / 63 |
| serious Total, serious adverse events | 14 / 66 | 15 / 63 |
Outcome results
Primary
Number of Participants With Cardiac Response and Non-Response
N-terminal pro-brain natriuretic peptide (NT-proBNP ) best response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment. Cardiac best response, as assessed by NT-proBNP alone, is defined as the most favorable category among response (ie, decrease in NT-proBNP from baseline of \>30% and \>300 ng/L), stable (ie, neither response nor progression), and progression (ie, increase in NT-proBNP from baseline of \>30% and \>300 ng/L) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Non-response is defined as either stable or progression.
Time frame: Baseline through 12 months of treatment
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NEOD001 24mg/kg | Number of Participants With Cardiac Response and Non-Response | Response | 26 Participants |
| NEOD001 24mg/kg | Number of Participants With Cardiac Response and Non-Response | Non-response | 40 Participants |
| Placebo | Number of Participants With Cardiac Response and Non-Response | Response | 30 Participants |
| Placebo | Number of Participants With Cardiac Response and Non-Response | Non-response | 33 Participants |
p-value: 0.31995% CI: [0.55, 1.21]Cochran-Mantel-Haenszel
Secondary
6MWT Distance
Change in 6 Minute Walk Test (6MWT) Distance (meters)
Time frame: Baseline to 12 months of treatment
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NEOD001 24mg/kg | 6MWT Distance | 19.25 meters |
| Placebo | 6MWT Distance | 8.00 meters |
p-value: 0.899295% CI: [-11.5, 23]ANCOVA
Secondary
Hepatic Best Response
Alkaline Phosphatase response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment in subjects with hepatic involvement
Time frame: Baseline through 12 months of treatment
Population: Hepatic Evaluable Population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NEOD001 24mg/kg | Hepatic Best Response | Response | 1 Participants |
| NEOD001 24mg/kg | Hepatic Best Response | Non-response | 4 Participants |
| Placebo | Hepatic Best Response | Response | 0 Participants |
| Placebo | Hepatic Best Response | Non-response | 4 Participants |
p-value: 0.4142Cochran-Mantel-Haenszel
Secondary
NIS-LL Total Score
Change in Neuropathy Impairment Score-Lower Limb (NIS-LL) Total Score in subjects with peripheral nerve involvement. NIS-LL is a scoring system graduated from 0 points to a maximum of 88 points (the absence of all motor, sensory, and reflex activity in the lower extremities). The scale is an additive of all deficits (64 potential points for muscle strength, 8 points for reflexes, and 16 points for sensory function) in the lower extremities. A score of 0 is normal and score of 88 is total impairment.
Time frame: Baseline to 12 months of treatment
Population: Peripheral Neuropathy Evaluable Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NEOD001 24mg/kg | NIS-LL Total Score | -1.2 score on a scale |
| Placebo | NIS-LL Total Score | -0.6 score on a scale |
p-value: 0.75795% CI: [-4.2, 3]Mixed Models Analysis
Secondary
NT-proBNP Slope
Rate of change in NT-proBNP (ng/L per infusion). Estimates of the intercept, slope, SE, and associated 95% CI for each treatment group, and the NEOD001 and placebo group difference comparisons are estimated using a general linear mixed effects model. The model fits a random intercept and slope for each subject and includes fixed effects for treatment group, time, treatment group by time interaction, IWRS stratification factors (hematologic response to first-line therapy: CR/VGPR, PR and NT-proBNP \<1800 ng/L, ≥1800 ng/L), and an unstructured covariance structure to model the within-subject errors. Time is represented in months as a continuous variable and includes all scheduled time points, including baseline. The p-value is associated with the visit by treatment group interaction term.
Time frame: Baseline through 12 months of treatment
Population: ITT population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NEOD001 24mg/kg | NT-proBNP Slope | 9.45 ng/L per infusion |
| Placebo | NT-proBNP Slope | 81.41 ng/L per infusion |
p-value: 0.072995% CI: [-150.72, 6.79]Mixed Models Analysis
Secondary
Number of Participants With Renal Best Response and Non-Response
Proteinuria and estimated Glomerular Filtration Rate (eGFR) response (Response or Non-Response \[Stable, Progression\]) from baseline through 12 months of treatment in subjects with renal involvement. Renal best response, as assessed by proteinuria, is defined as the most favorable category among response (ie, ≥30% decrease from baseline or \<0.5 g/24 hours postbaseline result if subject does not meet criteria for progression), stable (ie, neither response nor progression), and progression (ie, ≥25% decrease in eGFR from baseline) across all visits after the first infusion of study drug up to and through the end of the study. Subjects are considered non-responders until a response is achieved. Assessments that qualify as both a response and progression are counted as progression. Non-response is defined as either stable or progression.
Time frame: Baseline through 12 months of treatment
Population: Renal Evaluable Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NEOD001 24mg/kg | Number of Participants With Renal Best Response and Non-Response | Response | 7 Participants |
| NEOD001 24mg/kg | Number of Participants With Renal Best Response and Non-Response | Non-Response (Stable, Progression) | 6 Participants |
| Placebo | Number of Participants With Renal Best Response and Non-Response | Response | 6 Participants |
| Placebo | Number of Participants With Renal Best Response and Non-Response | Non-Response (Stable, Progression) | 12 Participants |
p-value: 0.352995% CI: [0.6, 3.94]Cochran-Mantel-Haenszel
Secondary
SF-36v2 PCS Score
Change in Short Form-36 (SF-36 version 2) questionnaire Physical Component Summary \[PCS\] Score. PCS scores are calculated based on responses to specific Short Form-36 (version 2) questions using a weight scoring method. The lower the PCS score the more disability, the higher the score the less disability. A score of 50 is the mean in the US General Population and the standard deviation is 10. Minimum is 0 and maximum value is 100.
Time frame: Baseline to 12 months of treatment
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| NEOD001 24mg/kg | SF-36v2 PCS Score | 0.19 score on a scale |
| Placebo | SF-36v2 PCS Score | 0.97 score on a scale |
p-value: 0.556395% CI: [-3.37, 1.81]Mixed Models Analysis