ATTR-PN, Familial Amyloid Polyneuropathy
Conditions
Keywords
FAP, Familial Amyloid Polyneuropathy, ATTR-PN, transthyretin, TTR, amyloid, polyneuropathy, familial, hereditary, amyloidosis, FoldRx
Brief summary
This study is designed to determine the long-term safety and tolerability of Fx-1006A as well as the effects of Fx-1006A on clinical outcomes in patients with ATTR-PN. All patients who enroll in this extension study will receive once-daily oral 20 mg Fx-1006A for 12 months; therefore, patients randomized to placebo in Study Fx-005 will cross over to active drug (Fx-1006A 20 mg) during this study. However, patients and their families as well as clinical Investigators and their clinical site staff will remain blinded to the original Fx-005 treatment assignment. It is intended that there will be no interruption in study medication administration between the two studies. The majority of safety and clinical outcomes assessments will be identical to those evaluated in Study Fx-005. Additional assessments for this open-label extension study include 24-hour Holter monitoring and skin biopsy for IENF; patients will be required to provide written informed consent to participate in this open-label extension study prior to having these additional procedures performed. The values obtained from procedures and evaluations conducted during the Month 18 visit of Study Fx-005 will be used as the Baseline values for this open-label extension study. The Baseline assessments of IENF and Holter monitoring may be conducted at either day of the Month 18 visit days of Study Fx-005, but prior to the first Fx-1006A dose in this open-label extension study. Clinic Visits will be conducted at Week 6 (± 2 days), and Month 3 (± 1 week), Month 6 (± 2 weeks), and Month 12 (± 2 weeks). Monthly telephone contacts (± 1 week of the scheduled date) will be made during months in which no investigative site visits are scheduled (Months 2, 4, 5, 7, 8, 9, 10, and 11) for assessment of adverse events and concomitant medications. Neurological evaluation by NIS-LL will be performed at Months 6 and 12. The NIS-LL will be assessed by utilizing the average of two successive NIS-LL clinical assessment scores obtained at least 24 hours apart within a one week period for each study visit. A dedicated neurologist will be required to perform NIS-LL scoring across all time-points for each individual patient enrolled in the study. Quality of life utilizing the Norfolk QOL-DN will be assessed at Months 6 and 12 (based on the total score as well as the five individual domains of the questionnaire). QST (utilizing CASE IV), NCS, HRDB, mBMI, and echocardiography will be conducted at Months 6 and 12. Holter monitoring will be conducted at Baseline and Months 6 and 12. Biopsies for IENF will be obtained at Baseline only. Assessments of troponin I and NT-pro-BNP levels will be made at each study visit. Blood samples for pharmacokinetic assessments (Fx-1006A concentrations as well as calculated steady-state parameters) and pharmacodynamic assessments (TTR stabilization) will be collected at Week 6 and Months 6 and 12. Safety and tolerability will be assessed throughout the study. Vital signs, 12-lead ECG, blood and urine samples for clinical laboratory tests (serum chemistry, hematology, coagulation panel, urinalysis, and urine pregnancy testing), adverse events, and concomitant medications will be assessed at each study visit. Eye examinations (including fundal photography) will be conducted at Months 6 and 12. Abbreviated physical examinations will be conducted at Week 6, and Months 3 and 6, and a complete physical examination will be conducted at Month 12. All patients will be contacted by telephone 30 days (± 1 week) after the last dose of study medication for assessment of adverse events and concomitant medications. Patients who complete the Month 12 visit of this open-label study may be allowed to continue receiving Fx-1006A under a compassionate use program. Patients who discontinue from the study at any time after enrollment (i.e., early termination) will have final safety assessments performed at the time of discontinuation. Any patient discontinuing after the Month 6 visit will have all safety and clinical outcomes assessments scheduled for the Month 12 visit performed.
Interventions
DRUGFx-1006A
Fx-1006A 20mg soft gelatin capsule administered orally once daily (at the same time each day) for 12 months.
Sponsors
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Male and non-pregnant female patients meeting all of the following criteria are eligible for enrollment in this study: * Patient has completed the Month 18 visit of Study Fx-005. * If female, patient is post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout the study. (A condom alone is not considered an acceptable method of birth control.) If male with a female partner of childbearing potential, willing to use an acceptable method of birth control for the duration of the study. For both females and males, acceptable birth control must be used for at least 3 months after the last dose of study medication. * Patient is, in the opinion of the investigator, willing and able to comply with the study medication regimen and all other study requirements. * Patient agrees not to participate in another investigational drug or device study while participating in this open-label extension study.
