Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM)

• ClinicalTrials.gov Identifier: NCT03860935
• Recruitment Status: Completed
• First Posted: March 4, 2019
• Last Update Posted: July 10, 2023
• Sponsor: Eidos Therapeutics, a BridgeBio company
• Information provided by (Responsible Party): Eidos Therapeutics, a BridgeBio company

Tracking Information

• First Submitted Date: February 27, 2019
• First Posted Date: March 4, 2019
• Last Update Posted Date: July 10, 2023
• Actual Study Start Date: March 19, 2019
• Actual Primary Completion Date: May 11, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2023)

• 6-Minute Walk Test (6MWT) through Month 12 [ Time Frame: 12 months ]
  Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes
• 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 [ Time Frame: 30 months ]
  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.

Original Primary Outcome Measures (submitted: February 28, 2019)

• 6 Minute Walk Test (6MWT) at Month 12 [ Time Frame: at Month 12 ]
  Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes
• All-cause mortality and frequency of cardiovascular-related hospitalization [ Time Frame: 30 months ]
  A hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalization over a 30-month period

Current Secondary Outcome Measures (submitted: July 6, 2023)

• Evaluate effects of acoramidis on quality of life (QoL) through Month 12 [ Time Frame: 12 months ]
  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.
• Evaluate 6-Minute Walk Test (6MWT) through Month 30 [ Time Frame: 30 months ]
  Change from baseline to Month 30 of treatment in the total distance walked in 6 minutes
• Evaluate effects of acoramidis on quality of life (QoL) through Month 30 [ Time Frame: 30 months ]
  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.
• Assess PD effects of circulating prealbumin by in vivo biomarker stabilization through Month 30 [ Time Frame: 30 months ]
  Change from baseline to Month 30 in serum TTR (prealbumin) level (an in vivo measure of TTR stabilization)
• Assess all-cause mortality [ Time Frame: 30 months ]
  All-Cause Mortality by Month 30 including death due to any cause, heart transplant, or CMAD
• Assess safety and tolerability through Month 12 [ Time Frame: 12 months ]
  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
• PD assessments of TTR stabilization through Month 12 [ Time Frame: 12 months ]
  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
• Efficacy by individual components and hierarchical combinations through Month 30 [ Time Frame: 30 months ]
  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
• Efficacy of acoramidis in reducing CV mortality [ Time Frame: 30 months ]
  Total number of deaths adjudicated as being related to cardiovascular causes
• Incidence of treatment-emergent events [ Time Frame: 30 months ]
  Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)

Original Secondary Outcome Measures (submitted: February 28, 2019)

• Kansas City Cardiomyopathy Questionnaire (KCCQ) at Month 12 [ Time Frame: at Month 12 ]
  Change from Baseline to Month 12 as measured in the heart-failure specific quality of life questionnaire, the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS). Scores are transformed to a range of 0-100, in which higher scores reflect better health status
• 6 Minute Walk Test (6MWT) at Month 30 [ Time Frame: at Month 30 ]
  Change from baseline to Month 30 of treatment in the total distance walked in 6 minutes
• Kansas City Cardiomyopathy Questionnaire (KCCQ) at Month 30 [ Time Frame: at Month 30 ]
  Change from Baseline to Month 30 as measured in the heart-failure specific quality of life questionnaire, the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS). Scores are transformed to a range of 0-100, in which higher scores reflect better health status
• Incidence of treatment-emergent events [ Time Frame: 12 months ]
  Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)
• Incidence of treatment-emergent events [ Time Frame: 30 months ]
  Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)
• AG10 Pharmacodynamic Assessments of TTR stabilization by Fluorescent Probe Exclusion Assay at Day 28 [ Time Frame: at Day 28 ]
  AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)
• AG10 Pharmacodynamic Assessments of TTR stabilization by Fluorescent Probe Exclusion Assay through Month 30 [ Time Frame: 30 months ]
  AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)
• AG10 Pharmacodynamic Assessments of TTR stabilization by Western Blot at Day 28 [ Time Frame: at Day 28 ]
  AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)
• AG10 Pharmacodynamic Assessments of TTR stabilization by Western Blot through Month 30 [ Time Frame: 30 months ]
  AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)
• All-cause mortality [ Time Frame: 30 months ]
  Total number of deaths in the study
• Frequency of cardiovascular-related hospitalization [ Time Frame: 30 months ]
  Number of times a subject is hospitalized for cardiovascular-related causes
• Cardiovascular-related mortality [ Time Frame: 30 months ]
  Total number of deaths adjudicated as being related to cardiovascular causes

Current Other Pre-specified Outcome Measures (submitted: July 6, 2023)

• Effects of acoramidis on circulating biomarker of myocardial wall stress [ Time Frame: 12 months ]
  Changes in level of NT-proBNP
• Effects of acoramidis on circulating biomarker of microvascular ischemia [ Time Frame: 12 months and 30 months ]
  Changes in level of Troponin I (TnI)
• Characterize PK of acoramidis [ Time Frame: 12 months and 30 months ]
  PK measures of acoramidis and its predominant metabolite after oral administration of acoramidis HCl 800 mg BID for steady state (every 3 months), in a subgroup of subjects followed at centers participating in the PK-PD substudy
• Evaluate effect of acoramidis on health-related quality of life questionnaire EuroQol EQ-5D-5L [ Time Frame: 12 months and 30 months ]
  Change from Baseline to Month 30 in the EQ-5D-5L score. EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain or discomfort and anxiety or depression. Each dimension in EQ-5D-5L has five response levels of function: no problem (Level 1); slight problem (Level 2); moderate problem (Level 3); severe problem (Level 4); and extreme problem (Level 5). The subject is asked to indicate his health state by ticking the box next to the most appropriate statement in each of the five dimensions. The digits for the five dimensions can be combined into a 5-digit number, the utility score, that describes the subject's health state. A lower value indicates better perceived health state. On EQ VAS, the subject circles a single rating of self-perceived health on a 0 to 100 mm scale representing "the worst imaginable health state" and "the best imaginable health state", respectively.
• Assess acoramidis activity across TTR mutations [ Time Frame: 12 months and 30 months ]
  Acoramidis binding to or stabilization across a panel of TTR mutations by additional assays

Original Other Pre-specified Outcome Measures (submitted: February 28, 2019)

• Effect of AG10 on levels of biomarkers of myocardial wall stress and microvascular ischemia [ Time Frame: 30 months ]
  Changes in levels of N-terminal pro-Brain-type Natriuretic Peptide (NT-proBNP) and Troponin I (TnI)
• AG10 Pharmacokinetic Assessments [ Time Frame: 30 months ]
  Pharmacokinetic measures of AG10 and its predominant metabolite after oral administration BID in subjects with symptomatic ATTR-CM for steady state (every 3 months), in a subgroup of subjects
• Effect of AG10 on health-related quality of life questionnaire EuroQol EQ-5D-5L [ Time Frame: 30 months ]
  Change from Baseline to Month 30 in the EQ-5D-5L score. The EQ-5D-5L consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The subject is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the subject's health state. A lower value indicates better perceived health state. A higher value on the EQ VAS represents better perceived health state.
• AG10 activity across TTR mutations [ Time Frame: At Baseline ]
  AG10 binding to or stabilization across a panel of TTR mutations by additional assays

Descriptive Information

• Brief Title: Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
• Official 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)
• 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).

Detailed Description

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed condition believed to affect more than 400,000 people worldwide. In ATTR-CM, the accumulation of transthyretin (TTR) amyloid results in thickening and stiffening of the heart, which often leads to heart failure or even death.

There are two forms of ATTR-CM:

• Wild Type* This form of the condition primarily develops in older individuals who do not carry gene mutations.
• Hereditary* This form of the condition comes from gene mutations passed down in families.

In this study we are researching the investigational drug acoramidis HCl 800 mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM versus placebo.

This is a 30 month, randomized, double-blind, placebo-controlled study. This means that, during the 30 month study, investigators conducting the research and study participants will not know whether the study participant is receiving acoramidis or placebo.

The primary outcomes of the study are:

1. The impact of acoramidis versus placebo on the change in distance walked on the 6 minute walk test (6MWT) after 12 months of treatment compared to baseline.
2. The impact of acoramidis versus placebo on the hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP, and change in from baseline in 6MWT over a 30-month fixed treatment duration.

At the end of 30 months, participants may be eligible to receive investigational acoramidis, and there is no placebo. This is called an "open label extension." This separate study may help us better understand the safety related to taking acoramidis over a longer period of time.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Amyloidosis
• Amyloid Cardiomyopathy
• Transthyretin Amyloidosis
• Cardiomyopathies
• Heart Diseases

Intervention

• Drug: acoramidis
  TTR stabilizer administered orally twice daily (BID)
  Other Names:

  • AG10
  • ALXN2060
• Drug: Placebo Oral Tablet
  Non-active control administered orally twice daily (BID)

Study Arms

• 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.
  Intervention: Drug: acoramidis
• 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.
  Intervention: Drug: Placebo Oral Tablet

• Publications *: Stern LK, Kittleson MM. Updates in Cardiac Amyloidosis Diagnosis and Treatment. Curr Oncol Rep. 2021 Mar 16;23(4):47. doi: 10.1007/s11912-021-01028-8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 6, 2023): 632
• Original Estimated Enrollment (submitted: February 28, 2019): 510
• Actual Study Completion Date: May 11, 2023
• Actual Primary Completion Date: May 11, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, Czechia, Denmark, Greece, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Poland, Portugal, Spain, United Kingdom, United States
• Removed Location Countries: Hungary

Administrative Information

• NCT Number: NCT03860935
• Other Study ID Numbers: AG10-301; 2018-004280-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eidos Therapeutics, a BridgeBio company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eidos Therapeutics, a BridgeBio company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Eidos Therapeutics, a BridgeBio company
• Verification Date: July 2023