Study of the Efficacy and Safety of AG10 in participants with Transthyretin Amyloid Polyneuropathy (ATTR-PN)

• Register: EUCTR
• Last refreshed on: 9 October 2023
• Main ID: EUCTR2018-004670-10-PT
• Date of registration: 04/06/2020
• Prospective Registration: Yes
• Primary sponsor: Eidos Therapeutics, Inc.
• Public title: Study of the Efficacy and Safety of AG10 in participants with Transthyretin Amyloid Polyneuropathy (ATTR-PN)
• Scientific title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects with Symptomatic Transthyretin Amyloid Polyneuropathy (ATTRibute-PN Trial) - Efficacy and Safety of AG10 in participants with Transthyretin Amyloid Polyneuropathy (ATTR-PN)
• Date of first enrolment: 31/08/2020
• Target sample size: 145
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-004670-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Brazil, Bulgaria, Canada, France, Germany, Hungary, Italy, Mexico, Netherlands, New Zealand, Poland, Portugal, Russian Federation, Spain, Taiwan, Turkey

Contacts

• Name: Sr. Director, Clinical Operations
• Affiliation: Eidos Therapeutics, Inc

• Name: Sr. Director, Clinical Operations
• Affiliation: Eidos Therapeutics, Inc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Be able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures;
2. Be male or female =18 to =90 years of age;
3. Have Stage I or II symptoms (polyneuropathy disability [PND] =IIIa) of ATTR-PN and an established diagnosis of ATTR-PN as defined by physical exam findings and/or neurophysiological test findings consistent with the diagnosis of ATTR-PN;
4. Have an NIS of 5 to 130 (inclusive) during screening;
5. Have a nerve conduction studies (NCS) score [sum of the sural sensory nerve action potential (SNAP), tibial compound muscle action potential (CMAP), ulnar SNAP, ulnar CMAP, and peroneal CMAP] of =2 points during screening. NCS is a component of mNIS+7;
6. Have a mutation consistent with ATTR-PN either documented in medical history or confirmed by genotyping obtained at Screening prior to randomization. *No genetic testing is needed for subjects who are recipients of domino liver transplants;
7. Have an anticipated survival of =2 years, in the opinion of the Investigator;
8. Have Karnofsky performance status =60 %;
9. Have serum albumin levels >3.0 g/dL;
10. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use a highly effective method of contraception beginning with randomization and continuing for 30 days after the last dose of AG10. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control. Postmenopausal state female subjects must be confirmed with plasma follicle-stimulating hormone (FSH) at Screening.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 87
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 58

Exclusion criteria:
1. Had a prior liver transplantation or is planning to undergo liver transplantation with a wild-type organ graft as treatment for symptomatic ATTR-PN during the study period. Note: Recipients of a “domino” liver transplant from an ATTR-PN donor who have developed ATTR-PN mediated by their graft are allowed under this protocol, as long as re-transplantation to treat ATTR-PN is not planned during the study period and meets all other eligibility criteria;
2. Has sensorimotor or autonomic neuropathy not related to ATTR-PN; for example, autoimmune disease or monoclonal gammopathy, malignancy, or alcohol abuse;
3. Has Vitamin B-12 levels below the lower limit of normal (LLN);
4. Has clinical evidence of untreated hyper/hypothyroidism;
5. Has leptomeningeal TTR amyloidosis;
6. Has Type 1 diabetes;
7. Has had Type 2 diabetes for =5 years;
8. Has active hepatitis B or C or known human immunodeficiency virus (HIV) infection;
9. Has NYHA heart failure classification >Class II;
10. Had acute coronary syndrome, uncontrolled cardiac arrhythmia, or a stroke within 90 days prior to Screening;
11. Has estimated glomerular filtration rate (eGFR) by Modification of Diet for Renal Disease (MDRD) formula <30 mL/min/1.73 m2 at Screening;
12. 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;
13. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
14. Has known hypersensitivity to Investigational Medicinal Product (IMP) (AG10 or placebo), its metabolites, or formulation excipients;
15. Is currently undergoing treatment for ATTR-PN with patisiran, inotersen, or other gene silencing agents, marketed drug products lacking a label indication for ATTR-PN (e.g., diflunisal, doxycycline), natural products or derivatives used as unproven therapies for ATTR-PN (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA]/ursodiol), within 14 days, or 90 days for patisiran and 180 days for inotersen prior to dosing. Prior to screening, tafamidis, if already prescribed to potential subjects as part of their established background therapy, is allowed at the labeled dosage and administration of 20 mg/day for the treatment of ATTR-PN with, in the opinion of the Investigator, evidence of disease progression while on tafamidis treatment;
16. Female subjects who are pregnant or breastfeeding. Breastfeeding females must agree to discontinue nursing before IMP is administered. A negative urine pregnancy test at Screening and on Day 1 prior to randomization are required for female subjects of childbearing potential;
17. In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or other condition that might jeopardize the subject’s safety, increase their risk from participation, or interfere with the study;
18. Participation in another investigational drug or investigational device study within 30 days prior to dosing or 5 half-lives of the investigational drug, whichever is longer, with potential residual effects that might confound the results of this study;
19. 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 condi

