A double-blind, randomized study looking at the efficacy, safety and tolerability of tafamidis meglumine (PF-06291826) 20 mg or 80 mg compared to placebo when taken daily by oral administration mouth in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2012-002465-35-GB
• Date of registration: 04/12/2013
• Prospective Registration: Yes
• Primary sponsor: FoldRx Pharmaceuticals, a Pfizer Company
• Public title: A double-blind, randomized study looking at the efficacy, safety and tolerability of tafamidis meglumine (PF-06291826) 20 mg or 80 mg compared to placebo when taken daily by oral administration mouth in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).
• Scientific title: A multicentre, international, phase 3, double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of daily oral dosing of tafamidis meglumine (PF-06291826) 20 mg or 80 mg in comparison to placebo in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).
• Date of first enrolment: 07/04/2014
• Target sample size: 400
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002465-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Brazil, Canada, Czech Republic, France, Germany, Italy, Japan, Netherlands, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Clinicaltrials.gov Call Center
• Affiliation: Pfizer Inc

• Name: Clinicaltrials.gov Call Center
• Affiliation: Pfizer Inc

Key inclusion & exclusion criteria

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 Release of Medical Information Form regarding access to medical records as well as vital status/transplant status follow-up by the site with the subject or the subject’s caregivers 30 months after study randomization. In some cases, sites may combine these two forms into one form, as is their standard practice.

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),

1. TTR genotyping is required at Screening unless documentation (ie original laboratory result, or copy) of a prior determination of a TTR genotype is produced.

2. Subjects with a confirmed diagnose of mutant (variant genotype) TTR-CM with concurrent monoclonal gammopathy of undetermined significance (MGUS) based on serum or urine light chain determinations, should be tested in the same manner as in the case of equivocal immunohistochemistry for subjects with wild type TTE-CM below.

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 alcian 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
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 30 days prior to the Baseline visit.

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 (e.g. verapamil diltiazem) 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 an estimated glomerular filtration rate (eGFR) of <25mL/min/1.73m2

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 30 days before the current study begins and/or during study participation. For diflunisal, tauroursodeoxycholate and doxycycline this time period will be within 30 days before the Baseline visit 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; male subjects with partners currently pregnant,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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Transthyretin amyloid cardiomyopathy (TTR-CM)
MedDRA version: 17.0 Level: LLT Classification code 10002020 Term: Amyloid cardiomyopathy System Organ Class: 100000004849

Intervention(s)

Trade Name: Vyndaqel 20 mg soft capsule
Product Name: Tafamidis meglumine
Product Code: PF-06291826-83, Fx-1006A
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Tafamidis
CAS Number: 951395-08-7
Current Sponsor code: PF-06291826, Fx-1006A
Other descriptive name: Tafamidis meglumine 20mg soft gelatin capsules
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule, soft
Route of administration of the placebo: Oral use

Primary Outcome(s)

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.

Main Objective: 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).

Secondary Objective: Not applicable

Timepoint(s) of evaluation of this end point: Both primary end points will be assessed throughout the study.

Secondary Outcome(s)

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.

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.

Secondary ID(s)

B3461028

Source(s) of Monetary Support

Pfizer Inc, 235 42nd Street, New York, NY 10017

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 16/02/2019
• Date Completed: 07/02/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-002465-35/results