E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) |
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E.1.1.1 | Medical condition in easily understood language |
hATTR amyloidosis is a hereditary disease caused by protein aggregates in the heart and the nervous system. It leads to heart disease, damage to the nerves, and gut and bladder problems. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019889 |
E.1.2 | Term | Hereditary neuropathic amyloidosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 ALN-TTRSC02 in patients with hATTR amyloidosis by evaluating the effect on neurologic impairment |
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E.2.2 | Secondary objectives of the trial |
• To determine the efficacy of ALN-TTRSC02 on quality of life, gait speed, neurologic impairment, nutritional status, and disability • To demonstrate the non-inferiority of ALN-TTRSC02 compared to patisiran with respect to serum TTR levels |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
● Male or female age 18 (or age of legal consent, whichever is older) to 85 years of age ● Have a diagnosis of hATTR amyloidosis with documented TTR mutation ● Have a Neuropathy Impairment Score of 5 to 130 (inclusive; this criterion must be met at the Screening Visit 2) ● Have a Polyneuropathy Disability score of ≤3b (this criterion must be met at the Screening Visit 2) ● Have a Karnofsky Performance Status (KPS) of ≥60% ●Patient is willing and able to comply with the study requirements and to provide written informed consent
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E.4 | Principal exclusion criteria |
• Has had a liver transplant or is likely, in the opinion of the Investigator, to undergo liver transplantation during the 18-month Treatment Period of the study • Has known other (non-hATTR) forms of amyloidosis or clinical evidence of leptomeningeal amyloidosis • Has a New York Heart Association heart failure classification >2 • Has any of the following laboratory parameter assessments: a. ALT and/or AST >1.5× upper limit of normal reference range (ULN); b. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert's Syndrome) c. INR >1.2 (patients on anticoagulant therapy with an INR of ≤3.5 will be allowed) • Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2 • Has known human immunodeficiency virus (HIV) infection; or evidence of acute or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection • Has other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease, monoclonal gammopathy) that the treating physician believes to be contributing to the neuropathy • Current or future participation in another investigational device or drug study • Is currently taking tafamidis, doxycycline, or tauroursodeoxycholic acid; acid; if previously on any of these agents, must have completed a 14-day wash-out prior to dosing (Day 1) • Is currently taking diflunisal; if previously on this agent, must have at least a 3-day washout prior to dosing (Day 1) |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) of the ALN-TTRSC02 group compared to the placebo arm of the Phase 3 patisiran-LNP study (ALN-TTR02-004; APOLLO)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline in the mNIS+7 of the ALN-TTRSC02 group compared to the placebo arm of the APOLLO study at Month 9
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E.5.2 | Secondary end point(s) |
• Change from baseline in the following parameters of the ALN-TTRSC02 group compared to the placebo arm of the APOLLO (patisiran) study: - Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score - Timed 10-meter walk test (10-MWT) - mNIS+7 - Modified body mass index (mBMI) - Rasch-built Overall Disability Scale (R-ODS) • Percent reduction in serum TTR levels in the ALN-TTRSC02 arm compared to the within-study patisiran arm |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline in the following clinical parameters of the ALN-TTRSC02 group compared to the placebo arm of the APOLLO (patisiran) study: - Norfolk QoL-DN total score at Month 9 - Timed 10-meter walk test (10-MWT) at Month 9 - mNIS+7 at Month 18 - Norfolk QoL-DN total score at Month 18 - 10-MWT) at Month 18 - Modified body mass index (mBMI) at Month 18 - Rasch-built Overall Disability Scale (R-ODS) at Month 18 • Percent reduction in serum TTR levels in the ALN-TTRSC02 arm compared to the within-study patisiran arm through Month 18 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
External control, with comparison to placebo arm of the Phase 3 APOLLO study of patisiran-LNP |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Placebo arm of completed Phase 3 APOLLO trial by the same sponsor in a similar patient population |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 |
Australia |
Brazil |
Canada |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Taiwan |
United States |
Cyprus |
France |
Sweden |
Bulgaria |
Netherlands |
Spain |
Germany |
Greece |
Italy |
Belgium |
Ireland |
Portugal |
Turkey |
United Kingdom |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |