Transthyretin Amyloidosis
Conditions
Keywords
124I-evuzamitide, Positron Emission Tomography (PET), ATTR-CM
Brief summary
This was a single center, prospective cohort study that is evaluating the ability of 124I-evuzamitide PET scanning to detect potential therapeutic changes in subjects under treatment for ATTR after one year had elapsed since their original 124I-evuzamitide PET scan. Ten previously scanned subjects re-consented to undergo another 124I-evuzamitide PET scan. Demographic, clinical and phenotypic data were collected to characterize potential changes since their previous scans.
Detailed description
Transthyretin cardiac amyloidosis (ATTR-CA) causes progressive heart disease that is often overlooked. It harms the heart muscle because the unstable, unfurled amyloid proteins fold up into large pieces that get caught in between layers of heart tissue, causing amyloid deposits. The earlier it is detected, the better for the patient. There is a need to improve the early diagnosis of this disease because echocardiography (sonograms of the heart) and cardiac MRI are not useful enough for this. There is an X-ray of the heart using a compound called PYP that can detect amyloid deposits earlier than ultrasound images or clinical signs, but it's not clear how early it does so. Also, it can't detect amyloid deposits outside the heart, which causes lots of pain and suffering in people with this disease. In the first phase of this study the radiation compound, evuzamitide, was shown to detect amyloidosis in the heart of selected subjects. So, the investigators used it to detect potential therapeutic changes in 10 subjects undergoing treatment for Transthyretin Amyloidosis. Changes in the uptake of evuzamitide were compared between subjects treated on stabilizer only, subjects treated on silencer only and subjects treated with two different combinations of stabilizer plus silencer
Interventions
DRUGI 124-Evuzamitide
Amyloid reactive protein used as imaging agent in whole body SPECT-CT imaging
Sponsors
Attralus, Inc.
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 105 Years
Healthy volunteers
Yes
Inclusion criteria
1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements. 2. Were enrolled in the initial pilot using 124I-Evuzamitide, on ATTR stabilizer and/or silencer therapy. Able to understand and sign the informed consent document after the nature of the study has been fully explained. 3. TTR genotype shown to be either Val122Ile or wild type.
Exclusion criteria
Overall Inclusion Criteria: 1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements. 2. Were enrolled in the initial pilot using 124I-Evuzamitide, on ATTR stabilizer and/or silencer therapy. Able to understand and sign the informed consent document after the nature of the study has been fully explained. 3. TTR genotype shown to be either Val122Ile or wild type. The presence of any of the following excludes eligibility for enrollment in this study: 1. Primary amyloidosis (AL) or secondary amyloidosis (AA). 2. Active malignancy or non-amyloid disease with expected survival of less than 1 year. 3. Heart failure, in the opinion of the investigator, primarily caused by something other than amyloidosis. 4. Ventricular assist device. 5. Impairment from stroke, injury or other medical disorder that precludes participation in the study. 6. Disabling dementia or other mental or behavioral disease. 7. Enrollment in a clinical trial not approved for co-enrollment. 8. Continuous intravenous inotropic therapy. 9. Inability or unwillingness to comply with the study requirements. 10. Chronic kidney disease requiring hemodialysis or peritoneal dialysis. 11. Patients taking heparin, or heparin derivatives (e.g. low molecular weight heparins) for anticoagulation. 12. Other reason that would make the subject inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters | Up to one month after imaging | Volumes of interest (VOIs) were manually traced on PET emission images fused with CT images to define the left ventricular (LV) and right ventricular (RV) contours, including cavity blood pool. Blood pool activity concentration was measured in a 10-mm-diameter left atrial spherical VOI. For 124I-evuzamitide, we used a threshold of mean + 2 standard deviations of blood pool activity concentration. |
| Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID) | Up to one month after imaging | Median percentage change in injected dose (%ID), calculated as VOI mean activity concentration x VOI volume/injected activity. |
| Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams | Up to one month after imaging | Cardiac amyloid activity (CAA) in grams is measured as VOI mean standardized uptake value times VOI volume. Standardized uptake value was defined as mean or maximal VOI activity concentration/(injected activity/bodyweight), while target-to-background ratio was considered VOI mean activity concentration/blood pool mean activity concentration. VOI volume was manually traced on PET emission images fused with CT images. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stabilizer Only Subjects treated with tafamidis selected to re-scan to determine the change over time in Evuzamitide uptake | 4 |
| Silencer Only Subjects treated with vutrisiran selected to re-scan to determine the change over time in Evuzamitide uptake | 1 |
