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

Sponsor

Eidos Therapeutics, a BridgeBio company (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03860935

Collaborator

(none)

510

Enrollment

104

Locations

Arms

49.4

Anticipated Duration (Months)

4.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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:

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.
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.

Study Design

Study Type:

Interventional

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 :

Mar 19, 2019

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

6 Minute Walk Test (6MWT) at Month 12 [at Month 12]
Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes
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 [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

Kansas City Cardiomyopathy Questionnaire (KCCQ) at Month 12 [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 [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 [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 [12 months]
Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)
Incidence of treatment-emergent events [30 months]
Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs)
Acoramidis pharmacodynamic assessments of TTR stabilization by Fluorescent Probe Exclusion Assay at Day 28 [at Month 12]
Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)
Acoramidis pharmacodynamic assessments of TTR stabilization by Fluorescent Probe Exclusion Assay through Month 30 [30 months]
Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Probe Exclusion Assay (FPE)
Acoramidis pharmacodynamic assessments of TTR stabilization by Western Blot at Day 28 [at Month 12]
Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)
Acoramidis pharmacodynamic assessments of TTR stabilization by Western Blot through Month 30 [30 months]
Acoramidis binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)
All-cause mortality [30 months]
Total number of deaths in the study due to all-cause
Frequency of cardiovascular-related hospitalization [30 months]
Number of times a subject is hospitalized for cardiovascular-related causes
Cardiovascular-related mortality [30 months]
Total number of deaths adjudicated as being related to cardiovascular causes

Other Outcome Measures

Effect of acoramidis on levels of biomarkers of myocardial wall stress and microvascular ischemia [30 months]
Changes in levels of N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and Troponin I (TnI)
Acoramidis pharmacokinetic assessments [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
Effect of acoramidis on health-related quality of life questionnaire EuroQol EQ-5D-5L [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.
Acoramidis activity across TTR mutations [At Baseline]
Acoramidis binding to or stabilization across a panel of TTR mutations by additional assays

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	Pacific Heart Institute	Santa Monica	California	United States	90404
3	University of Colorado Hospital - Anschutz Medical Campus	Aurora	Colorado	United States	80045
4	Yale School of Medicine	New Haven	Connecticut	United States	06473
5	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
6	University of Miami - Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
7	Piedmont Heart Institute Athens	Athens	Georgia	United States	30606
8	Emory Heart and Vascular Center	Atlanta	Georgia	United States	30322
9	Northwestern University	Chicago	Illinois	United States	60611
10	The University of Chicago Medical Center	Chicago	Illinois	United States	60637
11	NorthShore University Health System	Evanston	Illinois	United States	60201
12	Indiana University	Indianapolis	Indiana	United States	46202
13	MedStar Medical Group Cardiology at Franklin Square Medical Center	Baltimore	Maryland	United States	21218
14	Boston University School of Medicine	Boston	Massachusetts	United States	02118
15	Saint Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
16	Mayo Clinic	Rochester	Minnesota	United States	55905
17	Saint Luke's Hospital - Kansas City	Kansas City	Missouri	United States	64111
18	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
19	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
20	Montefiore Medical Center	Bronx	New York	United States	10461
21	North Shore University Hospital	Manhasset	New York	United States	11030
22	New York University Langone Health	New York	New York	United States	10010
23	Mount Sinai Hospital	New York	New York	United States	10029
24	Columbia University Medical Center	New York	New York	United States	10034
25	Laurelton Heart Specialist	Rosedale	New York	United States	11422
26	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27514
27	Duke University Health System	Durham	North Carolina	United States	27710
28	Cleveland Clinic	Cleveland	Ohio	United States	44195
29	Oregon Health and Science University	Portland	Oregon	United States	97239
30	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
31	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
32	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
33	The Medical University of South Carolina	Charleston	South Carolina	United States	29425
34	Prisma Health - Greenville Memorial Hospital	Greenville	South Carolina	United States	29605
35	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
36	University of Utah	Salt Lake City	Utah	United States	84132
37	Virginia Commonwealth University Medical Center	Richmond	Virginia	United States	23298
38	Carilion Clinic Roanoke Heart Institute	Roanoke	Virginia	United States	24014
39	University of Washington School of Medicine	Seattle	Washington	United States	98195
40	Providence Sacred Heart Medical Center	Spokane	Washington	United States	99204
41	Royal Adelaide Hospital	Adelaide		Australia
42	Box Hill Hospital	Box Hill		Australia
43	Royal Hobart Hospital	Hobart		Australia
44	Fiona Stanley Hospital	Murdoch		Australia
45	Saint Vincent's Hospital Sydney	Sydney		Australia	2010
46	Princess Alexandra Hospital	Woolloongabba		Australia
47	Ziekenhuis Oost-Limburg - Campus Sint-Jan	Genk	Limburg	Belgium
48	Jessa Ziekenhuis - Campus Virga Jesse	Hasselt	Limburg	Belgium
49	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende	Brugge	West Vlaanderen	Belgium
50	Onze-Lieve-Vrouw Ziekenhuis Aalst	Aalst		Belgium
51	Universitair Ziekenhuis Leuven	Leuven		Belgium
52	Hospital Cárdio Pulmonar	Salvador	Bahia	Brazil
53	Santa Casa de Misericordia - Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
54	CAPED - Centro Avançado de Pesquisa e Estudos para o Diagnóstico	Ribeirão Preto	Sao Paulo	Brazil	14026-900
55	INCOR	São Paulo	Sao Paulo	Brazil
56	Instituto de Cardiologia do Rio Grande do Sul	Porto Alegre		Brazil
57	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
58	University of British Columbia	Vancouver	British Columbia	Canada	V5Z 1M9
59	CancerCare Manitoba - St. Boniface	Winnipeg	Manitoba	Canada
60	Halifax Infirmary	Halifax	Nova Scotia	Canada	B3H 3A7
61	Toronto Heart Centre	Toronto	Ontario	Canada	M4P 1E4
62	University of Toronto	Toronto	Ontario	Canada	M5G 2N2
63	Centre Hospitalier de L'Universite de Montreal - Hôpital Notre-Dame	Montréal	Quebec	Canada	H2X 3H8
64	Hôpital du Sacré-Coeur de Montréal	Montréal	Quebec	Canada	H4J 1C5
65	Institut Universitaire de Cardiologie et de Pneumologie de Québec	Quebec City	Quebec	Canada	G1V 4G5
66	Hôpital régional de Rimouski	Rimouski	Quebec	Canada	G5L 5T1
67	Montreal Heart Institute	Montréal		Canada
68	St. Anne´s University Hospital	Brno Střed		Czechia
69	General University Hospital in Prague	Nové Město		Czechia
70	Institute for Clinical and Experimental Medicine	Prague		Czechia
71	Aarhus Universitetshospital	Aarhus	Dinamarca	Denmark	8200
72	Alexandra General Hospital of Athens	Athens	Attica	Greece
73	Mater Misericordiae University Hospital	Dublin		Ireland
74	Saint Vincents University Hospital	Dublin		Ireland
75	Hadassah University Hospital Ein Kerem	Jerusalem		Israel
76	The Chaim Sheba Medical Center	Tel Hashomer		Israel
77	Ospedale San Donato	Arezzo		Italy
78	Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi	Bologna		Italy
79	Azienda Ospedaliero - Universitaria Careggi	Firenze		Italy
80	Fondazione IRCCS Policlinico San Matteo	Pavia		Italy	27100
81	Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica	Pisa		Italy
82	Ospedale degli Infermi	Rimini		Italy
83	Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma	Roma		Italy
84	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-Do	Korea, Republic of	13620
85	Seoul National University Hospital	Seoul	Gyeonggi-Do	Korea, Republic of	13620
86	Maastricht Universitair Medisch Centrum	Maastricht	Limburg	Netherlands	6229 HX
87	Universitair Medisch Centrum Groningen	Groningen		Netherlands
88	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands
89	Middlemore Hospital	Otahuhu	Auckland	New Zealand	1640
90	Waikato Hospital	Hamilton	Waikato	New Zealand	3240
91	National Institute of Cardiology	Warsaw		Poland
92	Centro Hospitalar de Lisboa Norte EPE- Hospital Santa Maria	Lisboa		Portugal
93	Centro Hospitalar do Porto	Porto		Portugal	4099-001
94	Clínica Universidad de Navarra	Pamplona	Navarra	Spain
95	Hospital Universitari Germans Trias i Pujol	Barcelona		Spain
96	Hospital Juan Ramón Jiménez	Huelva		Spain	21005
97	Hospital Juan Ramón Jiménez	Huelva		Spain
98	Clinica Universidad de Navarra Madrid	Madrid		Spain
99	Hospital Universitario Puerta de Hierro	Madrid		Spain
100	Hospital Son Llàtzer	Palma De Mallorca		Spain
101	Hospital Clínico Universitario de Santiago de Compostela	Santiago De Compostela		Spain
102	Hospital Clínico Universitario de Valencia	Valencia		Spain
103	Royal Free Hospital	London	England	United Kingdom	NW3 2PF
104	Richmond Pharmacology	London		United Kingdom	SE1 1YR