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.

Measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Week 6

Time: Week 6

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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.

Measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Month 6 and 12

Time: Month 6, Month 12

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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.

Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs)

Time: Baseline up to 30 days after the last dose

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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.

Measure: Number of Participants With Greater Than or Equal to Grade 3 Treatment-Emergent Adverse Events

Time: Baseline up to 30 days after the last dose

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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).

Measure: Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings

Time: Day 1 up to Month 12

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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.

Measure: Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings

Time: Day 1 up to Month 12

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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.

Measure: Number of Participants With Clinically Significant Treatment-Emergent Holter Monitoring Findings

Time: Day 1 up to Month 12

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Measure: Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events

Time: Baseline up to Month 12

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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.

Measure: Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in the Neuropathy Impairment Score-Lower Limb (NIS-LL) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6, Month 12

Time: Month 6, Month 12

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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.

Measure: Change From Baseline in Total Quality of Life (TQOL) Score at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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).

Measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Nerve Conduction Studies (NCS) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Heart Rate Response to Deep Breathing (HRDB) at Month 6 and Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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).

Measure: Change From Baseline in Overall Quality of Life and Individual Domains of the Short-form-36 (SF-36) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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).

Measure: Change From Baseline in Echocardiography (ECHO) Parameters at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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Description: Left atrial volume was measured by echocardiography.

Measure: Change From Baseline in Left Atrial Volume at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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

Measure: Change From Baseline in Left Ventricular (LV) End Systolic Volume, Left Ventricle (LV) Stroke Volume at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Fractional Shortening at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Left Ventricular (LV) Ejection Fraction at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Left Ventricular Mass (LVM) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Isovolumetric Relaxation Time (IVRT), Mitral Deceleration Time at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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

Measure: Change From Baseline in Aortic Annulus Diameter at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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Description: Tricuspid peak velocity was measured by echocardiography.

Measure: Change From Baseline in Tricuspid Peak Velocity at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Tricuspid Pulmonary Artery Systolic Pressure (PASP) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Doppler Data at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in e:e' Lateral Ratio , Ratio of Peak Mitral Early Diastolic and Atrial Contraction Velocity (E/A Ratio) at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in Left Ventricular (LV) Mass/Voltage Ratio at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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

Measure: Change From Baseline in Left Atrial (LA) Volume Index at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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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.

Measure: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) at Week 2, Week 6, Month 3, Month 6, Month 12

Time: Baseline, Week 2, Week 6, Month 3, Month 6, Month 12

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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.

Measure: Change From Baseline in Karnofsky Performance Status Scale at Month 6, Month 12

Time: Baseline, Month 6, Month 12

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

Measure: Change From Baseline in Troponin I Levels at Week 2, Week 6 , Month 3, Month 6, Month 12

Time: Baseline, Week 2, Week 6 , Month 3, Month 6, Month 12

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