Principal Investigator: Josef Stehlik
Keywords: Amyloidosis , Heart failure Department: Cardiovascular Medicine
IRB Number: 00121465
Specialty: Cardiology
Sub Specialties:
Recruitment Status: Active, not recruiting

Contact Information

Jennifer Hong
jennifer.hong@hsc.utah.edu
801-213-2050

Brief Summary

Primary objectives:

1.) To determine the efficacy of acoramidis in the treatment of subjects with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM) by evaluating the difference between the acoramidis and placebo groups in the change from baseline to month 12 in the Six-Minute Walk test (6MWT).

2.) To determine the efficacy of AG10 in the treatment of subjects with symptomatic ATTR-CM by evaluating the difference between the acoramidis and placebo groups in the combined endpoint of All-Cause Mortality and the cumulative frequency of cardiovascular (CV)-related hospitalization and change from baseline in 6MWT.

Secondary objectives:

1.)To evaluate the effects of acoramidis on quality of life (QoL) in subjects with symptomatic ATTR-CM.

2.) To evaluate the effects of acoramidis on 6MWT, to evaluate the effects of acoramidis on health-related QoL as measured by a HF-specific instrument (KCCQ) in subjects with symptomatic ATTR-CM.

3.) To assess safety and tolerability of acoramidis in subjects with symptomatic ATTR-CM,

• To determine the efficacy of acoramidis treatment as measured by the components of the primary endpoint
• To determine the efficacy of acoramidis in reducing CV mortality in subjects with symptomatic ATTR-CM
• To describe the pharmacodynamic (PD) properties and the pharmacokinetic-pharmacodynamic (PK-PD) relationship of acoramidis as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and established ex vivo assays of TTR stabilization, and correlated with acoramidis PK
• To evaluate the safety and tolerability of acoramidis administered for 30 months to subjects with symptomatic ATTR-CM

Exploratory objectives:

• To evaluate the effects of acoramidis on circulating biomarkers of myocardial wall stress and microvascular ischemia in subjects with symptomatic ATTR-CM
• To characterize the population pharmacokinetics PK of acromamidis and its predominant metabolite administered orally twice daily (BID) in subjects with symptomatic ATTR-CM

• To describe the population PK (PopPK) of acoramidis in subjects with ATTR-CM

• To describe the PD properties and the pharmacokinetic (PK)-PD relationship of acoramidis as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and by established ex vivo assays of TTR stabilization, and correlated with acoramidis PK

• To evaluate the effects of acoramidis on health-related QoL as measured by EuroQol Health Outcomes Assessment tool (EQ-5D-5L) in subjects with symptomatic ATTR-CM

•  To assess the ability of acoramidis to bind and  stabilize a diverse array of pathogenic and likely pathogenic variant TTR tetrameric species, representing amino acid substitutions located  throughout the sequence of TTR that are responsible for a spectrum of clinical  presentations, from sera and/or plasma of subjects with ATTR-CM
 

Detailed Description

This is a phase 3 study which is designed to test a new drug longer and on more people. They are done to learn details about the use of the new drug in many people during their usual activities of daily living. This is also a randomized, double-blinded, placebo-controlled study which means that there will be two groups of participants, one that receives medication and one that receives a placebo. A placebo is a dummy treatment such as a pill which looks like the pill that contains the study drug but is not. Placebos contain no drugs or active ingredients. Study participants are given placebos so that the effects of a drug can be compared against no drug. Use of placebos also prevents the participant and the doctor from knowing whether or not the subject is getting the drug. In a “randomized trial” people are put in one group or the other by random chance. This means that a computer will decide by chance which group a person is in, not the doctors running the trial. If you choose to participate, you will randomized and both you and the clinical team will be blinded. This done to reduce bias while conducting the study.

