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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03860935
Recruitment Status : Active, not recruiting
First Posted : March 4, 2019
Last Update Posted : December 30, 2021
Sponsor:
Information provided by (Responsible Party):
Eidos Therapeutics, a BridgeBio company

Brief Summary:
Phase 3 efficacy and safety study to evaluate acoramidis (AG10) 800 mg administered orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM).

Condition or disease Intervention/treatment Phase
Amyloidosis Amyloid Cardiomyopathy Transthyretin Amyloidosis Cardiomyopathies Heart Diseases Drug: acoramidis Drug: Placebo Oral Tablet Phase 3

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 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 frequencies of deaths, cardiovascular-related hospitalizations, and change in distance walked on the 6MWT after 30 months of treatment.

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 510 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : May 2023


Arm Intervention/treatment
Experimental: acoramidis 800 mg
Subjects will receive acoramidis 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The frequencies of deaths, cardiovascular-related hospitalizations, and change in distance walked on the 6MWT will be assessed after 30 months of treatment.
Drug: acoramidis
TTR stabilizer administered orally twice daily (BID)
Other Names:
  • AG10
  • ALXN2060

Placebo Comparator: Placebo
Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The frequencies of deaths, cardiovascular-related hospitalizations, and change in distance walked on the 6MWT will be assessed after 30 months of treatment.
Drug: Placebo Oral Tablet
Non-active control administered orally twice daily (BID)




Primary Outcome Measures :
  1. 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

  2. A hierarchical combination of all-cause mortality, frequency of cardiovascular-related hospitalization, and change from baseline to Month 30 of treatment in the total distance walked in 6 minutes [ 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 all-cause), frequency of cardiovascular-related hospitalization over a 30-month period (number of times a subject is hospitalized for cardiovascular-related causes) and change from baseline to Month 30 of treatment 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.


Secondary Outcome Measures :
  1. Kansas City Cardiomyopathy Questionnaire (KCCQ) at Month 12 [ Time Frame: at Month 12 ]
    Change from Baseline to Month 12 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (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.

  2. 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

  3. Kansas City Cardiomyopathy Questionnaire (KCCQ) at Month 30 [ Time Frame: at Month 30 ]
    Change from Baseline to Month 30 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (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.

  4. Incidence of treatment-emergent events [ Time Frame: 12 months ]
    Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)

  5. Incidence of treatment-emergent events [ Time Frame: 30 months ]
    Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)

  6. Acoramidis pharmacodynamic assessments of TTR stabilization by Fluorescent Probe Exclusion Assay at Day 28 [ Time Frame: at Month 12 ]
    Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)

  7. Acoramidis pharmacodynamic assessments of TTR stabilization by Fluorescent Probe Exclusion Assay through Month 30 [ Time Frame: 30 months ]
    Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)

  8. Acoramidis pharmacodynamic assessments of TTR stabilization by Western Blot at Day 28 [ Time Frame: at Month 12 ]
    Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)

  9. Acoramidis pharmacodynamic assessments of TTR stabilization by Western Blot through Month 30 [ Time Frame: 30 months ]
    Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)

  10. All-cause mortality [ Time Frame: 30 months ]
    Total number of deaths in the study due to all-cause

  11. Frequency of cardiovascular-related hospitalization [ Time Frame: 30 months ]
    Number of times a subject is hospitalized for cardiovascular-related causes

  12. Cardiovascular-related mortality [ Time Frame: 30 months ]
    Total number of deaths adjudicated as being related to cardiovascular causes


Other Outcome Measures:
  1. Effect of acoramidis on levels of biomarkers of myocardial wall stress and microvascular ischemia [ Time Frame: 30 months ]
    Changes in levels of N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and Troponin I (TnI)

  2. Acoramidis pharmacokinetic assessments [ Time Frame: 30 months ]
    Pharmacokinetic measures of acoramidis 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

  3. Effect of acoramidis 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. 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.

  4. Acoramidis activity across TTR mutations [ Time Frame: At Baseline ]
    Acoramidis binding to or stabilization across a panel of TTR mutations by additional assays



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03860935


Locations
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Sponsors and Collaborators
Eidos Therapeutics, a BridgeBio company
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eidos Therapeutics, a BridgeBio company
ClinicalTrials.gov Identifier: NCT03860935    
Other Study ID Numbers: AG10-301
2018-004280-32 ( EudraCT Number )
First Posted: March 4, 2019    Key Record Dates
Last Update Posted: December 30, 2021
Last Verified: December 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eidos Therapeutics, a BridgeBio company:
Amyloidosis
ATTR-CM
Transthyretin
Amyloid
TTR
Additional relevant MeSH terms:
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Heart Diseases
Cardiomyopathies
Amyloidosis
Cardiovascular Diseases
Proteostasis Deficiencies
Metabolic Diseases