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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03860935
Recruitment Status : Recruiting
First Posted : March 4, 2019
Last Update Posted : February 21, 2020
Sponsor:
Information provided by (Responsible Party):
Eidos Therapeutics

Tracking Information
First Submitted Date  ICMJE February 27, 2019
First Posted Date  ICMJE March 4, 2019
Last Update Posted Date February 21, 2020
Actual Study Start Date  ICMJE March 19, 2019
Estimated Primary Completion Date April 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 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
  • Total number of deaths due to all-cause and frequency of cardiovascular-related hospitalization [ Time Frame: 30 months ]
    A hierarchical combination of all-cause mortality (total number of deaths due to all-cause) and frequency of cardiovascular-related hospitalization over a 30-month period
Original Primary Outcome Measures  ICMJE
 (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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2019)
  • 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.
  • 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 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.
  • 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 due to all-cause
  • 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
Original Secondary Outcome Measures  ICMJE
 (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: March 13, 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. 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.
  • AG10 activity across TTR mutations [ Time Frame: At Baseline ]
    AG10 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  ICMJE Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
Official Title  ICMJE 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)
Brief Summary Phase 3 efficacy and safety study to evaluate AG10 800 mg 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 AG10 800mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of AG10 in patients with ATTR-CM versus placebo

This is a 30 month, 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 AG10 or placebo

The primary outcomes of the study are:

  1. The impact of AG10 versus placebo on the 6 minute walk test after 12 months of treatment
  2. The impact of AG10 versus placebo on the frequencies of deaths and cardiovascular-related hospitalizations after 30 months of treatment

At the end of 30 months, participants may be eligible to receive investigational AG10, and there is no placebo. This is called an "open label extension." This part of the study may help us better understand the safety related to taking AG10 over a longer period of time

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Amyloidosis
  • Amyloid Cardiomyopathy
  • Transthyretin Amyloidosis
  • Cardiomyopathies
  • Heart Diseases
Intervention  ICMJE
  • Drug: AG10
    TTR stabilizer administered orally twice daily (BID)
  • Drug: Placebo Oral Tablet
    Non-active control administered orally twice daily (BID)
Study Arms  ICMJE
  • Experimental: AG10 800 mg
    Subjects will receive AG10 800 mg twice daily. 6 Minute Walk Test (6MWT) primary outcome will be assessed at the end of 12 months, followed by all-cause mortality and cardiovascular-related hospitalization assessed at the end of 30 months.
    Intervention: Drug: AG10
  • Placebo Comparator: Placebo
    Subjects will receive placebo to match twice daily. 6 Minute Walk Test (6MWT) primary outcome will be assessed at the end of 12 months, followed by all-cause mortality and cardiovascular-related hospitalization assessed at the end of 30 months.
    Intervention: Drug: Placebo Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 28, 2019)
510
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2023
Estimated Primary Completion Date April 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 prior to randomization
  • Biomarkers of myocardial wall stress, NT-proBNP level ≥300 pg/mL
  • 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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Vincent Knobel 4158871471 clinicaltrials@eidostx.com
Listed Location Countries  ICMJE Australia,   Canada,   Denmark,   Israel,   Italy,   Korea, Republic of,   New Zealand,   Portugal,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03860935
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Responsible Party Eidos Therapeutics
Study Sponsor  ICMJE Eidos Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Eidos Therapeutics
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP