A Study Comparing Two Forms of Tafamidis Without Food and the Amount of Tafamidis in the Blood With Food

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical trial is to compare a tablet and a capsule form of tafamidis without food and to assess the amount of tafamidis in blood after taking the tablet form with food. This study is seeking healthy participants over the age of 18. All participants in the study will receive either one tablet or capsule of study medicine on the first day without food, then receive one dose of the other tablet or capsule form 16 days later without food. All participants will then receive one dose of the tablet form with food 16 days later. We will evaluate the amounts in blood for 8 days after taking each dose of the study medicine. Participants will take part in this study for about 96 days. The first visit is a screening visit to ensure that participants are appropriate for the study. Up to 28 days later, eligible participants will visit the study clinic three times (and stay overnight in the clinical research center for 8 nights each time). The study team will also call participants over the phone 28 to 35 days after the last dose of medicine.

Official Title
-----------------
A PHASE 1, OPEN-LABEL, RANDOMIZED, CROSSOVER, SINGLE DOSE STUDY TO DETERMINE THE BIOEQUIVALENCE OF 12.2 MG TAFAMIDIS FREE ACID TABLETS AND COMMERCIAL 20 MG TAFAMIDIS MEGLUMINE CAPSULES ADMINISTERED UNDER FASTED CONDITIONS AND THE EFFECT OF FOOD ON ORAL BIOAVAILABILITY OF 12.2 MG TAFAMIDIS FREE ACID TABLETS IN HEALTHY ADULT PARTICIPANTS

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Tafamidis free acid tablet (Test)
* Drug: Tafamidis meglumine capsule (Reference)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening. Healthy female participants of nonchildbearing potential and/or male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, and laboratory tests. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). Exclusion Criteria: Medical Conditions: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy). History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. Hypersensitivity to any component of the formulations Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality or other conditions or situations related to COVID-19 pandemic (eg, Contact with positive case, residence, or travel to an area with high incidence) that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Prior/Concomitant Therapy: Use of prescription or nonprescription drugs, dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of study intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional details). Current use of any prohibited concomitant medication(s) or participant unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.9 Prior and Concomitant Therapy. Prior/Concurrent Clinical Study Experience: Previous administration with an investigational product (drug or vaccine) within 6 months (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Diagnostic Assessments: A positive urine drug test. Screening seated BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of seated rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF >450 ms, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT interval is >450 ms, this interval should be rate-corrected using the Fridericia method only and the resulting QTcF should be used for decision making and reporting. If QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or QRS values used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding a participant. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat test, if deemed necessary: AST or ALT level ≥ 1.5 × ULN; Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN. Other Exclusion Criteria: History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing. History of sensitivity to heparin or heparin induced thrombocytopenia. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. Use of tobacco or nicotine-containing products in excess of the equivalent of 5 cigarettes per day.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test tablet (fasted) followed by Reference capsule (fasted) followed by Test tablet (fed)<br>On Day 1 of each period, participants will receive a single dose of one of the tafamidis formulations under fasted or fed conditions. Each period is separated by a washout of at least 16 days between administration of study drug. | Drug: Tafamidis free acid tablet (Test)<br>* 12.2 mg tafamidis free acid tablet (Test)<br>Drug: Tafamidis meglumine capsule (Reference)<br>* Commercial 20 mg tafamidis meglumine capsule (Reference)<br>|
| Experimental: Reference capsule (fasted) followed by Test tablet (fasted) followed by Test tablet (fed)<br>On Day 1 of each period, participants will receive a single dose of one of the tafamidis formulations under fasted or fed conditions. Each period is separated by a washout of at least 16 days between administration of study drug. | Drug: Tafamidis free acid tablet (Test)<br>* 12.2 mg tafamidis free acid tablet (Test)<br>Drug: Tafamidis meglumine capsule (Reference)<br>* Commercial 20 mg tafamidis meglumine capsule (Reference)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve (AUCinf) | Area under the plasma concentration time profile from time zero extrapolated to infinite time | Hour 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 | 
| Maximum observed plasma concentration (Cmax) | Peak or maximum observed concentration | Hour 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tafamidis, B3461103