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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03860935
Registration number
NCT03860935
Ethics application status
Date submitted
27/02/2019
Date registered
4/03/2019
Date last updated
10/07/2023
Titles & IDs
Public title
Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
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Scientific title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects With Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial)
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Secondary ID [1]
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2018-004280-32
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Secondary ID [2]
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AG10-301
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Universal Trial Number (UTN)
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Trial acronym
ATTRibute-CM
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Amyloidosis
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Amyloid Cardiomyopathy
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Transthyretin Amyloidosis
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Cardiomyopathies
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Heart Diseases
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Condition category
Condition code
Cardiovascular
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Coronary heart disease
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Cardiovascular
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0
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Other cardiovascular diseases
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Metabolic and Endocrine
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Metabolic disorders
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Metabolic and Endocrine
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Other metabolic disorders
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Human Genetics and Inherited Disorders
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0
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - acoramidis
Treatment: Drugs - Placebo Oral Tablet
Experimental: acoramidis HCl 800 mg - Subjects will receive acoramidis HCl 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
Placebo Comparator: Placebo - Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
Treatment: Drugs: acoramidis
TTR stabilizer administered orally twice daily (BID)
Treatment: Drugs: Placebo Oral Tablet
Non-active control administered orally twice daily (BID)
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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6-Minute Walk Test (6MWT) through Month 12
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Assessment method [1]
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Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes
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Timepoint [1]
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12 months
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Primary outcome [2]
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A hierarchical combination of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT over a 30-month fixed treatment duration
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Assessment method [2]
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Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters).
The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the acoramidis treatment group will have a greater score than a subject in the placebo group.
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Timepoint [2]
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30 months
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Secondary outcome [1]
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Evaluate effects of acoramidis on quality of life (QoL) through Month 12
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Assessment method [1]
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Change from Baseline to Month 12 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status.
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Timepoint [1]
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12 months
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Secondary outcome [2]
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Evaluate 6-Minute Walk Test (6MWT) through Month 30
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Assessment method [2]
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Change from baseline to Month 30 of treatment in the total distance walked in 6 minutes
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Timepoint [2]
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30 months
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Secondary outcome [3]
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Evaluate effects of acoramidis on quality of life (QoL) through Month 30
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Assessment method [3]
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Change from Baseline to Month 30 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status.
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Timepoint [3]
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30 months
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Secondary outcome [4]
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Assess PD effects of circulating prealbumin by in vivo biomarker stabilization through Month 30
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Assessment method [4]
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Change from baseline to Month 30 in serum TTR (prealbumin) level (an in vivo measure of TTR stabilization)
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Timepoint [4]
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30 months
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Secondary outcome [5]
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Assess all-cause mortality
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Assessment method [5]
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All-Cause Mortality by Month 30 including death due to any cause, heart transplant, or CMAD
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Timepoint [5]
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30 months
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Secondary outcome [6]
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Assess safety and tolerability through Month 12
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Assessment method [6]
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Safety parameters to be assessed: treatment- emergent serious adverse events (SAEs) and adverse events (AEs), AEs leading to treatment discontinuation, abnormal physical exam findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential clinical concern
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Timepoint [6]
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12 months
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Secondary outcome [7]
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PD assessments of TTR stabilization through Month 12
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Assessment method [7]
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Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) at Month 12
TTR stabilization as measured in established ex-vivo assays (fluorescent probe exclusion [FPE] and Western blot) at Month 12 in the PK-PD substudy
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Timepoint [7]
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12 months
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Secondary outcome [8]
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Efficacy by individual components and hierarchical combinations through Month 30
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Assessment method [8]
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A hierarchical combination of All-Cause mortality and cumulative frequency of CV-related hospitalization over a 30-month fixed treatment duration
A hierarchical combination of All-Cause mortality, cumulative frequency of CV-related hospitalization, and change from baseline in 6MWT over a 30-month fixed treatment duration
Change in NT-proBNP from baseline to Month 30 of treatment
Cumulative frequency of CV-related hospitalization by Month 30
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Timepoint [8]
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30 months
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Secondary outcome [9]
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Efficacy of acoramidis in reducing CV mortality
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Assessment method [9]
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Total number of deaths adjudicated as being related to cardiovascular causes
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Timepoint [9]
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30 months
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Secondary outcome [10]
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Incidence of treatment-emergent events
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Assessment method [10]
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Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)
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Timepoint [10]
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30 months
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Eligibility
Key inclusion criteria
- Have an established diagnosis of ATTR-CM with either wild-type TTR or variant TTR
genotype
- Have a history of heart failure evidenced by at least one prior hospitalization for
heart failure or clinical evidence of heart failure without prior heart failure
hospitalization manifested by signs or symptoms of volume overload or elevated
intracardiac pressures or heart failure symptoms that required or require ongoing
treatment with a diuretic.
- New York Heart Association (NYHA) Class I-III symptoms due to ATTR cardiomyopathy.
- On stable doses of cardiovascular medical therapy
- Completed =150 m on the 6MWT on 2 tests that are within 15% of total distance walked
prior to randomization
- Biomarkers of myocardial wall stress, NT-proBNP level =300 pg/mL at screening
- Have left ventricular wall (interventricular septum or left ventricular posterior
wall) thickness =12 mm
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Minimum age
18
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Maximum age
90
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Had acute myocardial infarction, acute coronary syndrome or coronary
revascularization, or experienced stroke or transient ischemic attack within 90 days
prior to screening
- Has hemodynamic instability
- Likely to undergo heart transplantation within a year of screening
- Confirmed diagnosis of primary (light chain) amyloidosis
- Biomarkers of myocardial wall stress, NT-proBNP level =8500 pg/mL at screening
- Measure of kidney function, eGFR by MDRD formula <15 mL/min/1.73 m2
- Current treatment with marketed drug products and other investigational agents for the
treatment of ATTR-CM
- Current treatment with calcium channel blockers with conduction system effects (e.g.
verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed.
The use of digitalis will only be allowed if required for management of atrial
fibrillation with rapid ventricular response
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/03/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
11/05/2023
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Sample size
Target
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Accrual to date
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Final
632
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Recruitment in Australia
Recruitment state(s)
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Recruitment hospital [1]
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Royal Adelaide Hospital - Adelaide
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Recruitment hospital [2]
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Box Hill Hospital - Box Hill
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Recruitment hospital [3]
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Royal Hobart Hospital - Hobart
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Recruitment hospital [4]
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Fiona Stanley Hospital - Murdoch
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Recruitment hospital [5]
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Saint Vincent's Hospital Sydney - Sydney
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Recruitment hospital [6]
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Princess Alexandra Hospital - Woolloongabba
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Recruitment postcode(s) [1]
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- Adelaide
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Recruitment postcode(s) [2]
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- Box Hill
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Recruitment postcode(s) [3]
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- Hobart
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Recruitment postcode(s) [4]
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- Murdoch
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Recruitment postcode(s) [5]
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2010 - Sydney
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Recruitment postcode(s) [6]
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- Woolloongabba
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Recruitment outside Australia
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Eidos Therapeutics, a BridgeBio company
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Ethics approval
Ethics application status
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Summary
Brief summary
Phase 3 efficacy and safety study to evaluate acoramidis (AG10) HCl 800 mg administered
orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid
Cardiomyopathy (ATTR-CM).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03860935
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03860935
Download to PDF