Safety And Efficacy Evaluation Of Fx-1006A In Subjects With Transthyretin Amyloidosis

Karnofsky performance scale was used for rating participant activities of daily living. It rated participant on 11-step scale ranged from 0-100, higher score=participant is better able to carry out daily activities. The lower the score, the worse the survival for most serious illnesses. Score range: 100=normal no complaints; no evidence of disease, 90=able to carry on normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs or symptoms, 70=cares for self; unable to carry on normal activity or to do active work, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care and assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead, where lower score=worse survival for most serious illnesses.

Time frame: Baseline of B3461022 (Fx1A-201), Month 12

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Karnofsky performance scale was used for rating participant activities of daily living. It rated participant on 11-step scale ranged from 0-100, higher score=participant is better able to carry out daily activities. The lower the score, the worse the survival for most serious illnesses. Score range: 100=normal no complaints; no evidence of disease, 90=able to carry on normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs or symptoms, 70=cares for self; unable to carry on normal activity or to do active work, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care and assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead, where lower score=worse survival for most serious illnesses.

Time frame: Baseline of B3461022 (Fx1A-201), Month 60

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201), Month 12

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201), Month 60

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461022 (Fx1A-201), Month 12

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461022 (Fx1A-201), Month 60

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Karnofsky performance scale was used for rating participant activities of daily living. It rated participant on 11-step scale ranged from 0-100, higher score=participant is better able to carry out daily activities. The lower the score, the worse the survival for most serious illnesses. Score range: 100=normal no complaints; no evidence of disease, 90=able to carry on normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs or symptoms, 70=cares for self; unable to carry on normal activity or to do active work, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care and assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead, where lower score=worse survival for most serious illnesses.

Time frame: Baseline of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Ambulatory status for each NonVal30Met participant was collected using ambulatory data collection forms in B3461022 (Fx1A-201) or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Baseline of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Ambulatory status for each NonVal30Met participant was collected using ambulatory data collection forms in B3461022 (Fx1A-201) or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Month 12

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Ambulatory status for each NonVal30Met participant was collected using ambulatory data collection forms in B3461022 (Fx1A-201) or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Month 60

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005), Month 30

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005), Month 66

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461020 (Fx-005), Month 30

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461020 (Fx-005), Month 66

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

KPS: used for rating participant activities of daily living on 11-step scale from 0-100, higher score=participant is better able to carry out daily activities. Score range: 100=normal no complaints; no disease evidence, 90=able to carry normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs/symptoms, 70=cares for self; unable to carry on normal activity, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care, assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead. The lower the score the worse is survival for most serious illnesses. Data for KPS score was not collected in parent studies Fx-005 and Fx-006, therefore not reported for any time points from parent studies.

Time frame: Month 30 (Baseline of B3461023)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

KPS: used for rating participant activities of daily living on 11-step scale from 0-100, higher score=participant is better able to carry out daily activities. Score range: 100=normal no complaints; no disease evidence, 90=able to carry normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs/symptoms, 70=cares for self; unable to carry on normal activity, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care, assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead. The lower the score the worse is survival for most serious illnesses. Data for KPS score was not collected in parent studies Fx-005 and Fx-006, therefore not reported for any time points from parent studies.

Time frame: Month 66 (Month 36 of B3461023)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Ambulatory status for each Val30Met participant was collected using ambulatory data collection forms in \[B3461020 (Fx-005), B3461021 (Fx-006)\] or forms based on modified polyneuropathy disability (mPND) score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Baseline of B3461020 (Fx-005)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Ambulatory status for each Val30Met participant was collected using ambulatory data collection forms in \[B3461020 (Fx-005), B3461021 (Fx-006)\] or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Month 30

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Ambulatory status for each Val30Met participant was collected using ambulatory data collection forms in \[B3461020 (Fx-005), B3461021 (Fx-006)\] or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Month 66

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461020 (Fx-005)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.