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Symptomatic Transthyretin Amyloid Polineuropathy (ATTR-PN)
MedDRA version: 20.0 Level: LLT Classification code 10057949 Term: Familial amyloid polyneuropathy System Organ Class: 100000004850

Intervention(s)

Product Name: AG10
Product Code: AG10 HCl
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AG10 HCl
CAS Number: 2242751
Other descriptive name: 3-(3-(3,5-DIMETHYL-1H-PYRAZOL-4-YL)PROPOXY)-4-FLUOROBENZOIC ACID
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To determine the efficacy of AG10 in the treatment of subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) by evaluating the difference between the AG10 and placebo groups in Modified Neuropathy Impairment Score + 7 (mNIS+7) at 18 months of treatment relative to baseline

Timepoint(s) of evaluation of this end point: baseline, month 9 and month 18

Secondary Objective: Key secondary:
To evaluate the effects of AG10 on:
Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN), modified body mass index (mBMI), and Composite Autonomic Score (COMPASS-31) in subjects with symptomatic ATTR-PN
Other Secondary:
•To describe the pharmacodynamic (PD) properties of AG10 as assessed by serial measurements of an established assay of transthyretin (TTR) stabilization
• To assess the pharmacodynamic effects of AG10 as assessed by circulating prealbumin (TTR) concentration as an in vivo biomarker of stabilization
• To evaluate the effect of AG10 on health-related quality of life (QOL) and clinical outcome score as assessed by the Dyck/Rankin Score
• To assess the effect of AG10 on gait speed as a reflection of functional ability

Primary end point(s): change from baseline to Month 18 in mNIS+7 score

Secondary Outcome(s)

Secondary end point(s): 1.Change from baseline to Month 18 in Norfolk QOL-DN,
2.Change from baseline to Month 18 in mBMI,
3.Change from baseline to Month 18 in prealbumin levels
4.Change from baseline to Month 18 in COMPASS-31
5.Change from baseline to Month 18 of treatment in PD endpoints using established assay of TTR stabilization including Fluorescent Probe Exclusion (FPE) assay.
6.Change from baseline to Month 18 of treatment in Dyck/Rankin score at each assessed time point.
7.Change from baseline to Month 18 of treatment in gait speed.

Timepoint(s) of evaluation of this end point: 1. Baseline, 9 and 18 months
2. Baseline, 9 and 18 months
3. Baseline, 3, 6, 9, 13, 15 and 18 months
4. Baseline, 9 and 18 months
5. Baseline, 9 and 18 months
6. Baseline, 9 and 18 months
7. Baseline, 9 and 18 months

Secondary ID(s)

2018-004670-10-HU

AG10-333

Source(s) of Monetary Support

Eidos Therapeutics, Inc.

Ethics review

Status: Approved
Approval date: 31/08/2020
Contact: