Primary Outcomes

Description: TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI.

Secondary Outcomes

Description: TTR tetramer was assessed using a validated immunoturbidimetric assay. The FOI is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI.

Other Outcomes

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. On the basis of intensity, grade 3 was referred as severe, grade 4 as life-threatening and grade 5 as death.

Description: ECHO: investigator assessed test to assess cardiac function. ECHO abnormality criteria: any abnormality, valvular abnormality, pericardial effusion, abnormal regional wall motion, inferior vena cava respiratory variation, posterior (P) left ventricular (LV) wall/septal (S) thickness, right ventricular thickness, ejection fraction, ratio of early (E) diastolic transmitral flow and atrial(A) contraction velocity (E/A), ratio of 'E'to lateral/septal mitral annular velocity (e') (E/e'prime lateral, E/e'prime septal), E deceleration time (DT), isovolumic relaxation time (IVRT).

Description: ECG: investigator assessed test to assess cardiac function. ECG abnormality criteria: any abnormality, arrhythmia, rhythm, conduction, morphology, myocardial infarction, ST segment, T waves and abnormal U waves.

Description: Holter monitoring recorded heart rhythm. Holter monitoring abnormality criteria: any abnormality, atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (VT), sustained VT and sinus pause.

Description: NIS assessed cranial nerves(nerve 3,6; facial, palate and tongue weakness),muscle weakness (respiratory; neck, elbow(E), wrist(W), finger(F), hip, knee(K) flexion; shoulder, thumb abduction; brachioradialis; E, W, hip, K extension; F spread; toe, dorsal and plantar ankle flexors; toe extensors); score: 0-4, higher score=more weakness, reflexes(biceps and triceps brachii; brachioradialis; quadriceps femoris; triceps surae), index F and great toe sensation(touch pressure, pin-prick, vibration, joint position)score:0=normal,1=decreased or 2=absent. Total score=0-244, higher score=more impairment.

Description: NIS-LL: assessed muscle weakness, reflexes and 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) are scored on 0 to 4 scale, higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.

Description: Response to treatment was indicated by either improvement (decrease from baseline) or stabilization (change from baseline of 0 to less than [<] 2) in Neuropathy Impairment Score- Lower Limb (NIS-LL) score, based on mean of 2 scores in 1 week period. NIS-LL: assessed muscle weakness, reflexes, sensation. Each item scored separately for left, right limbs. Components of muscle weakness scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.

Description: TQOL= sum of all Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) items,a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on QOL of participants with DN; Item 1 to 7: related to symptoms and presence of symptom was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). Total TQOL score=-2 to 138;higher score=worse quality of life.

Description: Norfolk QOL-DN:35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7: scored as 1=symptom present, 0=symptom absent. Item 8-35: scored on 5-point Likert scale:0=no problem, 4=severe problem(except item 32: -2=much better, 0=about same, 2=much worse).Norfolk QOL-DN summarized in 5 domains (score range): physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptom(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12);higher score=greater impairment, for each. Total score=-2 to 138 (higher score=worse QOL).

Description: NCS: quantitative measures of peripheral nerve dysfunction consists of 5 attributes: peroneal nerve (PN) motor distal latency, PN compound muscle action potential, PN motor conduction velocity, tibial nerve distal motor latency, sural nerve sensory nerve action potential. Normal deviates (Z-score) summated into composite score (higher score=worsened nerve fiber function). Z-score is the defined position of the result in normal probability distribution with a mean of 0 and standard deviation (std) of 1 and describes how far a score is (in std) from the mean.

Description: HRDB test was used to evaluate the cardio-vagal response. Participant took a series of 8 deep breaths and average heart rate difference was measured and compared to normative data. The main factor affecting HRDB is age, with older patients showing less heart rate variability. R-R (time between two consecutive R waves in the electrocardiogram) response to deep breathing was reported as the normal deviates (Z-score), the defined position of the result in normal probability distribution with a mean of 0 and standard deviation (std) of 1 and describes how far a score is (in std) from the mean.

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

Description: SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health and two total scores (physical component summary [PCS] and mental component summary [MCS]. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

Description: Echocardiography was used to measure interventricular septal thickness (IVST), posterior left ventricular wall thickness (PLVWT), right ventricular wall thickness (RVWT), left atrial diameter (LAD): anterior-posterior (ant-post), medio-lateral, superior-inferior (sup-inf) and left ventricular end diastolic diameter (LVED), relative LV wall thickness (RLVWT).

Description: Left atrial volume was measured by echocardiography.

Description: Cardiac MRI was done to measure left ventricular (LV) end systolic volume, left ventricle (LV) stroke volume.

Description: Fractional shortening (FS) is the fraction of any diastolic dimension that is lost in systole. Percent of FS was calculated as difference between end-diastolic dimension (EDD) and end-systolic dimension (EDS) divided by EDD.

Description: Cardiac MRI was done to measure left ventricular ejection fraction (LVEF) which was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction.

Description: LV mass was calculated from the product of the myocardial volume and specific gravity of heart muscle, estimated by echocardiography. Increased LVM was associated with cardiovascular morbidity and mortality.

Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. IVRT is the time between the closure of the aortic valve and the opening of the mitral valve. Mitral deceleration time (MDT) was the time taken from the maximum E point wave to baseline. E wave arises due to early diastolic filling.

Description: The diameter at the base of the aortic root, the basal ring, is also called the aortic annulus diameter.

Description: Tricuspid peak velocity was measured by echocardiography.

Description: Systolic right ventricular pressure can be estimated on echocardiography by adding right atrial pressure (RAP) to the trans-tricuspid gradient derived from the tricuspid regurgitation velocity.

Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. Doppler principle was used to measure the mitral peak early (E) diastolic transmitral flow, mitral peak atrial (A) contraction velocity and annular velocities at the lateral and septal areas of the mitral annulus. s': systolic velocity during ejection, e': early diastolic mitral annular velocity, a': late diastolic mitral annular velocity.

Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. Ratio of early (E) diastolic transmitral flow velocity and atrial (A) contraction velocity (E/A) and ratio of the early (E) diastolic transmitral flow velocity to the mitral annular velocity (e') (E/e') were estimated.

Description: LV mass was calculated from the product of the myocardial volume and specific gravity of heart muscle, estimated by echocardiography. QRS score (the sum of QRS voltages in the peripheral leads) was used as an index of "electrical" LV mass.

Description: LA volume index (LAVI), was the value of LA volume divided by body surface area, to measure LA size.

Description: NT-proBNP was a cardiac marker which had the prognostic value for participants with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage.

Description: Karnofsky performance score is used to quantify participant's general well-being and activities of daily life and participants are classified based on their functional impairment. Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (no evidence of disease). Higher score means higher ability to perform daily tasks.

Description: Troponin I is a cardiac injury biomarker. Higher concentrations of this marker in blood are associated with heart injury.

Primary Outcomes

Description: Main characteristics included were education level and employment status which were asked from all participants and caregivers. Type of job (full-time, part-time) was asked only from those participants and caregivers who provided their employment status as employed. Those who were unemployed reported their cause of unemployment, whether it was due to ATTR or not.

Description: Duration of disease was defined as the time from diagnosis of disease until baseline visit. This outcome measure was planned to be assessed for reporting arm of participants diagnosed with ATTR.

Description: Genetic mutation leads to misfolding of protein transthyretin (TTR) which results in ATTR. In this outcome, number of participants with each type of resulted mutation type (Val30Met, wild type TTR, Phe64Leu, Ser77Tyr, Thr60Ala or other than these) were reported. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.

Description: TTR protein is primarily synthesized in the liver. Liver transplantation was considered as one of the measure to eliminate the main source of variant TTR. In the study, participants who were diagnosed with ATTR were asked for their liver transplantation status (whether they had transplantation or not). In this outcome measure, number of participants with liver transplant status were reported. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.

Description: Family history of participants diagnosed with ATTR was assessed to determine whether family history of ATTR was a significant risk factor for ATTR or not. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.

Description: Mobility, i.e., ability to walk was assessed as a part of loss of functioning in the participants diagnosed with ATTR. In this outcome, number of participants with their different mobility status along with the use of mobility aids (able to walk normally, some problems with feet but able to walk without difficulty, some difficulty walking but can walk without help, confined to bed all the time, need 1 cane or crutch to walk, need 2 canes/crutches or a walker to walk) were reported.

Description: SF-12 was a patient reported outcome survey that represented overall health status by measuring 8 health-related aspects of an individual: Body pain, general mental health, perception of general health, physical functioning, role limitations caused by mental condition, role limitations caused by a physical condition, social functioning, and vitality. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Responses on the SF-12 were also used to calculate 2 summary scores: Physical component score (PCS) and mental component score (MCS). The score range for each of these 2 summary scores was from 0 (poor health) to 100 (better health), where 100 indicated good health condition.

Description: HADS: participant rated 14-item questionnaire with 2 subscales; HADS-anxiety scale (HADS-A) and HADS-depression scale (HADS-D). HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items and the participant responds as to how each item applies to him/her over the past week prior to baseline visit, on 4-point response scale. Separate scores were calculated for anxiety and depression with score ranges from 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score range was from 0 to 21 for each subscale; higher score indicating greater severity of anxiety and depression symptoms.

Description: EQ-5D-3L: participant rated questionnaire to assess generic health status in two parts: single utility score and visual analog scale. For utility score, participants rated their current health state on 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression with each dimension having three levels of function: 1 indicates no problem; 2 indicates some problem; 3 indicates extreme problem. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score was transformed and results in a total score range of 0.05 to 1.00; higher scores indicating a better health state.

Description: EQ-5D: participant rated questionnaire to assess generic health status in two parts: single utility score and visual analog scale. The VAS component rated the current health state on a scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicating a better health state.

Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asked about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Percentage of work time missed of participants were recorded and reported.

Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asks about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.

Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asked about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.

Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asks about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.

Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).

Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).

Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).

Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs. Number of participants (diagnosed with ATTR) who visited non-medical practitioners (nutrition consultant/dietician, chiropractor, acupuncturist, massage therapist, occupational therapist or other than these) for symptomatic treatments were reported.

Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs. Number of visits of participants (diagnosed with ATTR) who visited non-medical practitioners (nutrition consultant/dietician, chiropractor, acupuncturist, massage therapist, occupational therapist or other than these) for symptomatic treatments were reported.

Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (expenditure on nutritional supplements, non-prescription medications and travel to receive medical care).

Description: Participants diagnosed with ATTR rated their pain due to the health condition based on 3 items: pain right now, average pain in the past week, and worst pain in the past week prior to baseline visit. All 3 items were rated on an 11-point numeric rating scale ranging from 0=none to 10=severe pain, where higher scores indicated severe pain.

Description: Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of neuropathy on the quality of life of participants diagnosed with ATTR. Scoring was 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. This outcome measure was planned to be analyzed only for the reporting arm of participants diagnosed with ATTR.

Description: Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of neuropathy on the quality of life of participants diagnosed with ATTR. It was 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. This outcome measure was analyzed only for the participants diagnosed with ATTR.

Description: KCCQ was a 23-item participant-completed questionnaire that assessed health status and health-related quality of life (HRQoL) in participants with heart failure. It was quantified in to following 10 summary scores: physical limitation, symptom frequency, symptom severity, and symptom stability, total symptoms, quality of life, social interference, self-efficacy, overall summary and clinical summary. Each summary score was scaled to range from 0 (minimum) to 100 (maximum), with higher scores representing greater disability. Total score ranged from 0 to 100, where higher scores indicated better functioning, fewer symptoms, and better disease specific quality of life.

Description: ZBI was a 22-item questionnaire designed to evaluate five broad aspects of caregiver burden in terms of personal and role strain associated with caregiving. Five broad aspects were: burden in the relationship, emotional well-being, social and family life, finances, loss of control over one's life. Each item rated on a 5 point scale anchored at 0 for "never" and 4 for "nearly always." Total score ranges from 0-88 with higher scores indicating increased burden of care.

Description: A questionnaire designed to evaluate aspects of caregiver burden in terms of personal and role strain associated with caregiving. Total score of ZBI scale ranges from 0-88 with higher scores indicating increased burden of care. Five subscale scores were also calculated: (1) Burden in the relationship (consist of 6-items, ranging from 0 to 24 where higher scores indicating increased burden in relationship); (2) Emotional well-being (consisting of 7-items, ranging from 0 to 28 where higher scores indicating worse condition; (3) Social and family life (consisting of 4-items, ranging from 0 to 16 where higher scores indicating worse life condition); (4) Finances (consisting of a single item, scored from 0 to 4 where higher scores indicating worse financial condition); and (5) Loss of control over one's life (consisting of 4-items, ranging from 0 to 16 where higher scores indicating worse control over life).

Description: Caregivers completed a series of questions related to the number of hours per week spent on providing care and support to the participants diagnosed with ATTR.

Description: Caregivers completed a series of questions related to the loss in their working time while providing care and support to the participants diagnosed with ATTR.

Description: Caregivers completed a series of questions related to the total cost spent on providing healthcare support to participants diagnosed with ATTR.

HP:0001271: Polyneuropathy

Genes 59

Protein Mutations 24

SNP 3

HP:0011034: Amyloidosis

Genes 30

Protein Mutations 20

SNP 0

HP:0001638: Cardiomyopathy

Genes 730

Protein Mutations 9

SNP 18