E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Symptomatic Transthyretin Amyloid Polineuropathy (ATTR-PN) |
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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. |
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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 |
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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 |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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. |
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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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
change from baseline to Month 18 in mNIS+7 score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline, month 9 and month 18 |
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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.
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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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |