Study of AG10 in Amyloid Cardiomyopathy

Study Description

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Brief Summary:

This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK and PD 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.

Condition or disease	Intervention/treatment	Phase
Familial ATTR-CM (ATTRm-CM, or FAC) and Wild-type ATTR-CM (ATTRwt-CM)	Drug: AG10; Drug: Placebo Oral Tablet	Phase 2

Detailed Description:

A Phase 2, Randomized, Placebo-controlled, Dose-ranging Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AG10 in Patients with Symptomatic Transthyretin Amyloid Cardiomyopathy.

The primary objective of this study is to evaluate the safety and tolerability of AG10 administered to adult patients with symptomatic transthyretin amyloid cardiomyopathy (ATTRCM).

This study will be a Phase 2, randomized, placebo-controlled, dose-ranging study in 45 male and/or female patients with symptomatic ATTR-CM aged 18 through 90 years.

If all doses are well tolerated, the duration of each patient's participation in the study will be 28 days of treatment. In addition, there will be a 28-day screening period before treatment and a 30-day follow-up period before the final Follow-up Visit.

This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK and PD 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. secondary objectives of this study are: to characterize the pharmacokinetics (PK) of AG10 administered orally twice daily in patients with symptomatic ATTRCM, and to describe the pharmacodynamic (PD) properties of AG10 as assessed by established assays of transthyretin (TTR) stabilization, including Fluorescent Probe Exclusion (FPE) assay and Western blot, and to describe the PKPD relationship of AG10 in adult patients with symptomatic ATTRCM.

Eligible patients will be randomized in a 1:1:1 ratio to placebo or one of two different doses of AG10 administered twice daily. A minimum of 30% of patients enrolled will be mutant ATTR-CM.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	49 participants
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)
Primary Purpose:	Treatment
Official Title:	A Phase 2, Randomized, Placebo-controlled, Dose-ranging Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AG10 in Patients With Symptomatic Transthyretin Amyloid Cardiomyopathy
Actual Study Start Date :	April 27, 2018
Estimated Primary Completion Date :	September 28, 2018
Estimated Study Completion Date :	September 28, 2018

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: AG10 Low Dose; Low dose group	Drug: AG10; TTR stabilizer
Active Comparator: AG10 High Dose; High dose group	Drug: AG10; TTR stabilizer
Placebo Comparator: Placebo	Drug: Placebo Oral Tablet; Nonactive control

Outcome Measures

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Primary Outcome Measures :

1. Assessment of safety and tolerability [ Time Frame: 28 Days ]
   Incidence of each treatment-emergent adverse events

Secondary Outcome Measures :

1. AG10 Pharmacokinetics AUC [ Time Frame: 28 Days ]
   Area under the plasma concentration-time curve (AUC)
2. AG10 Pharmacodynamic Assessments of TTR stabilization by Fluorescent Polarization Exclusion Assay [ Time Frame: 28 Days ]
   AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Fluorescent Polarization Exclusion Assay (FPE)
3. AG10 Pharmacodynamic Assessments of TTR stabilization by Western Blot [ Time Frame: 28 Days ]
   AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: Immunoblotting (Western Blot)
4. AG10 Pharmacodynamic Assessments: prealbumin [ Time Frame: 28 Days ]
   AG10 binding to and/or stabilization of TTR will be evaluated by established ex vivo assays: quantitation of prealbumin (TTR).

Eligibility Criteria

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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:

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 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 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 ALT or 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, 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.

Contacts and Locations

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Locations

United States, California
Cedars-Sinai Medical Center
Beverly Hills, California, United States, 90211
Stanford University
Palo Alto, California, United States, 94304
University of California San Francisco
San Francisco, California, United States, 94143
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Boston University
Boston, Massachusetts, United States, 02127
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29424
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

Eidos Therapeutics

More Information

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Responsible Party:	Eidos Therapeutics
ClinicalTrials.gov Identifier:	NCT03458130 History of Changes
Other Study ID Numbers:	AG10-201
First Posted:	March 8, 2018
Last Update Posted:	June 21, 2018
Last Verified:	June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases