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Clinical Trial Results:
Open-Label Safety and Efficacy Evaluation of FX-1006A in Subjects With Transthyretin (TTR) Amyloidosis

Summary
EudraCT number	2009-011535-12
Trial protocol	DE SE FR PT IT
Global end of trial date	08 Jul 2020

Results information
Results version number	v1(current)
This version publication date	23 Jul 2021
First version publication date	23 Jul 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B3461023

ISRCTN number

US NCT number

NCT00925002

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

22 Dec 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jul 2020

Was the trial ended prematurely?

Main objective of the trial

To obtain additional, long-term, open-label safety and efficacy data for tafamidis in subjects with transthyretin (TTR) familial amyloid polyneuropathy (ATTR-PN); To continue to provide the investigational product tafamidis to subjects with ATTR-PN who have completed Protocol Fx-006 (NCT00791492) or Protocol Fx1A-201 (NCT00630864).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Aug 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

10 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 7

Country: Number of subjects enrolled

Brazil: 5

Country: Number of subjects enrolled

France: 6

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Portugal: 49

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

United States: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects enrolled in B3461023 had ATTR-PN, had not undergone liver/heart transplantation, and completed either B3461021 (Fx-006 [NCT00791492]: extension to Fx-005 [NCT00409175]) or B3461022 (Fx1A-201 [NCT00630864]). Val30Met (V30M): valine replaced by methionine in position 30 of TTR protein; NonVal30Met (NonV30M): TTR mutations other than V30M.

Screening details

Baseline (except treatment-emergent adverse events) was last measurement prior to 1st dose in Fx-005 (V30M) or Fx1A-201 (NonV30M). V30M: data from Baseline to Month 18 from Fx-005; after Month 18 to Month 30 from Fx-006; after Month 30 from B3461023. NonV30M: Baseline to Month 12 from Fx1A-201, after Month 12 from B3461023.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Val30Met: Tafamidis Then Tafamidis

Arm description

Val30Met subjects who received tafamidis in study Fx-005 (B3461020), continued the same in study Fx-006 (B3461021), received tafamidis 20 milligrams (mg) soft gelatin capsule orally once daily for up to 10 years from the date of enrollment in this study B3461023 (Fx1A-303) or until they had an access to tafamidis for ATTR-PN via prescription, upon regulatory approval in respective countries.

Arm type

Experimental

Investigational medicinal product name

Tafamidis

Investigational medicinal product code

PF-06291826

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Subjects received tafamidis at a dose of 20 mg, orally once daily.

Val30Met: Placebo Then Tafamidis

Arm description

Val30Met subjects who received placebo in study Fx-005 (B3461020) and assigned to receive tafamidis in study Fx-006 (B3461021) and study B3461023 (Fx1A-303), received tafamidis 20 mg soft gelatin capsule orally once daily for up to 10 years from the date of enrollment in this study B3461023 (Fx1A-303) or until they had an access to tafamidis for ATTR-PN via prescription, upon regulatory approval in respective countries.

Arm type

Experimental

Investigational medicinal product name

Tafamidis

Investigational medicinal product code

PF-06291826

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Subjects received tafamidis at a dose of 20 mg, orally once daily.

NonVal30Met: Tafamidis

Arm description

NonVal30Met subjects who received tafamidis in study Fx1A-201 (B3461022), received tafamidis 20 mg soft gelatin capsule orally once daily for up to 10 years from the date of enrollment in this study B3461023 (Fx1A-303) or until they had an access to tafamidis for ATTR-PN via prescription, upon regulatory approval in respective countries.

Arm type

Experimental

Investigational medicinal product name

Tafamidis

Investigational medicinal product code

PF-06291826

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Subjects received tafamidis at a dose of 20 mg, orally once daily.

Number of subjects in period 1	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Started	38	37	18
Treated	38	37	18
Completed	32	28	8
Not completed	6	9	10
Adverse event, serious fatal	1	1	5
Subject withdrew consent	1	3	3
Adverse event, non-fatal	3	1	2
Unspecified	1	4	-

Baseline characteristics

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Reporting group title

Val30Met: Tafamidis Then Tafamidis

Reporting group description

Reporting group title

Val30Met: Placebo Then Tafamidis

Reporting group description

Reporting group title

NonVal30Met: Tafamidis

Reporting group description

Reporting group values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis	Total
Number of subjects	38	37	18	93
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	33	34	9	76
From 65-84 years	5	3	9	17
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	40.7 ± 14.03	38.6 ± 13.76	63.6 ± 9.15	-
Sex: Female, Male
Units: Subjects
Female	20	21	6	47
Male	18	16	12	46
Race/Ethnicity, Customized
Units: Subjects
Caucasian	33	34	17	84
Latino American	5	3	0	8
Afro-Caribbean	0	0	1	1

End points

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Reporting group title

Val30Met: Tafamidis Then Tafamidis

Reporting group description

Reporting group title

Val30Met: Placebo Then Tafamidis

Reporting group description

Reporting group title

NonVal30Met: Tafamidis

Reporting group description

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

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End point title

Val30Met Group: Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Baseline ^[1] ^[2]

End point description

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

End point type

Primary

End point timeframe

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

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
arithmetic mean (standard deviation)	6.8 ± 10.8	11.6 ± 14.1

No statistical analyses for this end point

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

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End point title

Val30Met Group: Change From B3461020 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 30 ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

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

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	36
Units: units on a scale
least squares mean (standard error)	3.8 ± 1.5	6.4 ± 1.6

No statistical analyses for this end point

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

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End point title

Val30Met Group: Change From B3461020 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 66 ^[5] ^[6]

End point description

End point type

Primary

End point timeframe

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

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	34	31
Units: units on a scale
least squares mean (standard error)	7.8 ± 1.6	11.3 ± 1.6

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Baseline ^[7] ^[8]

End point description

End point type

Primary

End point timeframe

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

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
arithmetic mean (standard deviation)	31.1 ± 24.4

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 12 ^[9] ^[10]

End point description

End point type

Primary

End point timeframe

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

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)	2.5 ± 2.0

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in Neuropathy Impairment Score Lower Limb (NIS-LL) Score at Month 60 ^[11] ^[12]

End point description

End point type

Primary

End point timeframe

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

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	7
Units: units on a scale
least squares mean (standard error)	12.0 ± 2.7

No statistical analyses for this end point

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

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End point title

Val30Met Group: Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Baseline ^[13] ^[14]

End point description

Norfolk QOL-DN: 35-item subject-rated questionnaire; assessed impact of DN on health related QOL of subjects 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. ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "N" signifies subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline of B3461020 (Fx-005)

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	36
Units: units on a scale
arithmetic mean (standard deviation)	24.1 ± 26.3	29.9 ± 30.1

No statistical analyses for this end point

Primary: 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

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End point title

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 ^[15] ^[16]

End point description

End point type

Primary

End point timeframe

Baseline of B3461020 (Fx-005), Month 30

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	37	36
Units: units on a scale
least squares mean (standard error)	0.1 ± 3.3	4.5 ± 3.4

No statistical analyses for this end point

Primary: 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

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End point title

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 ^[17] ^[18]

End point description

End point type

Primary

End point timeframe

Baseline of B3461020 (Fx-005), Month 66

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	33	31
Units: units on a scale
least squares mean (standard error)	5.2 ± 3.4	5.3 ± 3.5

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Total Quality of Life (TQOL) Score Assessed Using Norfolk Quality of Life for Diabetic Neuropathy (QOL-DN) Questionnaire at Baseline ^[19] ^[20]

End point description

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201)

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
arithmetic mean (standard deviation)	53.9 ± 34.2

No statistical analyses for this end point

Primary: 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

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End point title

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 ^[21] ^[22]

End point description

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201), Month 12

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)	0.9 ± 5.7

No statistical analyses for this end point

Primary: 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

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End point title

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 ^[23] ^[24]

End point description

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201), Month 60

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	7
Units: units on a scale
least squares mean (standard error)	12.9 ± 7.4

No statistical analyses for this end point

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

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End point title

Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 30 ^[25] ^[26]

End point description

KPS:used for rating subject ADLs on 11-step scale from 0-100, higher score=subject 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 indicated, death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead. Lower the score worse is survival for most serious illnesses. Data for KPS score was not collected in parent studies Fx-005 and Fx-006, not reported for any time points from parent studies. ITT population was analysed. "N"=subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Month 30 (Baseline of B3461023)

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	37	36
Units: units on a scale
arithmetic mean (standard deviation)	83.8 ± 12.99	80.3 ± 11.83

No statistical analyses for this end point

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

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End point title

Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 66 ^[27] ^[28]

End point description

End point type

Primary

End point timeframe

Month 66 (Month 36 of B3461023)

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	34	31
Units: units on a scale
arithmetic mean (standard deviation)	85.9 ± 10.76	78.7 ± 17.65

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Karnofsky Performance Scale (KPS) Score at Baseline ^[29] ^[30]

End point description

KPS: used for rating subject ADLs. It rated subject on 11-step scale ranged from 0-100, higher score=subject 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. ITT population was analysed.

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201)

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
arithmetic mean (standard deviation)	72.2 ± 13.53

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 12 ^[31] ^[32]

End point description

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201), Month 12

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)	-3.1 ± 2.57

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 60 ^[33] ^[34]

End point description

KPS:used for rating subject ADLs. It rated subject on 11-step scale ranged from 0-100, higher score=subject 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. ITT population analysed. "N"=subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201), Month 60

Notes
[33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	7
Units: units on a scale
least squares mean (standard error)	-12.4 ± 3.73

No statistical analyses for this end point

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Baseline

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End point title

Val30Met Group: Number of Subjects by Ambulation Stage at Baseline ^[35] ^[36]

End point description

Ambulatory status for each Val30Met subject was collected using ambulatory data collection forms in [Fx-005 (B3461020), Fx-006 (B3461021)] or forms based on modified polyneuropathy disability (mPND) score in B3461023 (after protocol amendment 1.1). The data were categorised to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "N" signifies subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline of B3461020 (Fx-005)

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	37	36
Units: subjects
Stage 1 (Normal)	37	36
Stage 2 (Some assistance required)	0	0
Stage 3 (Not ambulatory)	0	0

No statistical analyses for this end point

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 30

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End point title

Val30Met Group: Number of Subjects by Ambulation Stage at Month 30 ^[37] ^[38]

End point description

Ambulatory status for each Val30Met subject was collected using ambulatory data collection forms in [Fx-005 (B3461020), Fx-006 (B3461021)] or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorised to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "N" signifies subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Month 30

Notes
[37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	36
Units: subjects
Stage 1 (Normal)	37	34
Stage 2 (Some assistance required)	0	1
Stage 3 (Not ambulatory)	1	1

No statistical analyses for this end point

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 66

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End point title

Val30Met Group: Number of Subjects by Ambulation Stage at Month 66 ^[39] ^[40]

End point description

End point type

Primary

End point timeframe

Month 66

Notes
[39] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	24	18
Units: subjects
Stage 1 (Normal)	22	15
Stage 2 (Some assistance required)	2	3
Stage 3 (Not ambulatory)	0	0

No statistical analyses for this end point

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Baseline

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End point title

NonVal30Met Group: Number of Subjects by Ambulation Stage at Baseline ^[41] ^[42]

End point description

End point type

Primary

End point timeframe

Baseline of B3461022 (Fx1A-201)

Notes
[41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	12
Units: subjects
Stage 1 (Normal)	7
Stage 2 (Some assistance required)	5
Stage 3 (Not ambulatory)	0

No statistical analyses for this end point

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 12

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End point title

NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 12 ^[43] ^[44]

End point description

End point type

Primary

End point timeframe

Month 12

Notes
[43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	13
Units: subjects
Stage 1 (Normal)	7
Stage 2 (Some assistance required)	5
Stage 3 (Not ambulatory)	1

No statistical analyses for this end point

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 60

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End point title

NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 60 ^[45] ^[46]

End point description

End point type

Primary

End point timeframe

Month 60

Notes
[45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive analysis was planned for this endpoint.
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	7
Units: subjects
Stage 1 (Normal)	1
Stage 2 (Some assistance required)	6
Stage 3 (Not ambulatory)	0

No statistical analyses for this end point

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

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End point title

Val30Met Group: Change From B3461020 Baseline in NIS-LL Score at Month 6, 12, 18, 24, 42, 54, 78, 90, 102, 114 and 126 ^[47]

End point description

End point type

Secondary

End point timeframe

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

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
least squares mean (standard error)
NIS-LL: Change at Month 6 (n= 38, 37)	1.4 ± 1.5	0.6 ± 1.5
NIS-LL: Change at Month 12 (n= 38, 37)	1.4 ± 1.5	3.6 ± 1.5
NIS-LL: Change at Month 18 (n= 38, 37)	2.6 ± 1.5	4.4 ± 1.5
NIS-LL: Change at Month 24 (n= 38, 37)	3.4 ± 1.5	6.1 ± 1.5
NIS-LL: Change at Month 42 (n= 37, 35)	4.5 ± 1.5	8.9 ± 1.6
NIS-LL: Change at Month 54 (n= 36, 34)	6.3 ± 1.5	8.6 ± 1.6
NIS-LL: Change at Month 78 (n= 9, 7)	14.8 ± 2.4	9.8 ± 2.6
NIS-LL: Change at Month 90 (n= 9, 6)	17.1 ± 2.4	8.6 ± 2.8
NIS-LL: Change at Month 102 (n= 6, 5)	26.0 ± 2.8	12.5 ± 3.0
NIS-LL: Change at Month 114 (n= 4, 4)	22.0 ± 3.3	14.2 ± 3.3
NIS-LL: Change at Month 126 (n= 2, 2)	36.4 ± 4.6	12.6 ± 4.6

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[48]

End point description

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. ITT population was analysed.

End point type

Secondary

End point timeframe

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

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
arithmetic mean (standard deviation)
NIS-LL MW: Baseline	2.1 ± 6.4	4.2 ± 9.6
NIS-LL MW-Hip: Baseline	0.2 ± 0.8	0.3 ± 1.1
NIS-LL MW-Knee: Baseline	0.2 ± 0.9	0.4 ± 1.5
NIS-LL MW-Ankle: Baseline	0.4 ± 1.5	1.3 ± 3.7
NIS-LL MW-Toe: Baseline	1.3 ± 3.6	2.2 ± 4.2
NIS-LL Reflexes: Baseline	0.8 ± 1.8	1.8 ± 2.4
NIS-LL Sensory: Baseline	3.9 ± 3.7	5.6 ± 3.8

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[49]

End point description

NIS-LL: a subscale (of 37-item NIS questionnaire) that provided a total neuropathic deficit score for the lower limbs. It assess MW, 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 MW (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 MW 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. ITT population was analysed. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
least squares mean (standard error)
NIS-LL MW: Change at Month 6 (n= 38, 37)	0.6 ± 1.2	0.5 ± 1.2
NIS-LL MW: Change at Month 12 (n= 38, 37)	0.8 ± 1.2	2.4 ± 1.2
NIS-LL MW: Change at Month 18 (n= 38, 37)	1.3 ± 1.2	3.1 ± 1.2
NIS-LL MW: Change at Month 24 (n= 38, 37)	1.5 ± 1.2	4.0 ± 1.2
NIS-LL MW: Change at Month 30 (n= 38, 36)	2.5 ± 1.2	4.4 ± 1.2
NIS-LL MW: Change at Month 42 (n= 37, 35)	2.1 ± 1.2	6.3 ± 1.2
NIS-LL MW: Change at Month 54 (n= 36, 34)	3.1 ± 1.2	5.7 ± 1.2
NIS-LL MW: Change at Month 66 (n= 34, 31)	4.2 ± 1.2	7.4 ± 1.2
NIS-LL MW: Change at Month 78 (n= 9, 7)	8.7 ± 1.9	6.9 ± 2.1
NIS-LL MW: Change at Month 90 (n= 9, 6)	11.0 ± 1.9	5.4 ± 2.2
NIS-LL MW: Change at Month 102 (n= 6, 5)	18.2 ± 2.2	7.5 ± 2.4
NIS-LL MW: Change at Month 114 (n= 4, 4)	13.1 ± 2.6	9.1 ± 2.6
NIS-LL MW: Change at Month 126 (n= 2, 2)	27.9 ± 3.6	10.0 ± 3.6
NIS-LL MW-Hip: Change at Month 6 (n= 38, 37)	0.2 ± 0.3	-0.1 ± 0.3
NIS-LL MW-Hip: Change at Month 12 (n= 38, 37)	0.2 ± 0.3	0.3 ± 0.3
NIS-LL MW-Hip: Change at Month 18 (n= 38, 37)	0.3 ± 0.3	0.3 ± 0.3
NIS-LL MW-Hip: Change at Month 24 (n= 38, 37)	0.4 ± 0.3	0.4 ± 0.3
NIS-LL MW-Hip: Change at Month 30 (n= 38, 36)	0.7 ± 0.3	0.7 ± 0.3
NIS-LL MW-Hip: Change at Month 42 (n= 37, 35)	0.4 ± 0.3	0.7 ± 0.3
NIS-LL MW-Hip: Change at Month 54 (n= 36, 34)	0.5 ± 0.3	0.4 ± 0.3
NIS-LL MW-Hip: Change at Month 66 (n= 34, 31)	0.5 ± 0.3	0.5 ± 0.3
NIS-LL MW-Hip: Change at Month 78 (n= 9, 7)	0.7 ± 0.5	0.1 ± 0.5
NIS-LL MW-Hip: Change at Month 90 (n= 9, 6)	0.9 ± 0.5	0.0 ± 0.6
NIS-LL MW-Hip: Change at Month 102 (n= 6, 5)	2.1 ± 0.6	0.0 ± 0.6
NIS-LL MW-Hip: Change at Month 114 (n= 4, 4)	0.4 ± 0.7	0.9 ± 0.7
NIS-LL MW-Hip: Change at Month 126 (n= 2, 2)	2.3 ± 0.9	2.2 ± 0.9
NIS-LL MW-Knee: Change at Month 6 (n= 38, 37)	0.1 ± 0.3	0.1 ± 0.3
NIS-LL MW-Knee: Change at Month 12 (n= 38, 37)	0.1 ± 0.3	0.4 ± 0.3
NIS-LL MW-Knee: Change at Month 18 (n= 38, 37)	0.2 ± 0.3	0.6 ± 0.3
NIS-LL MW-Knee: Change at Month 24 (n= 38, 37)	0.3 ± 0.3	0.4 ± 0.3
NIS-LL MW-Knee: Change at Month 30 (n= 38, 36)	0.6 ± 0.3	0.6 ± 0.3
NIS-LL MW-Knee: Change at Month 42 (n= 37, 35)	0.4 ± 0.3	0.7 ± 0.3
NIS-LL MW-Knee: Change at Month 54 (n= 36, 34)	0.5 ± 0.3	0.4 ± 0.3
NIS-LL MW-Knee: Change at Month 66 (n= 34, 31)	0.4 ± 0.3	0.7 ± 0.3
NIS-LL MW-Knee: Change at Month 78 (n= 9, 7)	0.5 ± 0.5	1.0 ± 0.5
NIS-LL MW-Knee: Change at Month 90 (n= 9, 6)	1.6 ± 0.5	0.5 ± 0.6
NIS-LL MW-Knee: Change at Month 102 (n= 6, 5)	5.1 ± 0.5	1.1 ± 0.6
NIS-LL MW-Knee: Change at Month 114 (n= 4, 4)	0.4 ± 0.7	1.4 ± 0.7
NIS-LL MW-Knee: Change at Month 126 (n= 2, 2)	3.2 ± 0.9	3.7 ± 0.9
NIS-LL MW-Ankle: Change at Month 6 (n= 38, 37)	0.2 ± 0.5	0.3 ± 0.5
NIS-LL MW-Ankle: Change at Month 12 (n= 38, 37)	0.4 ± 0.5	0.7 ± 0.5
NIS-LL MW-Ankle: Change at Month 18 (n= 38, 37)	0.5 ± 0.5	1.1 ± 0.5
NIS-LL MW-Ankle: Change at Month 24 (n= 38, 37)	0.5 ± 0.5	1.6 ± 0.5
NIS-LL MW-Ankle: Change at Month 30 (n= 38, 36)	0.8 ± 0.5	1.4 ± 0.5
NIS-LL MW-Ankle: Change at Month 42 (n= 37, 35)	0.8 ± 0.5	2.3 ± 0.5
NIS-LL MW-Ankle: Change at Month 54 (n= 36, 34)	1.2 ± 0.5	2.0 ± 0.5
NIS-LL MW-Ankle: Change at Month 66 (n= 34, 31)	1.6 ± 0.5	2.8 ± 0.5
NIS-LL MW-Ankle: Change at Month 78 (n= 9, 7)	3.5 ± 0.7	2.5 ± 0.8
NIS-LL MW-Ankle: Change at Month 90 (n= 9, 6)	3.9 ± 0.7	2.6 ± 0.9
NIS-LL MW-Ankle: Change at Month 102 (n= 6, 5)	5.8 ± 0.9	3.2 ± 1.0
NIS-LL MW-Ankle: Change at Month 114 (n= 4, 4)	5.1 ± 1.0	3.7 ± 1.1
NIS-LL MW-Ankle: Change at Month 126 (n= 2, 2)	10.8 ± 1.4	2.1 ± 1.4
NIS-LL MW-Toe: Change at Month 6 (n= 38, 37)	-0.1 ± 0.5	0.3 ± 0.5
NIS-LL MW-Toe: Change at Month 12 (n= 38, 37)	-0.1 ± 0.5	1.2 ± 0.5
NIS-LL MW-Toe: Change at Month 18 (n= 38, 37)	0.2 ± 0.5	1.3 ± 0.5
NIS-LL MW-Toe: Change at Month 24 (n= 38, 37)	0.1 ± 0.5	1.8 ± 0.5
NIS-LL MW-Toe: Change at Month 30 (n= 38, 36)	0.3 ± 0.5	1.9 ± 0.5
NIS-LL MW-Toe: Change at Month 42 (n= 37, 35)	0.3 ± 0.5	2.7 ± 0.5
NIS-LL MW-Toe: Change at Month 54 (n= 36, 34)	0.6 ± 0.5	2.9 ± 0.5
NIS-LL MW-Toe: Change at Month 66 (n= 34, 31)	1.5 ± 0.5	3.6 ± 0.5
NIS-LL MW-Toe: Change at Month 78 (n= 9, 7)	3.9 ± 0.8	3.5 ± 0.9
NIS-LL MW-Toe: Change at Month 90 (n= 9, 6)	4.5 ± 0.8	2.5 ± 1.0
NIS-LL MW-Toe: Change at Month 102 (n= 6, 5)	5.1 ± 0.9	3.4 ± 1.0
NIS-LL MW-Toe: Change at Month 114 (n= 4, 4)	7.0 ± 1.1	3.3 ± 1.1
NIS-LL MW-Toe: Change at Month 126 (n= 2, 2)	11.4 ± 1.5	2.4 ± 1.5
NIS-LL Reflexes: Change at Month 6 (n= 38, 37)	0.2 ± 0.2	0.1 ± 0.2
NIS-LL Reflexes: Change at Month 12 (n= 38, 37)	0.4 ± 0.2	0.5 ± 0.2
NIS-LL Reflexes: Change at Month 18 (n= 38, 37)	0.4 ± 0.2	0.5 ± 0.2
NIS-LL Reflexes: Change at Month 24 (n= 38, 37)	0.7 ± 0.2	0.9 ± 0.2
NIS-LL Reflexes: Change at Month 30 (n= 38, 36)	0.5 ± 0.2	0.7 ± 0.2
NIS-LL Reflexes: Change at Month 42 (n= 37, 35)	0.7 ± 0.2	1.0 ± 0.2
NIS-LL Reflexes: Change at Month 54 (n= 36, 34)	0.9 ± 0.2	1.2 ± 0.2
NIS-LL Reflexes: Change at Month 66 (n= 34, 31)	1.1 ± 0.2	1.4 ± 0.2
NIS-LL Reflexes: Change at Month 78 (n= 9, 7)	1.5 ± 0.4	1.3 ± 0.4
NIS-LL Reflexes: Change at Month 90 (n= 9, 6)	1.4 ± 0.4	0.7 ± 0.5
NIS-LL Reflexes: Change at Month 102 (n= 6, 5)	2.0 ± 0.5	1.5 ± 0.5
NIS-LL Reflexes: Change at Month 114 (n= 4, 4)	3.0 ± 0.6	2.9 ± 0.6
NIS-LL Reflexes: Change at Month 126 (n= 2, 2)	3.6 ± 0.8	1.1 ± 0.8
NIS-LL Sensory: Change at Month 6 (n= 38, 37)	0.4 ± 0.5	0.4 ± 0.5
NIS-LL Sensory: Change at Month 12 (n= 38, 37)	-0.1 ± 0.5	1.1 ± 0.5
NIS-LL Sensory: Change at Month 18 (n= 38, 37)	0.6 ± 0.5	1.3 ± 0.5
NIS-LL Sensory: Change at Month 24 (n= 38, 37)	0.9 ± 0.5	1.6 ± 0.5
NIS-LL Sensory: Change at Month 30 (n= 38, 36)	0.5 ± 0.5	1.7 ± 0.5
NIS-LL Sensory: Change at Month 42 (n= 37, 35)	1.4 ± 0.5	2.0 ± 0.5
NIS-LL Sensory: Change at Month 54 (n= 36, 34)	2.0 ± 0.5	2.1 ± 0.6
NIS-LL Sensory: Change at Month 66 (n= 34, 31)	2.2 ± 0.5	2.9 ± 0.6
NIS-LL Sensory: Change at Month 78 (n= 9, 7)	4.3 ± 0.8	1.9 ± 0.9
NIS-LL Sensory: Change at Month 90 (n= 9, 6)	4.5 ± 0.8	2.8 ± 0.9
NIS-LL Sensory: Change at Month 102 (n= 6, 5)	5.5 ± 0.9	3.9 ± 1.0
NIS-LL Sensory: Change at Month 114 (n= 4, 4)	5.4 ± 1.1	2.6 ± 1.1
NIS-LL Sensory: Change at Month 126 (n= 2, 2)	4.6 ± 1.5	1.8 ± 1.5

