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

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• Amyloidosis 491

Amyloidosis

491 studies on the registry are indexed under Amyloidosis; 135 are open to participants now.

This study's enrollment of 93 is above the median of 40 across 304 interventional studies indexed under Amyloidosis.

Lead sponsor

Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.

Eligibility criteria

Study arms

• Active comparator
  Open-Label

  Drug: Tafamidis

Interventions

• DrugTafamidis

  20 mg oral Fx-1006A daily

Primary outcomes

1. Val30Met Group: Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Baseline

   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)

2. Val30Met Group: Change From B3461020 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 30

   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

3. Val30Met Group: Change From B3461020 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 66

   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

4. NonVal30Met Group: Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Baseline

   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)

5. NonVal30Met Group: Change From B3461022 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 12

   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

6. NonVal30Met Group: Change From B3461022 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 60

   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

7. Val30Met Group: Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Baseline

   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)

8. Val30Met Group: Change From B3461020 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 30

   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

9. Val30Met Group: Change From B3461020 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 66

   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

10. NonVal30Met Group: Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Baseline

    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)

11. NonVal30Met Group: Change From B3461022 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 12

    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

12. NonVal30Met Group: Change From B3461022 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 60

    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

13. Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 30

    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)

14. Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 66

    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)

15. NonVal30Met Group: Karnofsky Performance Scale (KPS) Score at Baseline

    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)

16. NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 12

    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

17. NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 60

    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

18. Val30Met Group: Number of Participants by Ambulation Stage at Baseline

    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)

19. Val30Met Group: Number of Participants by Ambulation Stage at Month 30

    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

20. Val30Met Group: Number of Participants by Ambulation Stage at Month 66

    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

21. NonVal30Met Group: Number of Participants by Ambulation Stage at Baseline

    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)

22. NonVal30Met Group: Number of Participants by Ambulation Stage at Month 12

    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

23. NonVal30Met Group: Number of Participants by Ambulation Stage at Month 60

    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

Secondary outcomes

1. Val30Met Group: Change From B3461020 Baseline in NIS-LL Score at Month 6, 12, 18, 24, 42, 54, 78, 90, 102, 114 and 126

   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

2. Val30Met Group: NIS-LL Subscales Scores: Muscle Weakness (MW), MW-Hip, MW-Knee, MW-Ankle, MW-Toe, NIS-LL Reflexes, NIS-LL Sensory at Baseline

   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)

3. Val30Met Group: Change From B3461020 Baseline in NIS-LL Subscales Scores: Muscle Weakness (MW), MW-Hip, MW-Knee, MW-Ankle, MW-Toe, NIS-LL Reflexes, NIS-LL Sensory at Month 6, 12, 18, 24, 30, 42, 54, 66, 78, 90, 102, 114 and 126

   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

4. NonVal30Met Group: Change From B3461022 Baseline in NIS-LL Score at Month 6, 24, 36, 48, 72, 84, 96, 108 and 120

   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

5. NonVal30Met Group: NIS-LL Subscales Scores: Muscle Weakness (MW), MW-Hip, MW-Knee, MW-Ankle, MW-Toe, NIS-LL Reflexes, NIS-LL Sensory at Baseline

   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)

6. NonVal30Met Group: Change From B3461022 Baseline in NIS-LL Subscales Scores: Muscle Weakness (MW), MW-Hip, MW-Knee, MW-Ankle, MW-Toe, NIS-LL Reflexes, NIS-LL Sensory at Month 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120

   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

7. Val30Met Group: Change From B3461020 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 6, 12, 18, 24, 42, 54, 78, 90, 102, 114, 126, 138

   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

8. Val30Met Group: TQOL Subscale Scores: Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Baseline

   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)

9. Val30Met:Change From Baseline in TQOL Subscale Scores:Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Month 6, 12, 18, 24, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138

   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

10. NonVal30Met Group: Change From B3461022 Baseline in Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Month 6, 24, 36, 48, 72, 84, 96, 108, 120

    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

11. NonVal30Met Group: TQOL Subscale Scores: Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Baseline

    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)

12. NonVal30Met Group: Change From Baseline in TQOL Subscale Scores: Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Month 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120

    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

13. Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 42, 54, 78, 90, 102, 114, 126 and 138

    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

14. NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 6, 24, 36, 48, 72, 84, 96, 108 and 120

    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

15. Val30Met Group: Number of Participants by Ambulation Stage at Week 12, Month 6, 9, 12, 18, 21, 24, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, 120, 123, 126, 129

    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

16. NonVal30Met Group: Number of Participants by Ambulation Stage at 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, 129

    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

17. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious AEs

    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

18. Number of Participants With Abnormality in Physical Examinations

    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

19. Number of Participants With Laboratory Test Abnormalities

    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

20. Number of Participants With Electrocardiogram (ECG) Abnormalities

    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

21. Number of Participants With Clinically Significant Changes From Baseline in Vital Signs

    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

22. Number of Participants With Any Concomitant Medications Usage

    Number of participants with any concomitant medications usage are reported.

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

Baseline characteristics

Publications

• Merlini G, Coelho T, Waddington Cruz M, Li H, Stewart M, Ebede B. Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years. Neurol Ther. 2020 Jun;9(1):105-115. doi: 10.1007/s40120-020-00180-w. Epub 2020 Feb 27. PubMed 32107748 ↗
• Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019 Dec;26(4):203-209. doi: 10.1080/13506129.2019.1643714. Epub 2019 Jul 27. PubMed 31353964 ↗
• Amass L, Li H, Gundapaneni BK, Schwartz JH, Keohane DJ. Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy. Orphanet J Rare Dis. 2018 Dec 17;13(1):225. doi: 10.1186/s13023-018-0947-7. PubMed 30558645 ↗
• Barroso FA, Judge DP, Ebede B, Li H, Stewart M, Amass L, Sultan MB. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years. Amyloid. 2017 Sep;24(3):194-204. doi: 10.1080/13506129.2017.1357545. Epub 2017 Jul 31. PubMed 28758793 ↗
• Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016 Sep;23(3):178-183. doi: 10.1080/13506129.2016.1207163. Epub 2016 Aug 5. PubMed 27494299 ↗

Related links

• To obtain contact information for a study center near you, click here. ↗

Study documents

• Study protocol · Jun 5, 2012
• Statistical analysis plan · Sep 11, 2014

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.