| Stabilizer and Silencer (Tafamidis + Patisiran) Subjects treated with tafamidis and patisiran selected to re-scan to determine the change over time in Evuzamitide uptake | 3 |
| Stabilizer and Silencer (Vutrisiran + Diflunisal) Subjects treated with vutrisiran and diflunisal selected to re-scan to determine the change over time in Evuzamitide uptake | 2 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | measurements were not usable due material error in imaging agent supplied | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Stabilizer Only | Silencer Only | Stabilizer and Silencer (Tafamidis + Patisiran) | Stabilizer and Silencer (Vutrisiran + Diflunisal) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 68.75 years | 65 years | 75 years | 60 years | 67.77 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| PYP Scan result PYP Score 0 - no uptake | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| PYP Scan result PYP Score 1 - less uptake than bone | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| PYP Scan result PYP Score 2 - as much uptake as bone | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| PYP Scan result PYP Score 2 or 3 - indeterminate whether uptake is equal to or greater than bone | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| PYP Scan result PYP Score 3 - more uptake than bone | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 0 Participants | 3 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 3 Participants | 2 Participants | 10 Participants |
| TTR Genotype Asp38Glu | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| TTR Genotype Thr60Ile | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| TTR Genotype V122i | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| TTR Genotype Val30Met | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| TTR Genotype Wild-Type | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 1 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 0 / 4 | 0 / 1 | 1 / 3 | 0 / 2 |
| serious Total, serious adverse events | 0 / 4 | 0 / 1 | 0 / 3 | 0 / 2 |
Outcome results
Primary
Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID)
Median percentage change in injected dose (%ID), calculated as VOI mean activity concentration x VOI volume/injected activity.
Time frame: Up to one month after imaging
Population: 1 subject was scanned but their measurements were not usable due material error in imaging agent supplied.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stabilizer Only | Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID) | 0.2 percent change |
| Silencer Only | Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID) | 0.8 percent change |
| Stabilizer and Silencer (Tafamidis + Patisiran) | Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID) | 1.3 percent change |
| Stabilizer and Silencer (Vutrisiran + Diflunisal) | Median of Change in Evuzamitide Uptake as Measured by Percentage Change in Injected Dose (%ID) | 0.3 percent change |
Primary
Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams
Cardiac amyloid activity (CAA) in grams is measured as VOI mean standardized uptake value times VOI volume. Standardized uptake value was defined as mean or maximal VOI activity concentration/(injected activity/bodyweight), while target-to-background ratio was considered VOI mean activity concentration/blood pool mean activity concentration. VOI volume was manually traced on PET emission images fused with CT images.
Time frame: Up to one month after imaging
Population: 1 subject was scanned but their measurements were not usable due material error in imaging agent supplied.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stabilizer Only | Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams | 180.2 grams |
| Silencer Only | Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams | 852.8 grams |
| Stabilizer and Silencer (Tafamidis + Patisiran) | Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams | 952.5 grams |
| Stabilizer and Silencer (Vutrisiran + Diflunisal) | Median of Uptake of Evuzamitide as Measured by Cardiac Amyloid Activity (CAA) in Grams | 155.4 grams |
Primary
Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters
Volumes of interest (VOIs) were manually traced on PET emission images fused with CT images to define the left ventricular (LV) and right ventricular (RV) contours, including cavity blood pool. Blood pool activity concentration was measured in a 10-mm-diameter left atrial spherical VOI. For 124I-evuzamitide, we used a threshold of mean + 2 standard deviations of blood pool activity concentration.
Time frame: Up to one month after imaging
Population: 1 subject was scanned but their measurements were not usable due material error in imaging agent supplied.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stabilizer Only | Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters | 78.7 mL |
| Silencer Only | Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters | 253.6 mL |
| Stabilizer and Silencer (Tafamidis + Patisiran) | Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters | 177.2 mL |
| Stabilizer and Silencer (Vutrisiran + Diflunisal) | Median of Uptake of Evuzamitide as Measured by Volume of Interest in Milliliters | 39.6 mL |