Clinical Trials Register

Summary
EudraCT Number:	2018-004670-10
Sponsor's Protocol Code Number:	AG10-333
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-05-25
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2018-004670-10

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

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

A.4.1

Sponsor's protocol code number

AG10-333

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1251-3220

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/330/2018

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Eidos Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Eidos Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eidos Therapeutics, Inc
B.5.2	Functional name of contact point	Sr. Director, Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	101 Montgomery Street, Suite 2000
B.5.3.2	Town/ city	San Francisco
B.5.3.3	Post code	CA 94104
B.5.3.4	Country	United States
B.5.4	Telephone number	001 415-651-3853
B.5.6	E-mail	mmcgovern@eidostx.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/096/18
D.3 Description of the IMP
D.3.1	Product name	AG10
D.3.2	Product code	AG10 HCl
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AG10 HCl
D.3.9.1	CAS number	2242751
D.3.9.3	Other descriptive name	3-(3-(3,5-DIMETHYL-1H-PYRAZOL-4-YL)PROPOXY)-4-FLUOROBENZOIC ACID
D.3.9.4	EV Substance Code	SUB193376
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Symptomatic Transthyretin Amyloid Polineuropathy (ATTR-PN)

E.1.1.1

Medical condition in easily understood language

Symptomatic Transthyretin Amyloid Polineuropathy (ATTR-PN) is a rare disease that occurs when a protein, called transthyretin, is accumulated in the peripheral nerves.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10057949
E.1.2	Term	Familial amyloid polyneuropathy
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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.

E.4

Principal 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 condition.

E.5 End points

E.5.1

Primary end point(s)

change from baseline to Month 18 in mNIS+7 score

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, month 9 and month 18

E.5.2

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.

E.5.2.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Brazil

Bulgaria

Canada

France

Germany

Hungary

Italy

Mexico

Netherlands

New Zealand

Poland

Portugal

Russian Federation

Spain

Taiwan

Turkey

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

145

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

All subjects who complete the double-blinded treatment period may be eligible to participate in an open label extension study of long-term AG10 treatment

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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