E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin amyloid cardiomyopathy (ATTR-CM) |
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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 |
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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 | 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 |
To obtain additional, long term, safety data for tafamidis in subjects with transthyretin amyloid cardiomyopathy (ATTR CM)
To provide investigational product, tafamidis, to enrolled subjects until local availability by prescription for the ATTR-CM indication. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female subjects with TTR amyloid cardiomyopathy who have completed 30 months of study treatment on Protocol B3461028. 2. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. 3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception hroughout the study and for at least 28 days after the last dose of assigned treatment. Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria): Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure; or Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum folliclestimulating hormone (FSH) level confirming the post-menopausal state. All other female subjects (including females with tubal ligations) will be considered o be of childbearing potential.
Cohort B Inclusion Criteria 1.Male or female subject of at least 18 years of age (or the minimum country specific age of consent if >18) and participates at a study site in an eligible country listed in Protocol Appendix 5. 2.Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study 3.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 4.A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: •Is not a Woman of Childbearing Potential (WOCBP) (see definition Section 4.3.1) OR •Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year) (see Section 4.3) during the intervention period and for at least 28 days after the last dose of study intervention, which corresponds to the time needed to eliminate any study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 5.Documentation of the genetic testing for transthyretin amyloidosis (ie, original laboratory result, or copy) 6.Documentation of diagnosis and criteria used (e.g. congestive heart failure and scintigraphy with tracer eg 99mTC DPD [99mTC 3,3 diphosphono 1,2 propano dicarboxylic acid], 99mTC PYP [Pyrophosphate] and also 99mTC HMDP [hydroxymethylene diphosphonate] or Congestive heart failure and presence of amyloid deposits in biopsy tissue, e.g. fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac [amyloid demonstrated per appropriate stain such as Congo red or alcian blue stain]) 7.Documentation that primary (light chain) amyloidosis disease has been evaluated and ruled out (ie, original laboratory result, or copy) 8.Evidence of NYHA classification I, II, III, or IV
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E.4 | Principal exclusion criteria |
1. Chronic use of diflunisal, TTR stabilizer, tauroursodeoxycholate, doxycycline, digitalis, patisiran, calcium channel blockers, investigational drug(s) or other experimental interventions, other than tafamidis, independently or as part of a study within 30 days prior to enrollment or inotersen within 6 months prior to enrollment. 2. Use of certain non-steroidal anti-inflammatory drugs (NSAIDs) 3. Liver and/or heart transplant, or implanted cardiac mechanical assist device. 4. Pregnant females (or planning to become pregnant during the study interval); breastfeeding females; male subjects with partners currently pregnant. 5. Require initiation of treatment with calcium channel blockers. 6. Urinary retention requiring chronic self-catheterization. 7. Breach of compliance with treatment/significant protocol violations during conduct of B3461028 for which the subject was accountable. 8. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of he study. 9. Other severe acute or chronic medical or psychiatric condition or laboratory bnormality that may increase the risk associated with study participation or investigational product administration, or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject an appropriate for entry into this study.
Cohort B Exclusion Criteria Subjects in Cohort B with any of the following characteristics/conditions will not be included in the study: 1.Chronic use of diflunisal, TTR stabilizer, tauroursodeoxycholate, doxycycline, digitalis, patisiran, calcium channel blockers, investigational drug(s) or other experimental interventions, other than tafamidis, independently or as part of a study within 30 days prior to enrollment or inotersen within 6 months prior to enrollment. 2.Use of certain non steroidal anti inflammatory drugs (NSAIDs) 3.Liver and/or heart transplant, or implanted cardiac mechanical assist device. 4.Require initiation of treatment with calcium channel blockers. 5.Urinary retention requiring chronic self catheterization. 6.Subjects with heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (eg prior myocardial infarction with documented history of cardiac enzymes and ECG changes), or uncorrected valvular disease and not primarily due to transthyretin amyloid cardiomyopathy. 7.Subjects who are investigational site staff members directly involved in the conduct of the study 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 study. 8.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 that 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints Safety as measured by: • All cause mortality. • Incidence of treatment emergent adverse events.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Both primary end points will be assessed throughout the study. |
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E.5.2 | Secondary end point(s) |
Cardiovascular-related mortality.
Frequency of all-cause hospitalization.
Frequency of cardiovascular-related hospitalization (including heart failure, arrhythmia, myocardial infarction, stroke and other cardiovascular-related events).
Change from baseline at each visit in Kansas City Cardiomyopathy Questionnaire. Overall Score and domain scores (Physical limitation, Symptom stability, Symptoms, Self-efficacy, Social limitation, and Quality of life) and domain summary scores (Functional summary and Clinical summary). New York Heart Association classification at each visit.
Change from baseline in Body Mass Index/modified Body Mass Index at each visit.
Assessment of physical examinations, use of concomitant medications, electrocardiograms (ECGs), clinical laboratory testing, vital signs at each visit. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Brief physical examination including weight measurement Collect all dispensed (used and unused) investigational product wallets Single 12-Lead ECG - perform ECG prior to any blood collection or blood pressure measurements (To be performed annually at Months 12, 24, 36, 48 or early discontinuation) Measure vital signs (systolic and diastolic blood pressure supine and standing, pulse rate supine and standing, respiration rate, and body temperature) Collect blood and urine samples for the following clinical laboratories. Administer Kansas City Cardiomyopathy Questionnaire. NYHA classification. Contraception check. Documentation of concomitant medications. Record capsule count for dosing adherence. Adverse event reporting. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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 | No |
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 | 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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
France |
Germany |
Hong Kong |
Italy |
Japan |
Netherlands |
Spain |
Sweden |
Taiwan |
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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Defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |