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Trial record 17 of 359 for:    transthyretin

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

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ClinicalTrials.gov Identifier: NCT03860935
Recruitment Status : Recruiting
First Posted : March 4, 2019
Last Update Posted : August 14, 2019
Sponsor:
Information provided by (Responsible Party):
Eidos Therapeutics

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)

Condition or disease Intervention/treatment Phase
Amyloidosis Amyloid Cardiomyopathy Transthyretin Amyloidosis Cardiomyopathies Heart Diseases Drug: AG10 Drug: Placebo Oral Tablet Phase 3

Detailed Description:

This Phase 3 prospective, randomized, multicenter, parallel-group study will evaluate the efficacy and safety of AG10 800 mg in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM) for a total of 30 months of blinded, placebo-controlled treatment.

At the end of 12 months of treatment (Part A) efficacy of AG10 will be assessed through analyses of the functional endpoint, 6 Minute Walk Test, and the health-related Quality of Life endpoint, heart failure-specific instrument Kansas City Cardiomyopathy Questionnaire.

At the end of 30 months of treatment (Part B) efficacy of AG10 will be further assessed through analysis of all-cause mortality and frequency of cardiovascular-related hospitalization.

All subjects who complete 30 months of blinded, placebo-controlled treatment may be eligible to participate in an open label extension study of long-term AG10 treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Actual Study Start Date : March 19, 2019
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : November 2022


Arm Intervention/treatment
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.
Drug: AG10
TTR stabilizer administered orally twice daily (BID)

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.
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. 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


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. 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)

  7. 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)

  8. 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)

  9. 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)

  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 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)

  2. 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

  3. 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.

  4. AG10 activity across TTR mutations [ Time Frame: At Baseline ]
    AG10 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 consecutive tests
  • Biomarkers of myocardial wall stress, NT-proBNP level ≥300 pg/mL
  • Have left ventricular wall (interventricular septum or left ventricular posterior wall) thickness ≥13 mm

Exclusion Criteria:

  • Had acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke within 90 days
  • 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 ≥7000 pg/mL pg/mL
  • Measure of kidney function, eGFR by MDRD formula < 15 mL/min/1.73 m2
  • Current treatment with other investigational agents for the treatment of ATTR-CM
  • Current treatment with calcium channel blockers or digitalis

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


Contacts
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Contact: Vincent Knobel 4158871471 clinicaltrials@eidostx.com

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Sponsors and Collaborators
Eidos Therapeutics

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Responsible Party: Eidos Therapeutics
ClinicalTrials.gov Identifier: NCT03860935     History of Changes
Other Study ID Numbers: AG10-301
2018-004280-32 ( EudraCT Number )
First Posted: March 4, 2019    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019

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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:
Amyloidosis
ATTR-CM
Transthyretin
Amyloid
TTR

Additional relevant MeSH terms:
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Heart Diseases
Cardiomyopathies
Amyloidosis
Amyloid Neuropathies, Familial
Cardiovascular Diseases
Proteostasis Deficiencies
Metabolic Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Nervous System Diseases
Amyloid Neuropathies
Peripheral Nervous System Diseases
Neuromuscular Diseases
Genetic Diseases, Inborn
Amyloidosis, Familial
Metabolism, Inborn Errors