The Effect Of Tafamidis Meglumine In Transthyretin Amyloid Polyneuropathy Patients

NIS-LL: assess muscle weakness, reflexes, sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae); sensation (touch pressure, pin-prick, vibration, joint position) scored 0 = normal, 1 = decreased, or 2 = absent. Total possible NIS-LL score range 0-88, high score = more impairment. Components of muscle weakness are scored to eight levels: 0 = Normal, 1 = 25% Weak, 2 = 50% Weak, 3 = 75% Weak, 3.25 = Move against gravity, 3.5 = Movement, gravity eliminated, 3.75 = Muscle flicker, no movement, 4 = Paralysis.

NIS-LL: assess muscle weakness, reflexes, sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae); sensation (touch pressure, pin-prick, vibration, joint position) scored 0 = normal, 1 = decreased, or 2 = absent. Total possible NIS-LL score range 0-88, high score = more impairment. Components of muscle weakness are scored to eight levels: 0 = Normal, 1 = 25% Weak, 2 = 50% Weak, 3 = 75% Weak, 3.25 = Move against gravity, 3.5 = Movement, gravity eliminated, 3.75 = Muscle flicker, no movement, 4 = Paralysis.

Norfolk QOL-DN: 35-item participant-rated questionnaire assess the impact of neuropathy on the quality of life of participants diagnosed with transthyretin amyloid (ATTR). Scoring is based on 35 questions that yield a TQOL as well as 5 subscale scores: activities of daily living, large fiber neuropathy/physical functioning, small fiber neuropathy, autonomic neuropathy, and symptoms. TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.

Norfolk QOL-DN: 35-item participant-rated questionnaire assess the impact of neuropathy on the quality of life of participants diagnosed with transthyretin amyloid (ATTR). It is summarized in 5 domains: (1) Activities of daily living (score ranges from 0 to 20, where higher score=worse quality of life); (2) Large fiber neuropathy/physical functioning (score ranges from -2 to 58, where higher score=worse condition); (3) Small fiber neuropathy (score ranges from 0 to 16, where higher score=worse condition); (4) Autonomic neuropathy (score ranges from 0 to 12, where higher score=worse condition) and (5) Symptoms (score ranges from 0 to 32, where higher score=less symptoms of disease). Total possible score range= -2 to 138, where higher score=worse quality of life.

BMI is calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). mBMI is calculated by multiplying BMI by serum albumin levels [gram/liter (g/L)]. mBMI is measured as kg/m^2*g/L. A progressive decline in mBMI indicates worsening of disease severity.

The SF-36 is a participant administered scale assessing general quality of life. It consists of self-administered 36-item questionnaire that measured 8 health domains: physical function, role-physical, bodily pain, general health, vitality, social function, role-emotional, and mental health. These 8 domains are also summarized as physical and mental component scores. The score for each domain and component score is the mean of the individual question scores, which are scaled from 0 (minimum) to 100 (maximum), where high scores in each dimension and high overall scores indicate a better quality of life.

EQ-5D-5L: standardized participant (aged >17 years) completed questionnaire consists of 2 components: a health state profile and an optional VAS. EQ-5D health state profile has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Responses to 5 dimensions comprise a health state/a single utility index value. E.g. if a participant responds "no problems" for each 5 dimensions, then health state was coded as "11111" with a predefined index value to it. Every health state (coded as combination of responses on each of 5 dimensions) has a unique predefined utility index value assigned to it, by EuroQol. Chinese value sets (with all possible health states) is used for adults in the study, range from -0.391 to 1. Higher (positive) scores = better health state.

An adverse event is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment emergent adverse event is defined as any adverse event started after the first dose. The TEAEs were collected until Week 77.

Vital signs categorical criteria: 1) pulse rate <40 beats per minute (bpm), or >120 bpm; 2) standing diastolic blood pressure (BP) <50 mmHg, or increase ≥20 mmHg, or decrease ≥20 mmHg; 3) standing systolic BP <90 mmHg, or increase ≥30 mmHg, or decrease ≥30 mmHg; 4) supine diastolic BP <50 mmHg, or increase ≥20 mmHg, or decrease ≥20 mmHg; 5) supine systolic BP <90 mmHg, or increase ≥30 mmHg, or decrease ≥30 mmHg.

ECG categorical criteria: 1) ECG mean heart rate <40 beats/minute, or >120 beats/minute; 2) PR interval not otherwise specified ≥300 milliseconds (msec), or baseline >200 msec and %increase ≥25%/ baseline ≤200 msec and %increase ≥50% (% change ≥25/50%); 3) QRS interval not otherwise specified ≥140 msec, or %change ≥50%; 4) QT interval not otherwise specified ≥500 msec; 5) corrected QT (QTc) interval not otherwise specified ≥450 and <480 msec, or ≥480 and <500 msec, or ≥500 msec; or change ≥30 and <60 msec, or change ≥60 msec.

Clinically significant ECHO findings include: left ventricular (LV) posterior wall thickness greater than or equal to (>=)13 mm, LV septal thickness >= 13 mm, right ventricular thickness >= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) >= 2, prime septal (E/E) >15, ejection fraction < 50 percent (%), E deceleration time <= 150 millisecond (ms), isovolumic relaxation time (IVRT) <= 70 ms, any valve thickening (> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion.

Protocol-required safety laboratory assessments include: Lymphocytes <0.8 × LLN; Neutrophils <0.8 × LLN, or >1.2 × ULN; Basophils >1.2 × ULN; Activated Partial Thromboplastin Time >1.1 × ULN; Prothrombin Time >1.1 × ULN; Prothrombin International Normalized Ratio >1.1 × ULN; Bilirubin >1.5 × ULN; Urate > 1.2 × ULN; Cholesterol >1.3 × ULN; Potassium <0.9 × LLN; Phosphate >1.2 × ULN; Bicarbonate >1.1 × ULN; Thyroid Stimulating Hormone >1.2 × ULN; URINE Protein ≥1; URINE Hemoglobin ≥1; Nitrite ≥1; URINE Erythrocytes ≥20; Epithelial Cells ≥6; and Casts >1.

The TTR (also referred to as pre-albumin) concentrations were determined as pharmacodynamic (PD) biomarkers.

The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration (post-denaturation) to the measured TTR concentration (pre-denaturation). Percent Stabilization (%) is the difference between the dosed FOI and the baseline FOI expressed as a percentage of the baseline FOI.

Responder was the participant who achieved TTR stabilization (ie, who had been TTR stabilized). Percentage of responders was number of responders / number of evaluable (i.e., analyzed) participants.