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in NIS-LL Score at Month 6, 24, 36, 48, 72, 84, 96, 108 and 120 ^[50]

End point description

End point type

Secondary

End point timeframe

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

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)
NIS-LL: Change at Month 6 (n= 18)	-0.7 ± 2.0
NIS-LL: Change at Month 24 (n= 18)	6.6 ± 2.0
NIS-LL: Change at Month 36 (n= 11)	10.9 ± 2.3
NIS-LL: Change at Month 48 (n= 10)	12.3 ± 2.4
NIS-LL: Change at Month 72 (n= 3)	14.6 ± 3.7
NIS-LL: Change at Month 84 (n= 2)	10.4 ± 4.4
NIS-LL: Change at Month 96 (n= 2)	13.9 ± 4.4
NIS-LL: Change at Month 108 (n= 2)	12.9 ± 4.4
NIS-LL: Change at Month 120 (n= 2)	13.9 ± 4.4

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[51]

End point description

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. ITT population was analysed.

End point type

Secondary

End point timeframe

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

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
arithmetic mean (standard deviation)
NIS-LL MW: Baseline	16.6 ± 16.9
NIS-LL MW-Hip: Baseline	1.6 ± 2.4
NIS-LL MW-Knee: Baseline	2.5 ± 3.8
NIS-LL MW-Ankle: Baseline	5.5 ± 6.0
NIS-LL MW-Toe: Baseline	6.9 ± 6.6
NIS-LL Reflexes: Baseline	5.6 ± 3.4
NIS-LL Sensory: Baseline	8.9 ± 5.4

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[52]

End point description

End point type

Secondary

End point timeframe

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

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)
NIS-LL MW: Change at Month 6 (n= 18)	-0.4 ± 1.5
NIS-LL MW: Change at Month 12 (n= 18)	2.3 ± 1.5
NIS-LL MW: Change at Month 24 (n= 18)	5.1 ± 1.5
NIS-LL MW: Change at Month 36 (n= 11)	7.3 ± 1.8
NIS-LL MW: Change at Month 48 (n= 10)	9.7 ± 1.9
NIS-LL MW: Change at Month 60 (n= 7)	8.0 ± 2.1
NIS-LL MW: Change at Month 72 (n= 3)	8.1 ± 3.0
NIS-LL MW: Change at Month 84 (n= 2)	5.7 ± 3.6
NIS-LL MW: Change at Month 96 (n= 2)	5.2 ± 3.6
NIS-LL MW: Change at Month 108 (n= 2)	6.2 ± 3.6
NIS-LL MW: Change at Month 120 (n= 2)	10.2 ± 3.6
NIS-LL MW-Hip: Change at Month 6 (n= 18)	-0.3 ± 0.6
NIS-LL MW-Hip: Change at Month 12 (n= 18)	0.6 ± 0.6
NIS-LL MW-Hip: Change at Month 24 (n= 18)	1.1 ± 0.6
NIS-LL MW-Hip: Change at Month 36 (n= 11)	0.9 ± 0.6
NIS-LL MW-Hip: Change at Month 48 (n= 10)	1.3 ± 0.6
NIS-LL MW-Hip: Change at Month 60 (n= 7)	0.0 ± 0.7
NIS-LL MW-Hip: Change at Month 72 (n= 3)	0.4 ± 0.9
NIS-LL MW-Hip: Change at Month 84 (n= 2)	1.4 ± 1.0
NIS-LL MW-Hip: Change at Month 96 (n= 2)	0.4 ± 1.0
NIS-LL MW-Hip: Change at Month 108 (n= 2)	0.4 ± 1.0
NIS-LL MW-Hip: Change at Month 120 (n= 2)	1.9 ± 1.0
NIS-LL MW-Knee: Change at Month 6 (n= 18)	0.0 ± 0.7
NIS-LL MW-Knee: Change at Month 12 (n= 18)	0.6 ± 0.7
NIS-LL MW-Knee: Change at Month 24 (n= 18)	1.3 ± 0.7
NIS-LL MW-Knee: Change at Month 36 (n= 11)	1.3 ± 0.8
NIS-LL MW-Knee: Change at Month 48 (n= 10)	1.8 ± 0.8
NIS-LL MW-Knee: Change at Month 60 (n= 7)	-0.2 ± 0.9
NIS-LL MW-Knee: Change at Month 72 (n= 3)	1.3 ± 1.1
NIS-LL MW-Knee: Change at Month 84 (n= 2)	0.7 ± 1.3
NIS-LL MW-Knee: Change at Month 96 (n= 2)	0.7 ± 1.3
NIS-LL MW-Knee: Change at Month 108 (n= 2)	0.7 ± 1.3
NIS-LL MW-Knee: Change at Month 120 (n= 2)	0.7 ± 1.3
NIS-LL MW-Ankle: Change at Month 6 (n= 18)	-0.2 ± 0.6
NIS-LL MW-Ankle: Change at Month 12 (n= 18)	0.7 ± 0.6
NIS-LL MW-Ankle: Change at Month 24 (n= 18)	1.5 ± 0.6
NIS-LL MW-Ankle: Change at Month 36 (n= 11)	2.7 ± 0.7
NIS-LL MW-Ankle: Change at Month 48 (n= 10)	3.3 ± 0.7
NIS-LL MW-Ankle: Change at Month 60 (n= 7)	4.6 ± 0.8
NIS-LL MW-Ankle: Change at Month 72 (n= 3)	2.8 ± 1.2
NIS-LL MW-Ankle: Change at Month 84 (n= 2)	2.0 ± 1.4
NIS-LL MW-Ankle: Change at Month 96 (n= 2)	2.0 ± 1.4
NIS-LL MW-Ankle: Change at Month 108 (n= 2)	2.0 ± 1.4
NIS-LL MW-Ankle: Change at Month 120 (n= 2)	2.0 ± 1.4
NIS-LL MW-Toe: Change at Month 6 (n= 18)	0.5 ± 0.7
NIS-LL MW-Toe: Change at Month 12 (n= 18)	0.8 ± 0.7
NIS-LL MW-Toe: Change at Month 24 (n= 18)	1.5 ± 0.7
NIS-LL MW-Toe: Change at Month 36 (n= 11)	2.6 ± 0.8
NIS-LL MW-Toe: Change at Month 48 (n= 10)	3.5 ± 0.8
NIS-LL MW-Toe: Change at Month 60 (n= 7)	3.9 ± 0.9
NIS-LL MW-Toe: Change at Month 72 (n= 3)	3.8 ± 1.3
NIS-LL MW-Toe: Change at Month 84 (n= 2)	1.7 ± 1.6
NIS-LL MW-Toe: Change at Month 96 (n= 2)	2.2 ± 1.6
NIS-LL MW-Toe: Change at Month 108 (n= 2)	3.2 ± 1.6
NIS-LL MW-Toe: Change at Month 120 (n= 2)	5.7 ± 1.6
NIS-LL Reflexes: Change at Month 6 (n= 18)	-0.1 ± 0.4
NIS-LL Reflexes: Change at Month 12 (n= 18)	-0.2 ± 0.4
NIS-LL Reflexes: Change at Month 24 (n= 18)	0.8 ± 0.4
NIS-LL Reflexes: Change at Month 36 (n= 11)	1.6 ± 0.5
NIS-LL Reflexes: Change at Month 48 (n= 10)	1.1 ± 0.5
NIS-LL Reflexes: Change at Month 60 (n= 7)	0.7 ± 0.6
NIS-LL Reflexes: Change at Month 72 (n= 3)	2.3 ± 0.9
NIS-LL Reflexes: Change at Month 84 (n= 2)	1.8 ± 1.1
NIS-LL Reflexes: Change at Month 96 (n= 2)	2.3 ± 1.1
NIS-LL Reflexes: Change at Month 108 (n= 2)	2.3 ± 1.1
NIS-LL Reflexes: Change at Month 120 (n= 2)	-2.2 ± 1.1
NIS-LL Sensory: Change at Month 6 (n= 18)	-0.1 ± 0.7
NIS-LL Sensory: Change at Month 12 (n= 18)	0.4 ± 0.7
NIS-LL Sensory: Change at Month 24 (n= 18)	0.9 ± 0.7
NIS-LL Sensory: Change at Month 36 (n= 11)	2.1 ± 0.8
NIS-LL Sensory: Change at Month 48 (n= 10)	1.7 ± 0.8
NIS-LL Sensory: Change at Month 60 (n= 7)	3.4 ± 0.9
NIS-LL Sensory: Change at Month 72 (n= 3)	4.2 ± 1.2
NIS-LL Sensory: Change at Month 84 (n= 2)	2.9 ± 1.4
NIS-LL Sensory: Change at Month 96 (n= 2)	6.4 ± 1.4
NIS-LL Sensory: Change at Month 108 (n= 2)	4.4 ± 1.4
NIS-LL Sensory: Change at Month 120 (n= 2)	5.9 ± 1.4

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[53]

End point description

Norfolk QOL-DN: 35-item subject-rated questionnaire; assessed impact of DN on health related QOL of subjects 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. ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
least squares mean (standard error)
TQOL: Change at Month 6 (n= 38, 36)	-2.2 ± 3.3	-0.5 ± 3.4
TQOL: Change at Month 12 (n= 38, 36)	-2.8 ± 3.3	5.4 ± 3.4
TQOL: Change at Month 18 (n= 38, 36)	-2.3 ± 3.3	6.4 ± 3.4
TQOL: Change at Month 24 (n= 38, 36)	-3.2 ± 3.3	2.0 ± 3.4
TQOL: Change at Month 42 (n= 36, 33)	3.2 ± 3.3	1.8 ± 3.4
TQOL: Change at Month 54 (n= 36, 33)	3.0 ± 3.3	2.1 ± 3.4
TQOL: Change at Month 78 (n= 9, 6)	7.0 ± 4.8	-3.9 ± 5.6
TQOL: Change at Month 90 (n= 7, 5)	3.2 ± 5.2	-2.0 ± 6.0
TQOL: Change at Month 102 (n= 5, 4)	15.8 ± 5.9	-7.3 ± 6.5
TQOL: Change at Month 114 (n= 4, 4)	18.9 ± 6.5	-9.0 ± 6.5
TQOL: Change at Month 126 (n= 2, 2)	48.1 ± 8.7	2.0 ± 8.7
TQOL: Change at Month 138 (n= 1, 1)	55.4 ± 12.0	26.0 ± 12.0

No statistical analyses for this end point

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

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End point title

Val30Met Group: TQOL Subscale Scores: Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Baseline ^[54]

End point description

Norfolk QOL-DN: 35-item subject-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 summarised in 5 domains (score range): physical functioning/large fiber neuropathy (PF/LFN) (-2 to 58), activities of daily living (ADLs) (0 to 20), symptoms (0 to 32), small fiber neuropathy (SFN) (0 to 16), autonomic neuropathy (AN) (0 to 12); higher score=greater impairment, for each. Total score= -2 to 138 (higher score=worse QOL). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline of B3461020 (Fx-005)

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
arithmetic mean (standard deviation)
Symptom: Baseline (n= 38, 36)	6.4 ± 5.4	6.8 ± 6.5
ADLs: Baseline (n= 38, 36)	1.4 ± 3.5	1.9 ± 4.6
PF/LFN: Baseline (n= 38, 36)	12.4 ± 14.4	15.9 ± 15.9
SFN: Baseline (n= 38, 36)	1.8 ± 3.2	3.1 ± 4.2
AN: Baseline (n= 38, 36)	2.1 ± 2.8	2.2 ± 2.8

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[55]

End point description

End point type

Secondary

End point timeframe

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

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
least squares mean (standard error)
Symptom: Change at Month 6 (n= 38, 36)	-0.2 ± 0.8	-0.1 ± 0.8
Symptom: Change at Month 12 (n= 38, 36)	-0.9 ± 0.8	1.5 ± 0.8
Symptom: Change at Month 18 (n= 38, 36)	-1.1 ± 0.8	0.6 ± 0.8
Symptom: Change at Month 24 (n= 37, 36)	-1.1 ± 0.8	0.1 ± 0.8
Symptom: Change at Month 30 (n= 37, 36)	-1.4 ± 0.8	-0.7 ± 0.8
Symptom: Change at Month 42 (n= 36, 33)	-0.4 ± 0.8	-0.9 ± 0.8
Symptom: Change at Month 54 (n= 36, 33)	-0.3 ± 0.8	0.2 ± 0.8
Symptom: Change at Month 66 (n= 33, 31)	0.6 ± 0.8	-0.4 ± 0.8
Symptom: Change at Month 78 (n= 9, 6)	0.0 ± 1.2	-2.8 ± 1.5
Symptom: Change at Month 90 (n= 7, 5)	1.0 ± 1.4	-2.0 ± 1.6
Symptom: Change at Month 102 (n= 5, 4)	-0.7 ± 1.6	-2.8 ± 1.7
Symptom: Change at Month 114 (n= 4, 4)	1.9 ± 1.7	-3.5 ± 1.7
Symptom: Change at Month 126 (n= 2, 2)	5.7 ± 2.4	-1.3 ± 2.4
Symptom: Change at Month 138 (n= 1, 1)	4.1 ± 3.3	3.9 ± 3.3
ADLs: Change at Month 6 (n= 38, 36)	0.0 ± 0.6	0.2 ± 0.6
ADLs: Change at Month 12 (n= 38, 36)	0.7 ± 0.6	0.9 ± 0.6
ADLs: Change at Month 18 (n= 38, 36)	1.0 ± 0.6	1.3 ± 0.6
ADLs: Change at Month 24 (n= 38, 36)	0.7 ± 0.6	1.0 ± 0.6
ADLs: Change at Month 30 (n= 37, 36)	1.1 ± 0.6	1.2 ± 0.6
ADLs: Change at Month 42 (n= 36, 33)	1.5 ± 0.6	1.4 ± 0.6
ADLs: Change at Month 54 (n= 36, 33)	0.9 ± 0.6	1.1 ± 0.6
ADLs: Change at Month 66 (n= 33, 31)	1.5 ± 0.6	2.0 ± 0.6
ADLs: Change at Month 78 (n= 9, 6)	2.3 ± 0.9	1.2 ± 1.0
ADLs: Change at Month 90 (n= 7, 5)	1.7 ± 0.9	0.6 ± 1.1
ADLs: Change at Month 102 (n= 5, 4)	5.6 ± 1.1	-0.8 ± 1.2
ADLs: Change at Month 114 (n= 4, 4)	5.6 ± 1.2	-0.3 ± 1.2
ADLs: Change at Month 126 (n= 2, 2)	7.5 ± 1.6	1.5 ± 1.6
ADLs: Change at Month 138 (n= 1, 1)	12.8 ± 2.2	7.2 ± 2.2
PF/LFN: Change at Month 6 (n= 38, 36)	-2.3 ± 1.7	-1.0 ± 1.7
PF/LFN: Change at Month 12 (n= 38, 36)	-2.9 ± 1.7	1.0 ± 1.7
PF/LFN: Change at Month 18 (n= 38, 36)	-2.7 ± 1.7	2.7 ± 1.7
PF/LFN: Change at Month 24 (n= 38, 36)	-3.2 ± 1.7	-0.5 ± 1.7
PF/LFN: Change at Month 30 (n= 37, 36)	-1.0 ± 1.7	1.9 ± 1.7
PF/LFN: Change at Month 42 (n= 36, 33)	0.6 ± 1.7	-0.1 ± 1.8
PF/LFN: Change at Month 54 (n= 36, 33)	0.8 ± 1.7	-0.4 ± 1.8
PF/LFN: Change at Month 66 (n= 33, 31)	1.3 ± 1.7	2.1 ± 1.8
PF/LFN: Change at Month 78 (n= 9, 6)	2.6 ± 2.5	-2.6 ± 2.9
PF/LFN: Change at Month 90 (n= 7, 5)	-0.7 ± 2.8	0.1 ± 3.2
PF/LFN: Change at Month 102 (n= 5, 4)	7.0 ± 3.1	-3.6 ± 3.5
PF/LFN: Change at Month 114 (n= 4, 4)	7.2 ± 3.5	-4.1 ± 3.5
PF/LFN: Change at Month 126 (n= 2, 2)	24.8 ± 4.7	1.8 ± 4.7
PF/LFN: Change at Month 138 (n= 1, 1)	24.7 ± 6.5	8.9 ± 6.5
SFN: Change at Month 6 (n= 38, 36)	0.2 ± 0.5	0.5 ± 0.5
SFN: Change at Month 12 (n= 38, 36)	0.5 ± 0.5	1.8 ± 0.5
SFN: Change at Month 18 (n= 38, 36)	0.4 ± 0.5	1.5 ± 0.5
SFN: Change at Month 24 (n= 38, 36)	0.3 ± 0.5	1.6 ± 0.5
SFN: Change at Month 30 (n= 37, 36)	1.1 ± 0.5	2.0 ± 0.5
SFN: Change at Month 42 (n= 36, 33)	1.7 ± 0.5	2.2 ± 0.5
SFN: Change at Month 54 (n= 36, 33)	1.9 ± 0.5	1.6 ± 0.5
SFN: Change at Month 66 (n= 33, 31)	1.9 ± 0.5	1.8 ± 0.5
SFN: Change at Month 78 (n= 9, 6)	1.9 ± 0.8	1.3 ± 0.9
SFN: Change at Month 90 (n= 7, 5)	1.7 ± 0.9	1.1 ± 1.0
SFN: Change at Month 102 (n= 5, 4)	3.0 ± 1.0	1.2 ± 1.1
SFN: Change at Month 114 (n= 4, 4)	2.8 ± 1.1	1.2 ± 1.1
SFN: Change at Month 126 (n= 2, 2)	8.3 ± 1.4	1.1 ± 1.5
SFN: Change at Month 138 (n= 1, 1)	11.8 ± 2.0	6.8 ± 2.0
AN: Change at Month 6 (n= 38, 36)	-0.1 ± 0.3	0.0 ± 0.4
AN: Change at Month 12 (n= 38, 36)	-0.3 ± 0.3	0.3 ± 0.4
AN: Change at Month 18 (n= 38, 36)	0.0 ± 0.3	0.5 ± 0.4
AN: Change at Month 24 (n= 38, 36)	-0.2 ± 0.3	0.0 ± 0.4
AN: Change at Month 30 (n= 37, 36)	0.2 ± 0.3	0.2 ± 0.4
AN: Change at Month 42 (n= 36, 33)	-0.3 ± 0.3	-0.7 ± 0.4
AN: Change at Month 54 (n= 36, 33)	-0.5 ± 0.3	-0.4 ± 0.4
AN: Change at Month 66 (n= 33, 31)	-0.3 ± 0.4	-0.3 ± 0.4
AN: Change at Month 78 (n= 9, 6)	0.1 ± 0.6	-1.1 ± 0.7
AN: Change at Month 90 (n= 7, 5)	-0.6 ± 0.6	-1.9 ± 0.7
AN: Change at Month 102 (n= 5, 4)	0.8 ± 0.7	-1.4 ± 0.8
AN: Change at Month 114 (n= 4, 4)	1.2 ± 0.8	-2.4 ± 0.8
AN: Change at Month 126 (n= 2, 2)	1.6 ± 1.1	-1.2 ± 1.1
AN: Change at Month 138 (n= 1, 1)	1.9 ± 1.5	-0.7 ± 1.5

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[56]

End point description

Norfolk QOL-DN: 35-item subject-rated questionnaire; assessed impact of DN on health related QOL of subjects 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. ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)
TQOL: Change at Month 6 (n= 17)	-4.0 ± 5.8
TQOL: Change at Month 24 (n= 18)	4.0 ± 5.7
TQOL: Change at Month 36 (n= 12)	15.8 ± 6.3
TQOL: Change at Month 48 (n= 9)	15.5 ± 6.9
TQOL: Change at Month 72 (n= 3)	16.2 ± 10.1
TQOL: Change at Month 84 (n= 2)	9.5 ± 11.9
TQOL: Change at Month 96 (n= 2)	11.5 ± 11.9
TQOL: Change at Month 108 (n= 2)	22.0 ± 11.9
TQOL: Change at Month 120 (n= 2)	28.5 ± 11.9

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: TQOL Subscale Scores: Symptom, ADLs, Physical Functioning/Large Fiber Neuropathy, Small Fiber Neuropathy, Autonomic Neuropathy Assessed Using Norfolk QOL-DN at Baseline ^[57]

End point description

Norfolk QOL-DN: 35-item subject-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 summarised 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). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure.

End point type

Secondary

End point timeframe

Baseline of B3461022 (Fx1A-201)

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
arithmetic mean (standard deviation)
Symptom: Baseline	10.3 ± 7.3
ADLs: Baseline	8.4 ± 6.9
PF/LFN: Baseline	28.7 ± 18.1
SFN: Baseline	4.5 ± 5.0
AN: Baseline	2.0 ± 2.1

No statistical analyses for this end point

Secondary: 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

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End point title

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 ^[58]

End point description

Norfolk QOL-DN: 35-item subject-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 summarised 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). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)
Symptom: Change at Month 6 (n= 17)	-0.8 ± 1.1
Symptom: Change at Month 12 (n= 18)	0.0 ± 1.1
Symptom: Change at Month 24 (n= 16)	-0.1 ± 1.1
Symptom: Change at Month 36 (n= 10)	2.9 ± 1.3
Symptom: Change at Month 48 (n= 9)	4.1 ± 1.3
Symptom: Change at Month 60 (n= 7)	2.6 ± 1.4
Symptom: Change at Month 72 (n= 3)	2.5 ± 1.9
Symptom: Change at Month 84 (n= 2)	0.5 ± 2.3
Symptom: Change at Month 96 (n= 2)	1.0 ± 2.3
Symptom: Change at Month 108 (n= 2)	2.5 ± 2.3
Symptom: Change at Month 120 (n= 2)	-0.5 ± 2.3
ADLs: Change at Month 6 (n= 17)	0.1 ± 1.1
ADLs: Change at Month 12 (n= 18)	1.1 ± 1.1
ADLs: Change at Month 24 (n= 18)	1.8 ± 1.1
ADLs: Change at Month 36 (n= 12)	3.5 ± 1.2
ADLs: Change at Month 48 (n= 9)	3.5 ± 1.3
ADLs: Change at Month 60 (n= 7)	3.1 ± 1.4
ADLs: Change at Month 72 (n= 3)	3.4 ± 1.9
ADLs: Change at Month 84 (n= 2)	3.2 ± 2.3
ADLs: Change at Month 96 (n= 2)	3.2 ± 2.3
ADLs: Change at Month 108 (n= 2)	4.2 ± 2.3
ADLs: Change at Month 120 (n= 2)	8.2 ± 2.3
PF/LFN: Change at Month 6 (n= 17)	-2.1 ± 3.4
PF/LFN: Change at Month 12 (n= 18)	-0.6 ± 3.3
PF/LFN: Change at Month 24 (n= 18)	0.6 ± 3.3
PF/LFN: Change at Month 36 (n= 12)	7.1 ± 3.7
PF/LFN: Change at Month 48 (n= 9)	5.8 ± 4.0
PF/LFN: Change at Month 60 (n= 7)	5.5 ± 4.3
PF/LFN: Change at Month 72 (n= 3)	4.5 ± 5.8
PF/LFN: Change at Month 84 (n= 2)	2.9 ± 6.8
PF/LFN: Change at Month 96 (n= 2)	5.4 ± 6.8
PF/LFN: Change at Month 108 (n= 2)	11.4 ± 6.8
PF/LFN: Change at Month 120 (n= 2)	15.4 ± 6.8
SFN: Change at Month 6 (n= 17)	-0.4 ± 0.9
SFN: Change at Month 12 (n= 18)	0.9 ± 0.9
SFN: Change at Month 24 (n= 18)	0.9 ± 0.9
SFN: Change at Month 36 (n= 12)	1.6 ± 1.0
SFN: Change at Month 48 (n= 9)	2.2 ± 1.2
SFN: Change at Month 60 (n= 7)	1.5 ± 1.3
SFN: Change at Month 72 (n= 3)	4.1 ± 1.7
SFN: Change at Month 84 (n= 2)	2.1 ± 2.1
SFN: Change at Month 96 (n= 2)	1.6 ± 2.1
SFN:Change at Month 108 (n= 2)	2.6 ± 2.1
SFN: Change at Month 120 (n= 2)	2.1 ± 2.1
AN: Change at Month 6 (n= 17)	-0.5 ± 0.4
AN: Change at Month 12 (n= 18)	0.0 ± 0.4
AN: Change at Month 24 (n= 18)	0.2 ± 0.4
AN: Change at Month 36 (n= 12)	0.1 ± 0.4
AN: Change at Month 48 (n= 9)	0.3 ± 0.5
AN: Change at Month 60 (n= 7)	0.2 ± 0.6
AN: Change at Month 72 (n= 3)	1.6 ± 0.8
AN: Change at Month 84 (n= 2)	0.6 ± 1.0
AN: Change at Month 96 (n= 2)	0.1 ± 1.0
AN: Change at Month 108 (n= 2)	1.1 ± 1.0
AN: Change at Month 120 (n= 2)	3.1 ± 1.0

No statistical analyses for this end point

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

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End point title

Val30Met Group: Karnofsky Performance Scale (KPS) Score at Month 42, 54, 78, 90, 102, 114, 126 and 138 ^[59]

End point description

KPS:used for rating subject ADLs on 11-step scale from 0-100, higher score=subject 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 indicated, death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead. Lower the score worse is survival for most serious illnesses. ITT population was analysed. "n"=subjects with available data for each specified category. 99999=upper limit of 95% CI could not be estimated due to less number of subjects with event.

End point type

Secondary

End point timeframe

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

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: units on a scale
arithmetic mean (standard deviation)
Month 42 (n= 37, 34)	83.8 ± 11.63	81.5 ± 11.32
Month 54 (n= 36, 34)	86.1 ± 10.22	82.1 ± 11.49
Month 78 (n= 9, 7)	78.9 ± 14.53	81.4 ± 16.76
Month 90 (n= 9, 6)	75.6 ± 15.09	81.7 ± 14.72
Month 102 (n= 7, 5)	68.6 ± 16.76	80.0 ± 10.00
Month 114 (n= 4, 4)	75.0 ± 12.91	82.5 ± 9.57
Month 126 (n= 2, 2)	75.0 ± 7.07	75.0 ± 21.21
Month 138 (n= 1, 1)	70.0 ± 99999	60.0 ± 99999

No statistical analyses for this end point

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

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End point title

NonVal30Met Group: Change From B3461022 Baseline in Karnofsky Performance Scale (KPS) Score at Month 6, 24, 36, 48, 72, 84, 96, 108 and 120 ^[60]

End point description

KPS:used for rating subject ADLs on 11-step scale from 0-100, higher score=subject 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 indicated, death not imminent, 20=very sick; hospital admission necessary, 10=moribund; fatal processes progressing rapidly and 0=dead. Lower the score worse is survival for most serious illnesses. ITT population was analysed. "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: units on a scale
least squares mean (standard error)
Change at Month 6 (n= 18)	-0.9 ± 2.57
Change at Month 24 (n= 18)	-5.3 ± 2.57
Change at Month 36 (n= 11)	-4.8 ± 3.09
Change at Month 48 (n= 10)	-10.6 ± 3.22
Change at Month 72 (n= 4)	-10.1 ± 4.76
Change at Month 84 (n= 2)	-3.3 ± 6.56
Change at Month 96 (n= 2)	-3.3 ± 6.56
Change at Month 108 (n= 2)	-3.3 ± 6.56
Change at Month 120 (n= 2)	-33.3 ± 6.56

No statistical analyses for this end point

Secondary: Val30Met Group: Number of Subjects 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

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End point title

Val30Met Group: Number of Subjects 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 ^[61]

End point description

Ambulatory status for each Val30Met subject was collected using ambulatory data collection forms in [Fx-005 (B3461020, Fx-006 (B3461021)] or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorised to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis
Number of subjects analysed	38	37
Units: subjects
Week 12: Stage 1 (Normal) (n=37,36)	37	36
Week 12:Stage 2 (Some assistance req.) (n=37,36)	0	0
Week 12: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 6: Stage 1 (Normal) (n= 37, 36)	37	36
Month 6:Stage 2 (Some assistance req.) (n= 37, 36)	0	0
Month 6: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 9: Stage 1 (Normal) (n= 37, 36)	37	36
Month 9:Stage 2 (Some assistance req.) (n= 37, 36)	0	0
Month 9: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 12: Stage 1 (Normal) (n= 37, 36)	37	36
Month 12:Stage 2 (Some assistance req.) (n= 37,36)	0	0
Month 12: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 18: Stage 1 (Normal) (n= 37, 36)	37	36
Month 18:Stage 2 (Some assistance req.) (n= 37,36)	0	0
Month 18: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 21: Stage 1 (Normal) (n= 37, 36)	37	36
Month 21:Stage 2 (Some assistance req.) (n= 37,36)	0	0
Month 21: Stage 3 (Not ambulatory) (n= 37, 36)	0	0
Month 24: Stage 1 (Normal) (n= 38, 36)	37	36
Month 24:Stage 2 (Some assistance req.) (n= 38,36)	0	0
Month 24: Stage 3 (Not ambulatory) (n= 38, 36)	1	0
Month 33: Stage 1 (Normal) (n= 37, 35)	37	34
Month 33:Stage 2 (Some assistance req.) (n= 37,35)	0	1
Month 33: Stage 3 (Not ambulatory) (n= 37,35)	0	0
Month 36: Stage 1 (Normal) (n= 37, 35)	35	34
Month 36:Stage 2 (Some assistance req.) (n= 37,35)	2	1
Month 36: Stage 3 (Not ambulatory) (n= 37, 35)	0	0
Month 39: Stage 1 (Normal) (n= 37, 35)	35	34
Month 39:Stage 2 (Some assistance req.) (n= 37,35)	2	1
Month 39: Stage 3 (Not ambulatory) (n= 37, 35)	0	0
Month 42: Stage 1 (Normal) (n= 37, 34)	36	33
Month 42:Stage 2 (Some assistance req.) (n= 37,34)	1	1
Month 42: Stage 3 (Not ambulatory) (n= 37, 34)	0	0
Month 45: Stage 1 (Normal) (n= 37, 34)	36	33
Month 45:Stage 2 (Some assistance req.) (n= 37,34)	1	1
Month 45: Stage 3 (Not ambulatory) (n= 37, 34)	0	0
Month 48: Stage 1 (Normal) (n= 36, 34)	34	32
Month 48:Stage 2 (Some assistance req.) (n= 36,34)	2	2
Month 48: Stage 3 (Not ambulatory) (n= 36, 34)	0	0
Month 51: Stage 1 (Normal) (n= 36, 34)	34	31
Month 51:Stage 2 (Some assistance req.) (n= 36,34)	2	3
Month 51: Stage 3 (Not ambulatory) (n= 36, 34)	0	0
Month 54: Stage 1 (Normal) (n=34, 31)	32	27
Month 54:Stage 2 (Some assistance req.) (n=34,31)	2	4
Month 54: Stage 3 (Not ambulatory) (n=34, 31)	0	0
Month 57: Stage 1 (Normal) (n=34, 31)	32	27
Month 57:Stage 2 (Some assistance req.) (n=34,31)	2	4
Month 57: Stage 3 (Not ambulatory) (n=34, 31)	0	0
Month 60: Stage 1 (Normal) (n=32, 31)	30	26
Month 60:Stage 2 (Some assistance req.) (n=32,31)	2	5
Month 60: Stage 3 (Not ambulatory) (n=32, 31)	0	0
Month 63: Stage 1 (Normal) (n=29, 27)	27	22
Month 63:Stage 2 (Some assistance req.) (n=29,27)	2	5
Month 63: Stage 3 (Not ambulatory) (n=29, 27)	0	0
Month 69: Stage 1 (Normal) (n=11, 8)	9	5
Month 69:Stage 2 (Some assistance req.) (n=11,8)	2	3
Month 69: Stage 3 (Not ambulatory) (n=11, 8)	0	0
Month 72: Stage 1 (Normal) (n=9, 7)	8	5
Month 72:Stage 2 (Some assistance req.) (n=9,7)	1	2
Month 72: Stage 3 (Not ambulatory) (n=9, 7)	0	0
Month 75: Stage 1 (Normal) (n=9, 6)	8	4
Month 75:Stage 2 (Some assistance req.) (n=9,6)	1	2
Month 75: Stage 3 (Not ambulatory) (n=9, 6)	0	0
Month 78: Stage 1 (Normal) (n=9, 6)	8	4
Month 78:Stage 2 (Some assistance req.) (n=9,6)	1	2
Month 78: Stage 3 (Not ambulatory) (n=9, 6)	0	0
Month 81: Stage 1 (Normal) (n=9, 6)	8	4
Month 81:Stage 2 (Some assistance req.) (n=9,6)	1	2
Month 81: Stage 3 (Not ambulatory) (n=9, 6)	0	0
Month 84: Stage 1 (Normal) (n=9, 6)	8	4
Month 84:Stage 2 (Some assistance req.) (n=9,6)	1	2
Month 84: Stage 3 (Not ambulatory) (n=9, 6)	0	0
Month 87: Stage 1 (Normal) (n=9, 6)	8	4
Month 87:Stage 2 (Some assistance req.) (n=9,6)	1	2
Month 87: Stage 3 (Not ambulatory) (n=9, 6)	0	0
Month 90: Stage 1 (Normal) (n=9, 5)	7	3
Month 90:Stage 2 (Some assistance req.) (n=9,5)	2	2
Month 90: Stage 3 (Not ambulatory) (n=9, 5)	0	0
Month 93: Stage 1 (Normal) (n= 7, 5)	5	3
Month 93:Stage 2 (Some assistance req.) (n= 7,5)	2	2
Month 93: Stage 3 (Not ambulatory) (n= 7, 5)	0	0
Month 96: Stage 1 (Normal) (n= 7, 4)	5	3
Month 96:Stage 2 (Some assistance req.) (n= 7,4)	1	1
Month 96: Stage 3 (Not ambulatory) (n= 7, 4)	1	0
Month 99: Stage 1 (Normal) (n= 5, 4)	4	3
Month 99:Stage 2 (Some assistance req.) (n= 5,4)	1	1
Month 99: Stage 3 (Not ambulatory) (n= 5, 4)	0	0
Month 102: Stage 1 (Normal) (n= 4, 4)	3	3
Month 102:Stage 2 (Some assistance req.) (n= 4,4)	1	1
Month 102: Stage 3 (Not ambulatory) (n= 4, 4)	0	0
Month 105: Stage 1 (Normal) (n= 4, 4)	3	3
Month 105:Stage 2 (Some assistance req.) (n= 4,4)	1	1
Month 105: Stage 3 (Not ambulatory) (n= 4, 4)	0	0
Month 108: Stage 1 (Normal) (n= 3, 4)	2	3
Month 108:Stage 2 (Some assistance req.) (n= 3,4)	1	1
Month 108: Stage 3 (Not ambulatory) (n= 3, 4)	0	0
Month 111: Stage 1 (Normal) (n= 2, 2)	2	1
Month 111:Stage 2 (Some assistance req.) (n= 2, 2)	0	1
Month 111: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 114: Stage 1 (Normal) (n= 2, 2)	2	1
Month 114:Stage 2 (Some assistance req.) (n= 2,2)	0	1
Month 114: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 117: Stage 1 (Normal) (n= 2, 2)	2	1
Month 117:Stage 2 (Some assistance req.) (n= 2,2)	0	1
Month 117: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 120: Stage 1 (Normal) (n= 2, 2)	2	1
Month 120:Stage 2 (Some assistance req.) (n= 2,2)	0	1
Month 120: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 123: Stage 1 (Normal) (n= 2, 2)	2	1
Month 123:Stage 2 (Some assistance req.) (n= 2,2)	0	1
Month 123: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 126: Stage 1 (Normal) (n= 2, 2)	2	1
Month 126:Stage 2 (Some assistance req.) (n= 2,2)	0	1
Month 126: Stage 3 (Not ambulatory) (n= 2, 2)	0	0
Month 129: Stage 1 (Normal) (n= 1, 1)	1	0
Month 129:Stage 2 (Some assistance req.) (n= 1,1)	0	1
Month 129: Stage 3 (Not ambulatory) (n= 1, 1)	0	0

No statistical analyses for this end point

Secondary: NonVal30Met Group: Number of Subjects 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

Top of page

End point title

NonVal30Met Group: Number of Subjects 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 ^[62]

End point description

Ambulatory status for each NonVal30Met subject was collected using ambulatory data collection forms in Fx1A-201 (B3461022) or forms based on mPND score in B3461023 (after protocol amendment 1.1). The data were categorised to 3 ambulation stages: Stage 1 (normal), Stage 2 (some assistance required), or Stage 3 (not ambulatory). ITT population included all enrolled subjects who had taken at least one dose of study medication, and who had baseline and at least one post-baseline NIS-LL measure. Here, "n"=subjects with available data for each specified category.

End point type

Secondary

End point timeframe

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

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint reports data for the reporting groups specified.

End point values	NonVal30Met: Tafamidis
Number of subjects analysed	18
Units: subjects
Month 3: Stage 1 (Normal) (n=12)	7
Month 3:Stage 2 (Some assistance required) (n=12)	5
Month 3: Stage 3 (Not ambulatory) (n=12)	0
Month 6: Stage 1 (Normal) (n=12)	7
Month 6:Stage 2 (Some assistance required) (n=12)	5
Month 6: Stage 3 (Not ambulatory) (n=12)	0
Month 15: Stage 1 (Normal) (n=14)	7
Month 15:Stage 2 (Some assistance required) (n=14)	5
Month 15: Stage 3 (Not ambulatory) (n=14)	2
Month 18: Stage 1 (Normal) (n=15)	7
Month 18:Stage 2 (Some assistance required) (n=15)	6
Month 18: Stage 3 (Not ambulatory) (n=15)	2
Month 21: Stage 1 (Normal) (n=15)	7
Month 21:Stage 2 (Some assistance required) (n=15)	6
Month 21: Stage 3 (Not ambulatory) (n=15)	2
Month 24: Stage 1 (Normal) (n=16)	8
Month 24:Stage 2 (Some assistance required) (n=16)	6
Month 24: Stage 3 (Not ambulatory) (n=16)	2
Month 27: Stage 1 (Normal) (n=15)	7
Month 27:Stage 2 (Some assistance required) (n=15)	7
Month 27: Stage 3 (Not ambulatory) (n=15)	1
Month 30: Stage 1 (Normal) (n=13)	5
Month 30:Stage 2 (Some assistance required) (n=13)	7
Month 30: Stage 3 (Not ambulatory) (n=13)	1
Month 33: Stage 1 (Normal) (n=13)	4
Month 33:Stage 2 (Some assistance required) (n=13)	8
Month 33: Stage 3 (Not ambulatory) (n=13)	1
Month 36: Stage 1 (Normal) (n=13)	3
Month 36:Stage 2 (Some assistance required) (n=13)	9
Month 36: Stage 3 (Not ambulatory) (n=13)	1
Month 39: Stage 1 (Normal) (n=12)	3
Month 39:Stage 2 (Some assistance required) (n=12)	8
Month 39: Stage 3 (Not ambulatory) (n=12)	1
Month 42: Stage 1 (Normal) (n=10)	2
Month 42:Stage 2 (Some assistance required) (n=10)	6
Month 42: Stage 3 (Not ambulatory) (n=10)	2
Month 45: Stage 1 (Normal) (n=8)	1
Month 45:Stage 2 (Some assistance required) (n=8)	6
Month 45: Stage 3 (Not ambulatory) (n=8)	1
Month 48: Stage 1 (Normal) (n=7)	2
Month 48:Stage 2 (Some assistance required) (n=7)	5
Month 48:Stage 3 (Not ambulatory) (n=7)	0
Month 51: Stage 1 (Normal) (n=7)	1
Month 51:Stage 2 (Some assistance required) (n=7)	6
Month 51:Stage 3 (Not ambulatory) (n=7)	0
Month 54: Stage 1 (Normal) (n=7)	1
Month 54:Stage 2 (Some assistance required) (n=7)	6
Month 54:Stage 3 (Not ambulatory) (n=7)	0
Month 57: Stage 1 (Normal) (n=7)	1
Month 57:Stage 2 (Some assistance required) (n=7)	6
Month 57:Stage 3 (Not ambulatory) (n=7)	0
Month 63: Stage 1 (Normal) (n=4)	1
Month 63:Stage 2 (Some assistance required) (n=4)	3
Month 63:Stage 3 (Not ambulatory) (n=4)	0
Month 66: Stage 1 (Normal) (n=4)	1
Month 66:Stage 2 (Some assistance required) (n=4)	3
Month 66:Stage 3 (Not ambulatory) (n=4)	0
Month 69: Stage 1 (Normal) (n=3)	1
Month 69:Stage 2 (Some assistance required) (n=3)	2
Month 69:Stage 3 (Not ambulatory) (n=3)	0
Month 72: Stage 1 (Normal) (n=3)	1
Month 72:Stage 2 (Some assistance required) (n=3)	2
Month 72:Stage 3 (Not ambulatory) (n=3)	0
Month 75: Stage 1 (Normal) (n=2)	1
Month 75:Stage 2 (Some assistance required) (n=2)	1
Month 75:Stage 3 (Not ambulatory) (n=2)	0
Month 78: Stage 1 (Normal) (n=2)	1
Month 78:Stage 2 (Some assistance required) (n=2)	1
Month 78:Stage 3 (Not ambulatory) (n=2)	0
Month 81: Stage 1 (Normal) (n=2)	1
Month 81:Stage 2 (Some assistance required) (n=2)	1
Month 81:Stage 3 (Not ambulatory) (n=2)	0
Month 84: Stage 1 (Normal) (n=2)	1
Month 84:Stage 2 (Some assistance required) (n=2)	1
Month 84:Stage 3 (Not ambulatory) (n=2)	0
Month 87: Stage 1 (Normal) (n=2)	1
Month 87:Stage 2 (Some assistance required) (n=2)	1
Month 87:Stage 3 (Not ambulatory) (n=2)	0
Month 90: Stage 1 (Normal) (n=2)	1
Month 90:Stage 2 (Some assistance required) (n=2)	1
Month 90: Stage 3 (Not ambulatory) (n=2)	0
Month 93: Stage 1 (Normal) (n=2)	1
Month 93:Stage 2 (Some assistance required) (n=2)	1
Month 93: Stage 3 (Not ambulatory) (n=2)	0
Month 96: Stage 1 (Normal) (n=2)	1
Month 96:Stage 2 (Some assistance required) (n=2)	1
Month 96: Stage 3 (Not ambulatory) (n=2)	0
Month 99: Stage 1 (Normal) (n=2)	1
Month 99:Stage 2 (Some assistance required) (n=2)	1
Month 99: Stage 3 (Not ambulatory) (n=2)	0
Month 102: Stage 1 (Normal) (n=2)	1
Month 102:Stage 2 (Some assistance required) (n=2)	1
Month 102: Stage 3 (Not ambulatory) (n=2)	0
Month 105: Stage 1 (Normal) (n=2)	1
Month 105:Stage 2 (Some assistance required) (n=2)	1
Month 105: Stage 3 (Not ambulatory) (n=2)	0
Month 108: Stage 1 (Normal) (n=2)	1
Month 108:Stage 2 (Some assistance required) (n=2)	1
Month 108: Stage 3 (Not ambulatory) (n=2)	0
Month 111: Stage 1 (Normal) (n=2)	1
Month 111:Stage 2 (Some assistance required) (n=2)	1
Month 111: Stage 3 (Not ambulatory) (n=2)	0
Month 114: Stage 1 (Normal) (n=2)	1
Month 114:Stage 2 (Some assistance required) (n=2)	1
Month 114: Stage 3 (Not ambulatory) (n=2)	0
Month 117: Stage 1 (Normal) (n=2)	1
Month 117:Stage 2 (Some assistance required) (n=2)	1
Month 117: Stage 3 (Not ambulatory) (n=2)	0
Month 120: Stage 1 (Normal) (n=2)	1
Month 120:Stage 2 (Some assistance required) (n=2)	1
Month 120: Stage 3 (Not ambulatory) (n=2)	0
Month 123: Stage 1 (Normal) (n=2)	1
Month 123:Stage 2 (Some assistance required) (n=2)	1
Month 123: Stage 3 (Not ambulatory) (n=2)	0
Month 126: Stage 1 (Normal) (n=1)	1
Month 126:Stage 2 (Some assistance required) (n=1)	0
Month 126: Stage 3 (Not ambulatory) (n=1)	0
Month 129: Stage 1 (Normal) (n=1)	1
Month 129:Stage 2 (Some assistance required) (n=1)	0
Month 129: Stage 3 (Not ambulatory) (n=1)	0

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious AEs

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious AEs

End point description

An AE was any untoward medical occurrence in a subject 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 hospitalisation; 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. Safety population included all enrolled subjects in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects
Treatment-Emergent AEs	35	33	18
Treatment-emergent SAEs	6	9	10

No statistical analyses for this end point

Secondary: Number of Subjects With Abnormality in Physical Examinations

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End point title

Number of Subjects With Abnormality in Physical Examinations

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects	29	32	14

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Test Abnormalities

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End point title

Number of Subjects With Laboratory Test Abnormalities

End point description

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

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects	21	21	12

No statistical analyses for this end point

Secondary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

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End point title

Number of Subjects With Electrocardiogram (ECG) Abnormalities

End point description

Twelve-lead ECGs were obtained for all subjects. 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. Safety population included all enrolled subjects in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects
QT Interval (msec): >450-480	8	7	6
QT Interval (msec): >480-500	3	2	4
QT Interval (msec): >500	2	1	6
QTcB (msec): >450-480	14	20	11
QTcB (msec): >480-500	6	3	5
QTcB (msec): >500	5	3	5
QTcF (msec): >450-480	7	7	7
QTcF (msec): >480-500	4	2	3
QTcF (msec): >500	5	3	5

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Changes from Baseline in Vital Signs

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End point title

Number of Subjects With Clinically Significant Changes from Baseline in Vital Signs

End point description

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%.

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects	38	37	18

No statistical analyses for this end point

Secondary: Number of Subjects With Any Concomitant Medications Usage

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End point title

Number of Subjects With Any Concomitant Medications Usage

End point description

Number of subjects with any concomitant medications usage are reported. Safety population included all enrolled subjects in the current study B3461023 (Fx1A-303) and who had taken at least one dose of study medication.

End point type

Secondary

End point timeframe

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

End point values	Val30Met: Tafamidis Then Tafamidis	Val30Met: Placebo Then Tafamidis	NonVal30Met: Tafamidis
Number of subjects analysed	38	37	18
Units: subjects	36	37	17

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

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

Adverse event reporting additional description

Same event may appear as both an AE and Serious Adverse Events (SAE). However, what is presented are distinct events. An event may be categorised as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event. Analysis performed on safety set.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Val30Met: Tafamidis Then Tafamidis

Reporting group description

Val30Met subjects who received tafamidis in study Fx-005 (B3461020), continued the same in study Fx-006 (B3461021), received tafamidis 20 mg soft gelatin capsule orally once daily for up to 10 years from the date of enrollment in this study B3461023 (Fx1A-303) or until they had an access to tafamidis for ATTR-PN via prescription, upon regulatory approval in respective countries.

