An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

• ClinicalTrials.gov Identifier: NCT00791492
• Recruitment Status: Completed
• First Posted: November 14, 2008
• Results First Posted: December 17, 2012
• Last Update Posted: December 17, 2012
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Familial Amyloid Polyneuropathy; ATTR-PN
• Intervention: Drug: Fx-1006A
• Enrollment: 86

Participant Flow

Recruitment Details	Participants who completed study FX-005 (NCT00409175), were eligible for the current study FX-006 (NCT00791492).
Pre-assignment Details

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Period Title: Overall Study
Started	45	41
TREATED	44	41
Completed	39	38
Not Completed	6	3
Reason Not Completed
Withdrawal by Subject	1	2
Liver transplantation	5	1

Baseline Characteristics

Arm/Group Title		Tafamidis-Tafamidis	Placebo-Tafamidis	Total
Arm/Group Description		Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Total of all reporting groups
Overall Number of Baseline Participants		44	41	85
Baseline Analysis Population Description		[Not Specified]
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	44 participants	41 participants	85 participants
		41.3 (13.4)	39.6 (13.2)	40.4 (13.3)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants	41 participants	85 participants
	Female	24 54.5%	23 56.1%	47 55.3%
	Male	20 45.5%	18 43.9%	38 44.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6
Description	Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than[<] 2) in 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:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	37	32
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	62.2; (44.8 to 77.5)	68.8; (50.0 to 83.9)

2. Primary Outcome

Title	Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12
Description	Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than[<] 2) in 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:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	33	30
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	54.5; (36.4 to 71.9)	60.0; (40.6 to 77.3)

3. Primary Outcome

Title	Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6
Description	Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms 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). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.
Time Frame	Baseline, Month 6

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline	21.05 (21.88)	38.09 (31.89)
Change at Month 6	0.03 (8.83)	-4.88 (15.29)

4. Primary Outcome

Title	Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12
Description	Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms 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). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.
Time Frame	Baseline, Month 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	32	30
Mean (Standard Deviation); Unit of Measure: units on a scale
	2.25 (8.91)	-2.33 (15.66)

5. Secondary Outcome

Title	Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12
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 scale 0 (normal) to 4 (paralysis), 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.
Time Frame	Baseline, Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline (n=38,33)	8.38 (13.23)	17.50 (20.82)
Change at Month 6 (n=37,32)	0.93 (3.65)	1.89 (4.55)
Change at Month 12 (n=33,30)	1.36 (4.77)	1.60 (8.20)

6. Secondary Outcome

Title	Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12
Description	Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptoms present, 0=symptoms 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), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment,for each. Total score=-2 to138(higher score=worse QOL).
Time Frame	Baseline, Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline: physical functioning (n=38,33)	9.45 (11.43)	19.88 (17.44)
Baseline: ADLs (n=38,33)	2.21 (4.38)	3.48 (5.13)
Baseline: symptoms (n=38,33)	5.34 (4.43)	7.48 (5.48)
Baseline: small fiber neuropathy (n=38,33)	2.50 (3.85)	4.42 (4.23)
Baseline: autonomic neuropathy (n=38,33)	1.55 (2.37)	2.82 (3.12)
Change at Month 6: physical functioning (n=37,32)	0.14 (4.08)	-3.00 (8.08)
Change at Month 6: ADLs (n=37,32)	-0.30 (1.45)	-0.59 (3.02)
Change at Month 6: symptoms (n=34,32)	0.00 (3.18)	-0.75 (4.27)
Change at Month 6: small fiber neuropathy(n=37,32)	-0.14 (2.64)	-0.09 (2.32)
Change at Month 6: autonomic neuropathy (n=37,32)	0.19 (1.33)	-0.44 (2.00)
Change at Month 12: physical functioning(n=32,30)	1.84 (6.00)	-0.83 (9.62)
Change at Month 12: ADLs (n=32,30)	0.13 (1.01)	-0.50 (3.35)
Change at Month 12: symptoms (n=32,30)	-0.66 (2.54)	-1.10 (3.32)
Change at Month 12:small fiber neuropathy(n=32,30)	0.41 (2.87)	0.40 (2.61)
Change at Month 12: autonomic neuropathy (n=32,30)	0.53 (1.46)	-0.30 (1.66)

7. Secondary Outcome

Title	Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12
Description	Summated 7 score: composite score included five Nerve Conduction Studies (NCS) attributes (peroneal nerve distal motor latency, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, tibial nerve distal motor latency, and sural nerve sensory nerve action potential amplitude) along with Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function.
Time Frame	Baseline, Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline (n=38,33)	6.68 (8.51)	10.06 (10.68)
Change at Month 6 (n=37,32)	-0.01 (2.99)	1.38 (3.58)
Change at Month 12 (n=33,30)	0.64 (3.23)	1.48 (4.02)

