Study of AG10 in Amyloid Cardiomyopathy
Condition: Familial ATTR-CM (ATTRm-CM, or FAC); Wild-type ATTR-CM (ATTRwt-CM)
MeSH terms: Cardiomyopathies
Intervention: AG10; Placebo Oral Tablet
Intervention description: TTR stabilizer; Nonactive control
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A randomized, doubleblind, placebo-controlled, dose-ranging design is considered to be the most appropriate study design for meeting this objective. On the basis of information gained from previous clinical experience with AG10, the doses used in this study will be selected to determine the dose with the better safety and tolerability profile.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 49.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No

Summary:

      This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled,
      dose-ranging study will evaluate the safety, tolerability, PK (Pharmacokinetic) and PD
      (Pharmacodynamic) of AG10 compared to placebo administered on a background of stable heart
      failure therapy. Screening and randomization will be followed by a 28-day blinded,
      placebo-controlled treatment period.
    

Eligibility criteria:

        Inclusion 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. Be a male or female ≥18 to ≤90 years of age.

          3. Have an established diagnosis of ATTR-CM with either wild-type transthyretin or a
             variant transthyretin genotype (assessed by genotyping, with patients with concurrent
             monoclonal gammopathy of undetermined significance requiring a confirmatory test using
             mass spectrometry) as defined by either positive endomyocardial biopsy or positive
             technetium pyrophosphate scan.

          4. Have a history of heart failure evidenced by at least one prior hospitalization for
             heart failure or clinical evidence of heart failure (without hospitalization)
             requiring medical management.

          5. Have New York Heart Association (NYHA) Class II-III symptoms.

          6. Male patients and female patients of childbearing potential who engage in heterosexual
             intercourse must agree to use appropriate method(s) of contraception.

          7. For patients 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.

        Exclusion Criteria:

          1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization
             within 90 days prior to Screening.

          2. Experienced stroke within 90 days prior to Screening.

          3. Has hemodynamic instability at Screening or Randomization that, in the judgment of the
             Principal Investigator (PI), would pose too great a risk for participation in the
             study.

          4. Has estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 at Screening.

          5. Is likely to undergo heart transplantation within the next year.

          6. Has confirmed diagnosis of light-chain amyloidosis.

          7. 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 >2 × ULN.

          8. Has abnormalities in clinical laboratory tests at Screening or Randomization that, in
             the judgment of the PI, would pose too great a risk for participation in the study.

          9. Known hypersensitivity to study drug (AG10 or placebo), its metabolites, or
             formulation excipient

         10. Current treatment with diflunisal, tafamidis, green tea, doxycycline,
             tauroursodeoxycholic acid (TUDCA)/Ursodiol, Patisiran or Inotersen within 14 days or 5
             half-lives of the prior investigational agent (whichever is longer) prior to
             Screening.

         11. Females who are pregnant or breastfeeding. Lactating females must agree to discontinue
             nursing before the study drug is administered. A negative serum pregnancy test at
             Screening and a negative urine pregnancy test at Randomization visit are required for
             female patients of childbearing potential.

         12. In the judgment of the investigator, has any clinically significant ongoing medical
             condition that might jeopardize the patient's safety or interfere with the study,
             including participation in another investigational drug or investigational device
             study within the 30 days prior to Screening with potential residual effects that might
             confound the results of this study.

         13. Has any laboratory abnormality or condition that, in the investigator's opinion, could
             adversely affect the safety of the patient or impair the assessment of study results.

         14. Has any condition that, in the opinion of the investigator, would preclude compliance
             with the study protocol such as a history of substance abuse, alcoholism or a
             psychiatric condition.

         15. Has participated in another investigational study within 14 days or 5 half-lives of
             the prior investigational agent (whichever is longer) prior to screening. Exceptions
             can be made in the case of observational and/or registry studies upon consultation
             with the Medical Monitor.

         16. Current treatment with, or chronic use of, a proton pump inhibitor (PPI) or
             histamine-receptor 2 (H2) antagonist within 14 days or 5 half-lives of the prior agent
             (whichever is longer) prior to Screening.