Karnofsky performance scale was used for rating participant activities of daily living. It rated participant on 11-step scale ranged from 0-100, higher score=participant is better able to carry out daily activities. The lower the score, the worse the survival for most serious illnesses. Score range: 100=normal no complaints; no evidence of disease, 90=able to carry on normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs or symptoms, 70=cares for self; unable to carry on normal activity or to do active work, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care and assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead, where lower score=worse survival for most serious illnesses.

Time frame: Baseline of B3461022, Month 6, 24, 36, 48, 72, 84, 96, 108 and 120

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201), 6, 24, 36, 48, 72, 84, 96, 108 and 120

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, right limbs with a total possible NIS-LL score range of 0 to 88, higher score=greater impairment. 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. NIS-LL Muscle Weakness score range is 0 to 64, high score=more impairment. NIS-LL Sensation score range is 0 to 16, high score=more impairment. NIS-LL Reflexes score range is 0 to 8, high score=more impairment.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201), Month 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461022 (Fx1A-201), Month 6, 24, 36, 48, 72, 84, 96, 108, 120

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1 to 7: scored as 1=symptom present, 0=symptom absent. Items 8 to 35: scored on 5-point Likert scale: 0=no problem to 4=severe problem (except item 32, where -1=somewhat better, -2=much better, 0=about the same, 1=somewhat worse, 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), symptoms (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).

Time frame: Baseline of B3461022 (Fx1A-201), Month 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, right limbs with a total possible NIS-LL score range of 0 to 88, higher score=greater impairment. 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. NIS-LL Muscle Weakness score range is 0 to 64, high score=more impairment. NIS-LL Sensation score range is 0 to 16, high score=more impairment. NIS-LL Reflexes score range is 0 to 8, high score=more impairment.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Ambulatory status for each NonVal30Met participant was collected using ambulatory data collection forms in B3461022 (Fx1A-201) or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Month 3, 6, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126 and 129

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1 to 7: scored as 1=symptom present, 0=symptom absent. Items 8 to 35: scored on 5-point Likert scale: 0=no problem to 4=severe problem (except item 32, where -1=somewhat better, -2=much better, 0=about the same, 1=somewhat worse, 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), symptoms (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).

Time frame: Baseline of B3461022 (Fx1A-201)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Complete physical examination included examination of the general appearance, head and neck, ears, eyes, nose, throat, respiratory, genitourinary, endocrine, cardiovascular, abdomen, skin, musculoskeletal, neurological, immunologic/allergies, hematologic/lymphatic. Abnormality in physical findings were based on investigator's decision.

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

Number of participants with any concomitant medications usage are reported.

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

Criteria for clinically significant changes: Supine and standing systolic blood pressure (BP): decrease from baseline of less than or equal to (\<=) -20 millimeter of mercury (mmHg), increase from baseline of greater than or equal to (\>=) 20 mmHg, systolic BP \<90 mmHg or \>180 mmHg; Supine and standing diastolic BP: decrease from baseline of \<=-15 mmHg, increase from baseline of \>= 15 mmHg, diastolic BP \<50 mmHg or \>105 mmHg; Supine and standing pulse rate: decrease from baseline of \<=-15 beats per minute (bpm), increase from baseline of \>=15 bpm, pulse rate \<50 bpm or \>120 bpm; Weight: decrease from baseline of \<=-7 percentage (%) or increase from baseline of \>=7%.

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

Twelve-lead ECGs were obtained for all participants. Criteria for QT interval, Bazett's correction formula (QTcB) and Fridericia's correction formula (QTcF): greater than (\>) 450-480 millisecond (msec), \>480-500 msec and \>500 msec. Findings were considered to be abnormal based on investigator's decision.

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

Abnormalities criteria: Serum chemistry (bilirubin\>1.5\*upper limit normal \[ULN\]; aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase; gamma glutamyl transferase \>3.0\*ULN; albumin\<0.8\*lower limit normal \[LLN\],\>1.2\*ULN; blood urea nitrogen, creatinine\>1.3\*ULN; free T4, thyrotropin, thyroxine \<0.8\*LLN,\>1.2\*ULN; glucose\<0.6\*LLN,\>1.5\*ULN); Coagulation (prothrombin time, prothrombin int. normalized ratio \>1.1\*ULN); Hematology(basophils; eosinophils, monocytes \>1.2\*ULN; leukocytes \<0.6\*LLN,\>1.5\*ULN; lymphocytes, neutrophils \<0.8\*LLN, \>1.2\*ULN).

