E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM) |
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E.1.1.1 | Medical condition in easily understood language |
Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a rare disease that occurs when a protein, called transthyretin, is accumulated in the heart. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
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 | 10002020 |
E.1.2 | Term | Amyloid cardiomyopathy |
E.1.2 | System Organ Class | 100000004849 |
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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 |
Part A: To determine the efficacy of AG10 in the treatment of subjects with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM) by evaluating the difference between the AG10 and placebo groups in the change from baseline in the Six-Minute Walk test (6MWT) Part B: To determine the efficacy of AG10 in the treatment of subjects with symptomatic ATTR-CM by evaluating the difference between the AG10 and placebo groups in the combined endpoint of All-Cause Mortality and the cumulative frequency of cardiovascular (CV)-related hospitalization
Key Secondary Part A: To evaluate the effects of AG10 on quality of life (QoL) in subjects with symptomatic ATTR-CM Part B: •To evaluate the effects of AG10 on 6MWT •To evaluate the effects of AG10 on QoL in subjects with symptomatic ATTR-CM
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E.2.2 | Secondary objectives of the trial |
Part A: •To assess safety and tolerability of AG10 in subjects with symptomatic ATTR-CM •To assess the PD effects of AG10 as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and established ex vivo assays of TTR stabilization
Part B: •To determine the efficacy of AG10 treatment as measured by the components of the primary endpoint •To determine the efficacy of AG10 in reducing CV mortality in subjects with symptomatic ATTR-CM •To describe the PD properties and the PK-PD relationship of AG10 as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and established ex vivo assays of TTR stabilization, and correlated with AG10 PK •To evaluate the safety and tolerability of AG10 administered for 30 months to subjects with symptomatic ATTR-CM |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
CMR Substudy (part of original protocol v1.1 (UK) dated 06-Feb-2019)
Up to fifty eligible UK patients enrolled in the main study will be invited to participate in a cardiac magnetic resonance (CMR) scan substudy.
Subjects may only participate in the CMR substudy if they are eligible for participation in the main study (i.e. they must meet all of the main study inclusion criteria and none of the exclusion criteria at Screening).
CMR Substudy - Exlporatory Objective: To assess biventricular structure and function and myocardial tissue characterization in a separate substudy. |
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E.3 | Principal inclusion criteria |
To be eligible to participate in the study, subjects must meet all the following 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 male or female ≥18 to ≤90 years of age. 3.Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype confirmed by genotyping, based on either 1. endomyocardial biopsy with confirmatory TTR amyloid typing by either mass spectrometry immunoelectron microscopy, or immunohistochemistry; or 2. positive technetium-99m (99mTc)-pyrophosphate or -bisphosphonate (DPD or HMPD) scan, combined with accepted laboratory criteria excluding a diagnosis of AL amyloidosis (based on both immunofixation electrophoresis (IFE) of serum and urine, and serum free light chain (sFLC) analysis). Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may require confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by either mass spectrometry immunoelectron microscopy or immunohistochemistry. 4.Have a.a history of heart failure evidenced by at least one prior hospitalization for heart failure or b.clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, or peripheral edema) or c.heart failure symptoms that required or require ongoing treatment with a diuretic. 5.Have NYHA Class I-III symptoms due to ATTR-CM. 6.Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use highly effective methods 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. 7.For subjects 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. 8.Have completed ≥150 m on the 6MWT at least 2 tests >24 hours to ≤3 weeks apart and prior to randomization. The distance walked must be within 15% on two tests. If one of the first two tests is not ≥150 m or the first two tests are not within 15% of distance walked, a third test must be conducted ≤3 weeks of the first test. If the third test is still not ≥150 m or within 15% of one of the first two tests, the subject will not be eligible for participation. 9.Must have NT-proBNP levels ≥300 pg/mL at Screening. 10.Must have LV wall (interventricular septum or LV posterior wall) thickness ≥12 mm as measured by transthoracic echocardiogram (ECHO) or cardiac magnetic resonance (CMR) documented in medical history within 10 years of Screening or at Screening ECHO or CMR.
