| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Transthyretin amyloid cardiomyopathy (TTR-CM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A condition characterized by the buildup of abnormal deposits of a protein called amyloid in the body's organs and tissues that include the heart, which can result in worsening of its function |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002020 |
| E.1.2 | Term | Amyloid cardiomyopathy |
| E.1.2 | System Organ Class | 100000004849 |
|
| 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 |
| The primary objective of this study is to assess the efficacy of an oral dose of 20 mg or 80 mg tafamidis meglumine soft-gel capsules based on all-cause mortality and on frequency of cardiovascular-related hospitalizations as well as to assess safety and tolerability in comparison to placebo. Tafamidis or placebo will be administered once daily, in addition to standard of care, for 30 months in subjects diagnosed with variant or wild-type TTR cardiomyopathy (TTR-CM). |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated Informed Consent Document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study and evidence of a personally signed and dated separate Medical Release Form regarding access to medical records as well as vital status follow-up by the site with the subject or the subject’s caregivers 30 months after study randomization.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures,
3. Age greater than or equal to 18 and less than or equal to 90 years old at the time of randomization,
4. Medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or clinical evidence of HF (without 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, peripheral edema) that required/requires treatment with a diuretic for improvement,
5. Subject has documented TTR amyloid cardiomyopathy in accordance with institutional site standard of care, which is defined as:
a. Variant TTR amyloid cardiomyopathy defined by all of the following:
i. presence of a variant TTR genotype associated with cardiomyopathy and presenting with a cardiomyopathy phenotype (e.g., a history of congestive heart failure),
ii. evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness > 12 mm,
iii. presence of amyloid in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid
demonstrated per appropriate stain such as Congo red or alcin blue stain).
b. Wild-type TTR amyloid cardiomyopathy defined by all of the following:
i. absence of a variant TTR genotype,
ii. evidence of cardiac involvement by echocardiography with an enddiastolic
interventricular septal wall thickness > 12 mm,
iii. presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid demonstrated per appropriate stain such as Congo red or alcin blue stain),
iv. TTR precursor protein identification by mass spectrometry.
6. Biopsy to determine the presence of amyloid and demonstration of TTR precursor
protein must be done during Screening or documented as having been performed
within 5 years prior to enrollment,
7. Subject must be able to read in native language and complete self-administered
questionnaires independently,
8. Subject’s symptoms of HF are optimally managed and clinically stable with no
cardiovascular-related hospitalizations within 2 weeks prior to Baseline, as assessed by the Principal Investigator,
9. Male and female subjects of childbearing potential must agree to use two highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active,
10. Subject must have a Screening visit NT-proBNP concentration ≥ 600 pg/mL,
11. Subjects must be able to complete > 100 m on the 6-Minute Walk Test. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Subjects with echocardiogram assessment at Screening that is not deemed interpretable by the central echocardiogram reader for the measurement of wall thickness,
2. Subjects using non-steroidal anti-inflammatory drugs (NSAIDs) that are not
allowable in the protocol within 2 weeks prior to randomization
3. Subjects with an mBMI below 600,
4. Subjects with a history of drug or alcohol abuse within the past 5 years that in the
opinion of the investigator would interfere with compliance with study procedures or follow-up visits,
5. Subjects taking or have previously taken tafamidis,
6. Subjects requiring treatment with calcium channel blockers or digitalis,
7. Subjects with primary (light chain) or secondary (serum amyloid A) amyloidosis,
8. Subjects who have prior liver or heart transplantation,
9. Subject has positive serology for hepatitis B (HBsAg), hepatitis C (anti-HCV), or HIV,
10. Subjects with renal failure requiring dialysis and/or have a creatinine clearance of
< 25 mL/min.,
11. Subjects with urinary retention requiring self-catheterization,
12. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
13. Subjects who have symptoms indicative of New York Heart Association Classification IV at the Screening or Baseline visit,
14. Subjects with liver function test abnormalities (alanine transaminase and/or
aspartate transaminase) greater than 2 times the upper limit of normal that are considered to be due to reduced liver function or active liver disease,
15. Subjects with participation in studies involving investigational drug(s) (Phases 1-
4) within 60 days before the current study begins and/or during study participation. For diflunisal, this time period will be at least 2 weeks prior to enrollment and/or any time during study participation,
16. Subjects with other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study,
17. Subjects who are pregnant females; breastfeeding females; males and females of
childbearing potential; males and females of childbearing potential who are unwilling or unable to use two (2) highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days, after last dose of investigational product;
18. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker is indicated but will not be placed,
19. Subjects with evidence for prior myocardial infarction by documented history of cardiac enzymes and ECG changes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. All-cause mortality and
2. Frequency of cardiovascular-related hospitalizations over the duration of the trial, which is defined as the number of times a subject is hospitalized (i.e., admitted to a hospital) for cardiovascular-related morbidity. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Both primary end points will be assessed throughout the study. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints
1. Change from Baseline to Month 30 in the distance walked during 6-Minute Walk Test (6MWT),
2. Change from Baseline to Month 30 in the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS).
Other secondary endpoints
1. Cardiovascular-related mortality,
2. Frequency of cardiovascular-related hospitalization,
3. All-cause mortality,
4. TTR stabilization at Month 1. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Distance walked during 6 Minute Walk Test (6MWT) at baseline (Day 1) and Months 6, 12, 18, 24 and 30 or end of treatment.
2. Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at baseline (Day 1) and Months 6, 12, 18 and 30 or end of treatment.
|
|
| 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 | 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 | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Canada |
| France |
| Italy |
| Japan |
| Sweden |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 9 |
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