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. Treatment-emergent AEs were events that emerged after enrollment in B3461023 (Fx1A-303) or which worsened during the course of B3461023 (Fx1A-303) relative to the pretreatment state. AEs included both SAEs and non-SAEs.

Time frame: From Baseline (i.e., Day 0 of B3461023) up to 10 years

Population: Safety population included all enrolled participants in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1 to 7: scored as 1=symptom present, 0=symptom absent. Items 8 to 35: scored on 5-point Likert scale: 0=no problem to 4=severe problem (except item 32, where -1=somewhat better, -2=much better, 0=about the same, 1=somewhat worse, 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), symptoms (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).

Time frame: Baseline of B3461020 (Fx-005), Month 6, 12, 18, 24, 30, 42, 54, 66, 78, 90, 102, 114, 126 and 138

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, 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.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005), Month 6, 12, 18, 24, 42, 54, 78, 90, 102, 114 and 126

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, right limbs with a total possible NIS-LL score range of 0 to 88, higher score=greater impairment. 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. NIS-LL Muscle Weakness score range is 0 to 64, high score=more impairment. NIS-LL Sensation score range is 0 to 16, high score=more impairment. NIS-LL Reflexes score range is 0 to 8, high score=more impairment.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005), Month 6, 12, 18, 24, 30, 42, 54, 66, 78, 90, 102, 114 and 126

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Norfolk QOL-DN: 35-item participant-rated questionnaire; assessed impact of DN on health related QOL of participants with DN. Scoring was based on 35 questions that yield a TQOL as well as 5 subscale scores: symptoms, activities of daily living (ADLs), large fiber neuropathy/physical functioning, small fiber neuropathy, and autonomic neuropathy. TQOL score: sum of all items, total possible score range= -2 to 138, where higher score=worse QOL.

Time frame: Baseline of B3461020 (Fx-005), Month 6, 12, 18, 24, 42, 54, 78, 90, 102, 114, 126, 138

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Karnofsky performance scale was used for rating participant activities of daily living. It rated participant on 11-step scale ranged from 0-100, higher score=participant is better able to carry out daily activities. The lower the score, the worse the survival for most serious illnesses. Score range: 100=normal no complaints; no evidence of disease, 90=able to carry on normal activity; minor signs/symptoms of disease, 80=normal activity with effort; some signs or symptoms, 70=cares for self; unable to carry on normal activity or to do active work, 60=requires occasional assistance, but able to care for most personal needs, 50=requires considerable assistance and frequent medical care, 40=disabled; requires special care and assistance, 30=severely disabled; hospital admission is indicated although death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead, where lower score=worse survival for most serious illnesses.

Time frame: Baseline of B3461023, Month 42, 54, 78, 90, 102, 114, 126 and 138

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess muscle weakness, reflexes, sensation; scored separately for left, right limbs with a total possible NIS-LL score range of 0 to 88, higher score=greater impairment. 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. NIS-LL Muscle Weakness score range is 0 to 64, high score=more impairment. NIS-LL Sensation score range is 0 to 16, high score=more impairment. NIS-LL Reflexes score range is 0 to 8, high score=more impairment.

Time frame: Baseline (i.e. last measurement prior to first dose) of B3461020 (Fx-005)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

Ambulatory status for each Val30Met participant was collected using ambulatory data collection forms in \[B3461020 (Fx-005), B3461021 (Fx-006)\] or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorized to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory).

Time frame: Week 12, Month 6, 9, 12, 18, 21, 24, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126 and 129

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.

Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1 to 7: scored as 1=symptom present, 0=symptom absent. Items 8 to 35: scored on 5-point Likert scale: 0=no problem to 4=severe problem (except item 32, where -1=somewhat better, -2=much better, 0=about the same, 1=somewhat worse, 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), symptoms (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).

Time frame: Baseline of B3461020 (Fx-005)

Population: ITT population included all enrolled participants who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, 'number analyzed'=participants with available data for each specified category.