CMR Substudy: 1. Eligible to enroll in AG10-301 study 2. Signed informed consent for CMR substudy
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria at the Screening visit will not be eligible to participate in the study: 1.Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior to Screening. 2.Stroke or TIA within 90 days prior to Screening. 3.Has hemodynamic instability at Screening or Randomization that, in the judgment of the Investigator, would pose too great a risk for participation in the study. 4.Is likely to undergo heart transplantation within a year of Screening. 5.Has confirmed diagnosis of light-chain (AL) amyloidosis. 6.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. 7.Has NT-proBNP levels ≥8500pg/mL at Screening. 8.Has estimated glomerular filtration rate (eGFR) by MDRD formula < 15 mL/min/1.73 m2 at Screening. 9.Known hypersensitivity to IMP (AG10 or placebo), its metabolites, or formulation excipients. 10.Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a labeled indication for ATTRCM (e.g., diflunisal, doxycycline), or with natural products or derivatives used as unproven therapies for ATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA]/ursodiol) within 14 days prior to dosing; treatment with patisiran, inotersen, or other gene silencing agent: within 90 days for patisiran, 180 days for inotersen, and 5 half-lives for any other gene silencing agent, prior to dosing. If, during participation in the study, subjects gain access to tafamidis, they will be permitted to initiate therapy with tafamidis as a concomitant medication if they have completed at least 12 months of blinded study therapy. 11.Requires treatment with calcium channel blockers with conduction system effects (e.g., verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response. 12.Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before IMP is administered. A negative urine pregnancy test at Screening and at Randomization are required for female subjects of childbearing potential. 13.In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or condition that might jeopardize the subject’s safety, increase their risk from participation, or interfere with the study. 14.Participation in another investigational drug or investigational device study within 30 days prior to dosing with potential residual effects that might confound the results of this study. 15.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.
CMR substudy Exclusion Criteria: 1. Contraindication or sensitivity to MRI contrast agents 2. Orthopnoea of sufficient severity to preclude supine scanning at screening 3. Weight or body girth exceeds the limits of the CMR machine specifications 4. Contraindication for MRI scanning, as assessed by local MRI safety questionnaire/checklist, which includes but is not limited to: 4.1 Pacemakers or other implanted cardiac devices and non-MR conditional heart valves 4.2 Intracranial aneurysm clips (except Sugita), or other metallic objects 4.3 Intra-orbital metal fragments 4.4 Any other metal implants, such as cochlear implants and artificial joints, or metal fragments 4.4 History of severe claustrophobia 5. Any other pre-existing condition which, in the investigator’s opinion, contraindicates CMR scanning |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: Change from baseline to Month 12 of treatment in distance walked during the 6MWT Part B: A hierarchical combination of All-Cause mortality and CV-related hospitalization over a 30-month period
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A -Distance walked during the 6MWT: Prior to randomization, Month 6, 9,12 Part B -All-cause mortality and CV-related hospitalization: Month 0-30 |
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E.5.2 | Secondary end point(s) |
Key Secondary Part A -Change from baseline to Month 12 of treatment in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) Part B: -Change from baseline to Month 30 of treatment in distance walked during the 6MWT -Change from baseline to Month 30 of treatment in KCCQ-OS Other secondary Part A -Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) and established ex vivo assays of TTR stabilization at Day 28 and subsequent visits Part B -All-Cause Mortality by Month 30 -Cumulative frequency of CV-related hospitalization by Month 30 -CV Mortality by Month 30 -Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) and established ex vivo assays of TTR stabilization -Describe the PK-PD relationship of AG10 in adult subjects with symptomatic ATTR-CM in the population PK-PD (PopPK-PD) substudy |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary Part A -KCCQ-OS: Day 1, Month 3, 6, 9, 12 Part B -Distance walked during the 6MWT: Prior to randomization, Month 6, 9, 12, 18, 24, 30 -KCCQ-OS: Day 1, Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30 Other secondary Part A - TTR (prealbumin) level and ex vivo assays of TTR stabilization: Day 1, Day 28, Month 3, 6, 9, 12 Part B - All-Cause Mortality: Month 0-30 - Cumulative frequency of CV-related hospitalization: Month 0-30 - CV Mortality: Month 0-30 - TTR (prealbumin) level ex vivo assays of TTR stabilization: Day 1, Day 28, Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30 - PK PD assessments: Day 1, Day 28, Month 3, 6, 9, 12, 15, 18, 21, 24,27, 30 |
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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 | 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 | Yes |
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 | 70 |
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 |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
New Zealand |
Poland |
Portugal |
Russian Federation |
Spain |
Turkey |
United Kingdom |
United States |
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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 | |
E.8.9.1 | In the Member State concerned months | 62 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 62 |