Inclusion Criteria

Inclusion Criteria
To be eligible to participate in the study, subjects must meet all the following criteria:
1. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
2. Male or female ≥18 to ≤90 years of age at time of randomization.
3. Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype (confirmed by genotyping) based on either (1) tissue biopsy with confirmatory TTR amyloid typing by either confirmatory TTR amyloid typing by either
mass spectrometry, or immunoelectron microscopy, or  immunohistochemistry; or (2) positive 99mTc-pyrophosphate (PYP)  or -bisphosphonate  (DPD or HMDP/HDP)  scan, combined with accepted laboratory criteria excluding a diagnosis of AL amyloidosis (based on both immunofixation electrophoresis (IFE) of serum and/or urine, and serum free light chain (sFLC) analysis). Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may require confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by either mass spectrometry, immunoelectron microscopy or immunohistochemistry.
4. Have
a. a history of heart failure evidenced by at least one prior hospitalization for heart failure or
b. clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, or peripheral edema) or
c. heart failure symptoms that required or require ongoing treatment with a diuretic.
5. Have NYHA Class I-III symptoms due to ATTR CM.
6. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use acceptable method(s) of contraception beginning with randomization and continuing for 30 days after the last dose of IMP. A male subject who is sexually active with a female of childbearing potential and has no had a vasectomy must agree to use a double barrier method of birth control.
7. Subjects taking cardiovascular medical therapy, with the exception of diuretic dosing, must be on stable doses (defined as no greater than 50% dose adjustment and no categorical changes of medications) for at least 2 weeks prior to Screening.
8. Have completed ≥150 m on the 6MWT on at least 2 tests > 24 hours to ≤ 3 weeks apart and  prior to randomization. The distance walked must be within 15% on two tests. 

9. If one of the first two tests is not ≥ 150 m or the first two tests are not within 15% of distance walked, a
third test must be conducted ≤ 3 weeks of the first test. If the third test is st
10. Must have NT-proBNP levels ≥300 pg/mL at Screening.
11. Must have LV wall (interventricular septum or LV posterior wall) thickness ≥12 mm as measured by transthoracic echocardiogram (echo) or cardiac magnetic resonance (CMR) documented in medical history within 10 years of Screening or at Screening echo or CMR.

If a study participant becomes pregnant, an amendment will be submitted to add authorization to collect information about the baby.

 

Exclusion Criteria

Exclusion Criteria
Subjects who meet any of the following criteria at the Screening visit will not be eligible to participate in the study:
1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior to Screening.
2.Stroke or transient ischemic attack (TIA) within 90 days prior to Screening.
3. Has hemodynamic instability at Screening or Randomization that, in the judgment of the Investigator, would pose too great a risk for participation in the study.
4. Is likely to undergo heart transplantation within a year of Screening.
5. Has confirmed diagnosis of light-chain amyloidosis (AL).
6. Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >3 × ULN.
7. Has NT-proBNP levels ≥8500 pg/mL at Screening.
8. Has estimated glomerular filtration rate (eGFR) by modification of diet for renal disease (MDRD) formula < 15 mL/min/1.73 m2 at Screening.
9. Known hypersensitivity to study drug (acoramidis or placebo), its metabolites, or formulation excipients.
10. Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a labeled indication for ATTR-CM (e.g., diflunisal, doxycycline); or with natural products or derivatives used as unproven therapies for ATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA]/ursodiol), within 14 days prior to dosing; treatment with patisiran, inotersen, or other gene silencing agent within 90 days for patisiran, 180 days for inotersen  and 5 half-lives for any other gene silencing agent prior to dosing. If, during participation in the study, subjects gain access to tafamidis, they will be permitted to initiate therapy with tafamidis as a concomitant medication if they have completed at least 12 months of blinded study therapy.
11. Requires 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.
12. Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before IMP is administered. A negative urine pregnancy test at Screening and at Randomization are required for female subjects of childbearing potential.
13. In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or condition that might jeopardize the subject’s safety, increase their risk from participation, or interfere with the study.
14. Participation in another investigational clinical trial within 30 days prior to dosing with potential residual effects that might confound the results of this study. Participation in observational and/or registry studies should be discussed with the Medical Monitor. 
15. Has any condition that, in the opinion of the Investigator or Medical Monitor, would preclude compliance with the study protocol such as a history of substance abuse, alcoholism or a psychiatric condition.