Reporting group title

NonVal30Met: Tafamidis

Reporting group description

Reporting group title

Val30Met: Placebo Then Tafamidis

Reporting group description

Serious adverse events	Val30Met: Tafamidis Then Tafamidis	NonVal30Met: Tafamidis	Val30Met: Placebo Then Tafamidis
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 38 (15.79%)	10 / 18 (55.56%)	9 / 37 (24.32%)
number of deaths (all causes)	3	7	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central Nervous System Lymphoma
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Vascular disorders
Deep Vein Thrombosis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic Hypotension
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Heart Transplant
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
General disorders and administration site conditions
Chest Pain
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disease Progression
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Oedema Peripheral
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Amyloidosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Reproductive system and breast disorders
Cervical Dysplasia
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural Effusion
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional State
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight Decreased
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower Limb Fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia Fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist Fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina Unstable
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Amyloidosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac Arrest
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac Failure
subjects affected / exposed	2 / 38 (5.26%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiac Failure Acute
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial Effusion
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular Tachycardia
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dementia Alzheimer's Type
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Syncope
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient Ischaemic Attack
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile Neutropenia
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Vomitting
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatomegaly
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal Impairment
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Muscular Weakness
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial Cyst
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Device Related Infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Urinary Tract Infection
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitamin D Deficiency
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	Val30Met: Tafamidis Then Tafamidis	NonVal30Met: Tafamidis	Val30Met: Placebo Then Tafamidis
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 38 (89.47%)	18 / 18 (100.00%)	32 / 37 (86.49%)
Vascular disorders
Hypotension
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	1	1	2
Orthostatic Hypotension
subjects affected / exposed	2 / 38 (5.26%)	4 / 18 (22.22%)	1 / 37 (2.70%)
occurrences all number	2	4	1
Peripheral Vascular Disorder
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Surgical and medical procedures
Carpal Tunnel Decompression
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Chest Pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Early Satiety
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Exercise Tolerance Decreased
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Fatigue
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	4 / 37 (10.81%)
occurrences all number	1	2	4
Gait Disturbance
subjects affected / exposed	3 / 38 (7.89%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	3	1	1
Implant Site Pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Malaise
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Oedema Peripheral
subjects affected / exposed	3 / 38 (7.89%)	4 / 18 (22.22%)	1 / 37 (2.70%)
occurrences all number	3	4	2
Social circumstances
Walking Disability
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	4 / 37 (10.81%)
occurrences all number	2	0	4
Reproductive system and breast disorders
Benign Prostatic Hyperplasia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Erectile Dysfunction
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	1	0	3
Vulvovaginal Pruritus
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 38 (7.89%)	4 / 18 (22.22%)	0 / 37 (0.00%)
occurrences all number	3	4	0
Dysphonia
subjects affected / exposed	0 / 38 (0.00%)	3 / 18 (16.67%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Dyspnoea
subjects affected / exposed	2 / 38 (5.26%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	2	2	1
Psychiatric disorders
Depression
subjects affected / exposed	3 / 38 (7.89%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	5	1	0
Insomnia
subjects affected / exposed	2 / 38 (5.26%)	1 / 18 (5.56%)	2 / 37 (5.41%)
occurrences all number	2	1	2
Investigations
Blood Cholesterol Increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Blood Thyroid Stimulating Hormone Increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Haemoglobin Increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Hepatic Enzyme Increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Weight Decreased
subjects affected / exposed	2 / 38 (5.26%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	2	2	1
Injury, poisoning and procedural complications
Burns Second Degree
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Contusion
subjects affected / exposed	0 / 38 (0.00%)	3 / 18 (16.67%)	0 / 37 (0.00%)
occurrences all number	0	5	0
Fall
subjects affected / exposed	0 / 38 (0.00%)	12 / 18 (66.67%)	0 / 37 (0.00%)
occurrences all number	0	25	0
Head Injury
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Joint Injury
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	2 / 37 (5.41%)
occurrences all number	0	1	2
Limb Injury
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	5	0	0
Medication Error
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Muscle Injury
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Procedural Pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Skin Abrasion
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	1	2	0
Skin Laceration
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Thermal Burn
subjects affected / exposed	6 / 38 (15.79%)	1 / 18 (5.56%)	5 / 37 (13.51%)
occurrences all number	10	1	8
Tooth Fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Traumatic Ulcer
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Wound
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Cardiac disorders
Arrhythmia
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Atrial Fibrillation
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Bundle Branch Block Bilateral
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Cardiac Failure
subjects affected / exposed	2 / 38 (5.26%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	2	2	1
Cardiomyopathy
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Mitral Valve Incompetence
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Tachycardia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Balance Disorder
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Burning Sensation
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Carotid Artery Stenosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Dizziness
subjects affected / exposed	3 / 38 (7.89%)	3 / 18 (16.67%)	1 / 37 (2.70%)
occurrences all number	3	4	1
Fine Motor Skill Dysfunction
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Headache
subjects affected / exposed	4 / 38 (10.53%)	1 / 18 (5.56%)	4 / 37 (10.81%)
occurrences all number	4	1	5
Hypoaesthesia
subjects affected / exposed	0 / 38 (0.00%)	4 / 18 (22.22%)	4 / 37 (10.81%)
occurrences all number	0	4	4
Memory Impairment
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Migraine
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Neuralgia
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	2	0	3
Neuropathy Peripheral
subjects affected / exposed	1 / 38 (2.63%)	5 / 18 (27.78%)	2 / 37 (5.41%)
occurrences all number	2	6	2
Paraesthesia
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	5	0	1
Presyncope
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Sciatica
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Syncope
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	3	0	1
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Vertigo
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Vertigo Positional
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Eye disorders
Cataract
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Dry Eye
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	2 / 37 (5.41%)
occurrences all number	0	1	3
Eye Pruritus
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Vision Blurred
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	4 / 38 (10.53%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	5	0	0
Abdominal Pain
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Abdominal Pain Lower
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Abdominal Pain Upper
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	3	0	2
Constipation
subjects affected / exposed	3 / 38 (7.89%)	1 / 18 (5.56%)	3 / 37 (8.11%)
occurrences all number	4	2	3
Dental Caries
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Diarrhoea
subjects affected / exposed	2 / 38 (5.26%)	4 / 18 (22.22%)	2 / 37 (5.41%)
occurrences all number	2	6	3
Dry Mouth
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Dysphagia
subjects affected / exposed	0 / 38 (0.00%)	3 / 18 (16.67%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Gastritis
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Gastrointestinal Disorder
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Gastrointestinal Motility Disorder
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Haemorrhoids
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Inguinal Hernia
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Nausea
subjects affected / exposed	3 / 38 (7.89%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	3	4	1
Odynophagia
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Vomitting
subjects affected / exposed	4 / 38 (10.53%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	4	1	1
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	0	0	3
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Alopecia
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	2	0
Blister
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Decubitus Ulcer
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	2 / 37 (5.41%)
occurrences all number	1	2	4
Eczema
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	2 / 37 (5.41%)
occurrences all number	0	1	2
Night Sweats
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Pruritus
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Purpura
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Skin Lesion
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	0	0	3
Skin Ulcer
subjects affected / exposed	3 / 38 (7.89%)	2 / 18 (11.11%)	2 / 37 (5.41%)
occurrences all number	6	2	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Haematuria
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Nephrolithiasis
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	2	4	1
Renal Failure
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Urinary Retention
subjects affected / exposed	4 / 38 (10.53%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	4	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 38 (5.26%)	2 / 18 (11.11%)	2 / 37 (5.41%)
occurrences all number	2	2	2
Arthritis
subjects affected / exposed	2 / 38 (5.26%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	2	1	2
Back Pain
subjects affected / exposed	5 / 38 (13.16%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	7	0	4
Foot Deformity
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Muscle Atrophy
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Muscle Spasms
subjects affected / exposed	3 / 38 (7.89%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	3	1	0
Muscular Weakness
subjects affected / exposed	2 / 38 (5.26%)	3 / 18 (16.67%)	3 / 37 (8.11%)
occurrences all number	3	4	4
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Musculoskeletal Stiffness
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Neck Pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Pain in Extremity
subjects affected / exposed	2 / 38 (5.26%)	2 / 18 (11.11%)	5 / 37 (13.51%)
occurrences all number	2	4	10
Tendonitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Burn Infection
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	3	0	0
Cellulitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Conjunctivitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Diverticulitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Ear Infection
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	2	0	3
Gastroenteritis
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	0 / 37 (0.00%)
occurrences all number	2	0	0
Gastroenteritis Viral
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Gingivitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Hordeolum
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Infected Skin Ulcer
subjects affected / exposed	4 / 38 (10.53%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	5	0	3
Influenza
subjects affected / exposed	3 / 38 (7.89%)	1 / 18 (5.56%)	7 / 37 (18.92%)
occurrences all number	3	1	10
Nasopharyngitis
subjects affected / exposed	5 / 38 (13.16%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	9	0	3
Onychomycosis
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	3 / 37 (8.11%)
occurrences all number	0	2	3
Pharyngitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 18 (0.00%)	3 / 37 (8.11%)
occurrences all number	2	0	4
Pneumonia
subjects affected / exposed	1 / 38 (2.63%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	1	2	1
Pneumonia Streptococcal
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Pyelonephritis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Respiratory Tract Infection
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Rhinitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	0	1	1
Sinusitis
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	1 / 37 (2.70%)
occurrences all number	0	4	3
Skin Infection
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	3	0	1
Tooth Abscess
subjects affected / exposed	1 / 38 (2.63%)	0 / 18 (0.00%)	4 / 37 (10.81%)
occurrences all number	1	0	6
Tracheobronchitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Upper Respiratory Tract Infection
subjects affected / exposed	3 / 38 (7.89%)	3 / 18 (16.67%)	3 / 37 (8.11%)
occurrences all number	3	4	3
Urinary Tract Infection
subjects affected / exposed	6 / 38 (15.79%)	2 / 18 (11.11%)	6 / 37 (16.22%)
occurrences all number	11	2	10
Vaginal Infection
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	2 / 37 (5.41%)
occurrences all number	6	0	2
Vulvovaginal Mycotic Infection
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Wound Infection
subjects affected / exposed	3 / 38 (7.89%)	0 / 18 (0.00%)	1 / 37 (2.70%)
occurrences all number	3	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	1 / 37 (2.70%)
occurrences all number	1	1	1
Fluid Overload
subjects affected / exposed	0 / 38 (0.00%)	2 / 18 (11.11%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Hypokalaemia
subjects affected / exposed	1 / 38 (2.63%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	1	1	0
Vitamin B12 Deficiency
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0
Vitamin D Deficiency
subjects affected / exposed	0 / 38 (0.00%)	1 / 18 (5.56%)	0 / 37 (0.00%)
occurrences all number	0	1	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

27 Jun 2011

Synopsis (Section 2), Sections 5.1, 6.4, 8.10, 8.11, 10.7.5, Appendix 1: Added text relating to assessment of ambulatory status: subject ambulation determined by the Investigator at every 6-month clinic visit and during each 3-month telephone follow-up (in between clinic visits), and at the end of study visit. Synopsis (Section 2), Sections 3.4, 5.1, 8.5, 8.11, 10.6, Appendix 1: Added text relating to clinical laboratory testing that involve blood samples taken at Baseline, every 6-month clinic visit, and at the end of study visit. Section 9 (Adverse Events): Entire Section 9 updated per new procedures (Pfizer). Appendix 1 (Schedule of Events): Visit windows added.

05 Jun 2012

Extension of study duration to up to 10 years or until subject has access to tafamidis for ATTR-PN via prescription. Upon regulatory approval for the treatment of ATTR-PN in their respective country and access to prescription tafamidis, subjects may be withdrawn from the study. The decision to withdraw subjects in a country will be done in consultation between the investigator and the sponsor. Section 8: Adverse Event Reporting – updated to reflect most updated requirements from Pfizer.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Prior to B3461023, V30M subjects completed 18 months blinded treatment (placebo or tafamidis) in Fx-005 followed by 12 months tafamidis in Fx-006; nonV30M subjects completed 12 months tafamidis in Fx1A-201.

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Clinical trials

Clinical Trial Results: Open-Label Safety and Efficacy Evaluation of FX-1006A in Subjects With Transthyretin (TTR) Amyloidosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Primary: 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

Primary: 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

Primary: 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

Primary: 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

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

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

Primary: 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

Primary: 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

Primary: 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

Primary: 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

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

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

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

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

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

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

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

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

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

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

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Baseline

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Baseline

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 30

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 30

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 66

Primary: Val30Met Group: Number of Subjects by Ambulation Stage at Month 66

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Baseline

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Baseline

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 12

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 12

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 60

Primary: NonVal30Met Group: Number of Subjects by Ambulation Stage at Month 60

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

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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

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

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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

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

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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

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

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

Secondary: 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

Secondary: 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

Clinical Trial Results:
Open-Label Safety and Efficacy Evaluation of FX-1006A in Subjects With Transthyretin (TTR) Amyloidosis