8. Secondary Outcome

Title	Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12
Description	Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function.
Time Frame	Baseline, Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: units on a scale
Baseline (n=38,33)	4.78 (4.33)	7.08 (4.39)
Change at Month 6 (n=36,32)	0.43 (1.51)	0.38 (1.08)
Change at Month 12 (n=32,30)	0.59 (1.28)	0.50 (1.48)

9. Secondary Outcome

Title	Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12
Description	BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation. A progressive decline in mBMI indicated worsening of disease severity.
Time Frame	Baseline, Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	33
Mean (Standard Deviation); Unit of Measure: (kilogram/square meter)*(gram/liter)
Baseline (n=38,33)	23.94 (2.97)	22.71 (5.15)
Change at Month 6 (n=37,32)	-0.13 (0.81)	0.42 (1.14)
Change at Month 12 (n=33,30)	-0.12 (1.16)	0.73 (1.45)

10. Secondary Outcome

Title	Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12
Description	Troponin I was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular [LV] wall stress).
Time Frame	Baseline, Week 6, Month 3, 6, 12

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	29	30
Median (Full Range); Unit of Measure: nanogram/milliliter (ng/mL)
Baseline (n=29,30)	0.2; (0.2 to 0.5)	0.2; (0.2 to 0.2)
Change at Week 6 (n=28,29)	0.0; (0.0 to 0.1)	0.0; (0.0 to 0.0)
Change at Month 3 (n=29,30)	0.0; (-0.1 to 0.3)	0.0; (0.0 to 0.7)
Change at Month 6 (n=29,30)	0.0; (0.0 to 0.6)	0.0; (0.0 to 0.1)
Change at Month 12 (n=26,28)	0.0; (-0.3 to 0.4)	0.0; (0.0 to 0.0)

11. Secondary Outcome

Title	Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12
Description	NT-proBNP was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ LV wall stress).
Time Frame	Baseline, Week 6, Month 3, 6, 12

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	33	34
Median (Full Range); Unit of Measure: picogram/milliliter (pg/mL)
Baseline (n=33,34)	41.0; (19.0 to 2879.0)	75.0; (20.0 to 1127.0)
Change at Week 6 (n=33,33)	6.0; (-650.0 to 525.0)	-1.0; (-292.0 to 97.0)
Change at Month 3 (n=33,34)	11.0; (-52.0 to 1355.0)	1.0; (-514.0 to 229.0)
Change at Month 6 (n=33,33)	9.0; (-210.0 to 3878.0)	0.0; (-473.0 to 170.0)
Change at Month 12 (n=30,29)	15.0; (-104.0 to 3840.0)	-6.0; (-342.0 to 410.0)

12. Secondary Outcome

Title	Intraepidermal Nerve Fiber (IENF) Density
Description	IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. It is used in diagnosing various neuropathic conditions.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	11	5
Mean (Standard Deviation); Unit of Measure: fibers/mm
Left distal leg	8.2 (9.8)	8.0 (9.2)
Left proximal thigh	16.1 (12.6)	15.3 (11.9)

13. Secondary Outcome

Title	Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer
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.
Time Frame	Month 6, 12

Outcome Measure Data

Analysis Population Description

ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	36	32
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Month 6	94; (81 to 99)	97; (83 to 99)
Month 12	94; (80 to 99)	93; (77 to 99)

14. Other Pre-specified Outcome

Title	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE: 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/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug, up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time Frame	Baseline up to 30 days after last dose of study medication

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	44	41
Measure Type: Number; Unit of Measure: participants
	5	4

15. Other Pre-specified Outcome

Title	Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3
Description	AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent 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.
Time Frame	Baseline up to 30 days after last dose of study medication

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	44	41
Measure Type: Number; Unit of Measure: participants
	6	4

16. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings
Description	Clinically significant ECHO findings included: LV posterior wall thickness greater than or equal to (>=)13 mm, LV septal thickness >= 13 mm, right ventricular thickness >= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) >= 2, prime septal (E/E) >15, ejection fraction < 50 percent (%), E deceleration time <= 150 millisecond (ms), isovolumic relaxation time (IVRT) <= 70 ms, any valve thickening (> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion.
Time Frame	Baseline, Day 1 up to Month 12 (anytime on-treatment)

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	38	34
Measure Type: Number; Unit of Measure: participants
Baseline (n=38,34)	23	18
Anytime on-treatment (n=21,23)	16	13

17. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings
Description	Clinically significant ECG findings included: corrected QT (QTc) > 450 ms, QTc >500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.
Time Frame	Baseline, Day 1 up to Month 12 (anytime on-treatment)

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	44	41
Measure Type: Number; Unit of Measure: participants
Baseline (n=44,41)	16	17
Anytime on-treatment (n=28,24)	6	6

