Amyloidosis
Conditions
Keywords
Amyloidosis, NEOD001, RAIN
Brief summary
This is a 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 have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant \[ASCT\]) and have persistent renal dysfunction.
Detailed description
This is a 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 have a maintained hematologic response to their most recent treatment for AL amyloidosis (e.g., chemotherapy, autologous stem cell transplant \[SCT\]) and have persistent renal dysfunction. Subject screening will occur during the 28 days prior to the first administration of study drug (i.e. month 1 day 1). If screening assessments are completed and all eligibility requirements are met, the subject will be enrolled. Study visits will occur every 28 days based on scheduling from month 1 day 1. A ±5-day window is allowed for visits starting after month 1. Subjects may receive up to 12 infusions of study drug. Subjects who discontinue study drug before the initial End of Study (EOS) visit should have an Early Treatment Discontinuation (ETD) Visit 30 (±5) days after their final administration of study drug. After completing 12 months of treatment and the confirmatory EOS visit, a subject may enter an open-label extension (OLE) study, during which subjects will receive active treatment with NEOD001 for 12 months and may receive concurrent chemotherapy.
Interventions
DRUGNEOD001
NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates
DRUGPlacebo
Saline bag
Sponsors
Tufts Medical Center
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. 18 years of age or older 2. Biopsy-proven diagnosis of AL amyloidosis by immunohistochemistry or mass spectroscopy of a tissue biopsy excluding bone marrow 3. Screening renal biopsy for RAIN confirming AL amyloidosis as exclusive or dominant cause of renal damage 4. Persistent renal involvement from diagnosis with proteinuria (predominantly albumin) \> 500mg/day in a 24-hour urine collection 5. CKD 1 to 3 (eGFR \> 30) 6. ≥1 prior systemic hematologic therapy for a free light chain (FLC) producing hematologic malignancy underlying the initial diagnosis of AL amyloidosis with at least a partial FLC response (PR, VGPR, CR) to treatment deemed stable and not requiring further treatment 7. ECOG Performance Status ≤ 2 8. Clinical laboratory values: 1. Absolute neutrophil count \> 1000/μL 2. Platelet count \> 75,000/μL 3. Total bilirubin ≤ 1.5X ULN 4. Alkaline phosphatase ≤ 5X ULN 5. NT-proBNP \< 1800 pg/mL 9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
Exclusion criteria
1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis 2. Female patients who are lactating, breastfeeding, or pregnant 3. Patients who have not been treated or who have received chemotherapy within 6 months, or SCT within 12 months, for the light-chain producing hematologic disease causing AL amyloidosis, at the time of the first dose of NEOD001 (month 1 day 1) 4. Patients who at initial diagnosis or later met the International Myeloma Working Group (IMWG) definition of active multiple myeloma requiring therapy (Appendix 3) 5. Patients whose screening renal biopsies for RAIN show dominant causes of renal damage not related to AL amyloidosis 6. Medically documented cardiac syncope, uncompensated congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive atrial or ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically significant uncompensated autonomic insufficiency 7. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens 8. Ongoing or active infection, known HIV positive, known to be hepatitis B surface antigen-positive or has known or suspected active hepatitis C infection. 9. Psychiatric illness/social situations that would limit compliance with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Renal Response After Treatment With NEOD001 | Baseline to 13 Months | A renal response is a ≥ 30% reduction in proteinuria in the absence of a ≥ 25% decrease in eGFR. A confirmed renal response is one that has been documented as present one month after 12 monthly treatments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measured GFR at Study Entry | Baseline | The aim of this study is to assess the performance of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine in comparison to iothalamate clearance measured in AL amyloidosis patients. Iothalamate will be given subcutaneously. Urine and plasma samples will then be obtained. All laboratory tests for samples obtained for GFR measurement will be performed at Mayo Clinic Rochester. Quantification of iothalamate in urine and plasma will be performed using a tandem mass spectrometric method. |
| Time to CKD 4 or 5 | Baseline to 13 Months | Months to Chronic Kidney Disease level 4 or 5 |
| Time to eGFR ≤ 15 or Dialysis | Baseline to 13 Months | Months to estimated Glomerular Filtration Rate ≤ 15 or dialysis |
| All Cause of Mortality at 26 Months | Baseline to 26 months | Death at 26 months from Baseline due to any cause |
| Time to ≥ 40% Reduction in eGFR | Baseline to 13 Months | Months to ≥ 40% reduction in estimated glomerular filtration rate |
| Renal Response in Patients With Maintained Hematologic Responses After 24 Monthly Treatments. | Baseline to 26 months | A renal response is a ≥ 30% decrease in proteinuria or drop of proteinuria below 0.5 g/24h in the absence of renal progression. |
| Time to Doubling of Creatinine | Baseline to 13 Months | Months to doubling of serum creatinine |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| NEOD001 Study Drug given IV every 28 days at 24mg/kg
NEOD001: NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates | 6 |
| Placebo Placebo
Placebo: Saline bag | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 6 | 6 |
Baseline characteristics
| Characteristic | NEOD001 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Continuous | 60 years | 54.5 years | 57.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 6 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
Confirmed Renal Response After Treatment With NEOD001
A renal response is a ≥ 30% reduction in proteinuria in the absence of a ≥ 25% decrease in eGFR. A confirmed renal response is one that has been documented as present one month after 12 monthly treatments.
Time frame: Baseline to 13 Months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
All Cause of Mortality at 26 Months
Death at 26 months from Baseline due to any cause
Time frame: Baseline to 26 months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Measured GFR at Study Entry
The aim of this study is to assess the performance of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine in comparison to iothalamate clearance measured in AL amyloidosis patients. Iothalamate will be given subcutaneously. Urine and plasma samples will then be obtained. All laboratory tests for samples obtained for GFR measurement will be performed at Mayo Clinic Rochester. Quantification of iothalamate in urine and plasma will be performed using a tandem mass spectrometric method.
Time frame: Baseline
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Renal Response in Patients With Maintained Hematologic Responses After 24 Monthly Treatments.
A renal response is a ≥ 30% decrease in proteinuria or drop of proteinuria below 0.5 g/24h in the absence of renal progression.
Time frame: Baseline to 26 months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Time to ≥ 40% Reduction in eGFR
Months to ≥ 40% reduction in estimated glomerular filtration rate
Time frame: Baseline to 13 Months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Time to CKD 4 or 5
Months to Chronic Kidney Disease level 4 or 5
Time frame: Baseline to 13 Months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Time to Doubling of Creatinine
Months to doubling of serum creatinine
Time frame: Baseline to 13 Months
Population: Trial was closed prior to completion, therefore data were not collected.
Secondary
Time to eGFR ≤ 15 or Dialysis
Months to estimated Glomerular Filtration Rate ≤ 15 or dialysis
Time frame: Baseline to 13 Months
Population: Trial was closed prior to completion, therefore data were not collected.