18. Other Pre-specified Outcome

Title	Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings
Description	Clinically significant Holter monitor findings included: atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (<30 beats), sustained ventricular tachycardia (>= 30 beats), sinus pause (RR >2.0 second, where RR=60/heart rate), ventricular premature contractions.
Time Frame	Baseline, Day 1 up to Month 12 (anytime on-treatment)

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication. 'n' signifies participants for this measure at specified time point for each arm group.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	44	41
Measure Type: Number; Unit of Measure: participants
Baseline (n=44,41)	20	21
Anytime on-treatment (n=24,20)	8	7

19. Other Pre-specified Outcome

Title	Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events
Description	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An 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.
Time Frame	Baseline up to Month 12

Outcome Measure Data

Analysis Population Description

Safety population included participants who received at least one dose of study medication.

Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description:	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
Overall Number of Participants Analyzed	44	41
Measure Type: Number; Unit of Measure: participants
	0	0

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Tafamidis-Tafamidis	Placebo-Tafamidis
Arm/Group Description	Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.	Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months.
All-Cause Mortality
	Tafamidis-Tafamidis	Placebo-Tafamidis
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Tafamidis-Tafamidis	Placebo-Tafamidis
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/44 (11.36%)	4/41 (9.76%)
Blood and lymphatic system disorders
Anaemia * 1	0/44 (0.00%)	1/41 (2.44%)
Gastrointestinal disorders
Vomiting * 1	2/44 (4.55%)	1/41 (2.44%)
Nausea * 1	1/44 (2.27%)	1/41 (2.44%)
Immune system disorders
Hypersensitivity * 1	1/44 (2.27%)	0/41 (0.00%)
Infections and infestations
Catheter sepsis * 1	1/44 (2.27%)	0/41 (0.00%)
Catheter site infection * 1	1/44 (2.27%)	0/41 (0.00%)
Infection * 1	0/44 (0.00%)	1/41 (2.44%)
Meningitis * 1	0/44 (0.00%)	1/41 (2.44%)
Osteomyelitis * 1	0/44 (0.00%)	1/41 (2.44%)
Urinary tract infection * 1	0/44 (0.00%)	1/41 (2.44%)
Investigations
Blood electrolytes decreased * 1	1/44 (2.27%)	0/41 (0.00%)
Metabolism and nutrition disorders
Dehydration * 1	0/44 (0.00%)	1/41 (2.44%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma * 1	1/44 (2.27%)	0/41 (0.00%)
Skin and subcutaneous tissue disorders
Skin lesion * 1	1/44 (2.27%)	0/41 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA v10.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Tafamidis-Tafamidis	Placebo-Tafamidis
	Affected / at Risk (%)	Affected / at Risk (%)
Total	24/44 (54.55%)	24/41 (58.54%)
Eye disorders
Punctate keratitis * 1	3/44 (6.82%)	3/41 (7.32%)
Dry eye * 1	2/44 (4.55%)	3/41 (7.32%)
Gastrointestinal disorders
Diarrhoea * 1	4/44 (9.09%)	3/41 (7.32%)
Vomiting * 1	2/44 (4.55%)	4/41 (9.76%)
Infections and infestations
Urinary tract infection * 1	5/44 (11.36%)	6/41 (14.63%)
Influenza * 1	3/44 (6.82%)	7/41 (17.07%)
Nasopharyngitis * 1	5/44 (11.36%)	3/41 (7.32%)
Upper respiratory tract infection * 1	2/44 (4.55%)	3/41 (7.32%)
Injury, poisoning and procedural complications
Thermal burn * 1	4/44 (9.09%)	4/41 (9.76%)
Nervous system disorders
Headache * 1	2/44 (4.55%)	6/41 (14.63%)
Psychiatric disorders
Anxiety * 1	1/44 (2.27%)	5/41 (12.20%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA v10.0

Limitations and Caveats

Instead of intended endpoint 'heat pain and cooling threshold', results of 'summated 3 score for small nerve fiber function' were reported. Designation of outcomes as primary and secondary was based on study team input as study did not specify this.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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. Epub 2016 Aug 5.

Coelho T, Maia LF, da Silva AM, Cruz MW, Planté-Bordeneuve V, Suhr OB, Conceiçao I, Schmidt HH, Trigo P, Kelly JW, Labaudinière R, Chan J, Packman J, Grogan DR. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013 Nov;260(11):2802-14. doi: 10.1007/s00415-013-7051-7. Epub 2013 Aug 22.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00791492
• Other Study ID Numbers: FX-006; B3461021
• First Submitted: November 13, 2008
• First Posted: November 14, 2008
• Results First Submitted: November 16, 2012
• Results First Posted: December 17, 2012
• Last Update Posted: December 17, 2012