Exclusion criteria
Patients meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 | Month 6 | Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference. |
| Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12 | Month 12 | Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference. |
| Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 | Baseline, Month 6 | Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life. |
| Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12 | Baseline, Month 12 | Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer | Month 6, 12 | TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI. |
| Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Baseline, Month 6, 12 | Summated 7 score: composite score included five Nerve Conduction Studies (NCS) attributes (peroneal nerve distal motor latency, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, tibial nerve distal motor latency, and sural nerve sensory nerve action potential amplitude) along with Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function. |
| Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Baseline, Month 6, 12 | Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function. |
| Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Baseline, Month 6, 12 | BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation. A progressive decline in mBMI indicated worsening of disease severity. |
| Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Baseline, Week 6, Month 3, 6, 12 | Troponin I was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular \[LV\] wall stress). |
| Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Baseline, Week 6, Month 3, 6, 12 | NT-proBNP was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ LV wall stress). |
| Intraepidermal Nerve Fiber (IENF) Density | Baseline | IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. It is used in diagnosing various neuropathic conditions. |
| Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Baseline, Month 6, 12 | NIS-LL: assessed muscle weakness, reflexes and sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) are scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment. |
| Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline, Month 6, 12 | Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptoms present, 0=symptoms absent. Item 8-35:scored on 5-point Likert scale: 0=no problem,4=severe problem (except item 32: -2=much better, 0=about same, 2=much worse). Norfolk QOL-DN summarized in 5 domains(score range):physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment,for each. Total score=-2 to138(higher score=worse QOL). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3 | Baseline up to 30 days after last dose of study medication | AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent events=between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings | Baseline, Day 1 up to Month 12 (anytime on-treatment) | Clinically significant ECHO findings included: LV posterior wall thickness greater than or equal to (\>=)13 mm, LV septal thickness \>= 13 mm, right ventricular thickness \>= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) \>= 2, prime septal (E/E) \>15, ejection fraction \< 50 percent (%), E deceleration time \<= 150 millisecond (ms), isovolumic relaxation time (IVRT) \<= 70 ms, any valve thickening (\> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion. |
| Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings | Baseline, Day 1 up to Month 12 (anytime on-treatment) | Clinically significant ECG findings included: corrected QT (QTc) \> 450 ms, QTc \>500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms. |
| Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings | Baseline, Day 1 up to Month 12 (anytime on-treatment) | Clinically significant Holter monitor findings included: atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (\<30 beats), sustained ventricular tachycardia (\>= 30 beats), sinus pause (RR \>2.0 second, where RR=60/heart rate), ventricular premature contractions. |
| Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events | Baseline up to Month 12 | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) | Baseline up to 30 days after last dose of study medication | An Adverse Event (AE) was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug, up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
Countries
Argentina, Brazil, France, Germany, Portugal, Sweden
Participant flow
Recruitment details
Participants who completed study FX-005 (NCT00409175), were eligible for the current study FX-006 (NCT00791492).
Participants by arm
| Arm | Count |
|---|---|
| Tafamidis-Tafamidis Participants who received tafamidis (Fx-1006A) 20 milligram (mg) capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months. | 44 |
| Placebo-Tafamidis Participants who received placebo matched to tafamidis (Fx-1006A) 20 mg capsule orally once daily for 18 months during previous study FX-005 (NCT00409175), received tafamidis (Fx-1006A) 20 mg capsule orally once daily for 12 months. | 41 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Liver transplantation | 5 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Tafamidis-Tafamidis | Placebo-Tafamidis | Total |
|---|---|---|---|
| Age Continuous | 41.3 years STANDARD_DEVIATION 13.4 | 39.6 years STANDARD_DEVIATION 13.2 | 40.4 years STANDARD_DEVIATION 13.3 |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 47 Participants |
| Sex: Female, Male Male | 20 Participants | 18 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 44 | 24 / 41 |
| serious Total, serious adverse events | 5 / 44 | 4 / 41 |
Outcome results
Primary
Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12
Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.
Time frame: Baseline, Month 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12 | 2.25 units on a scale | Standard Deviation 8.91 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12 | -2.33 units on a scale | Standard Deviation 15.66 |
Primary
Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6
Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.
Time frame: Baseline, Month 6
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 | Baseline | 21.05 units on a scale | Standard Deviation 21.88 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 | Change at Month 6 | 0.03 units on a scale | Standard Deviation 8.83 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 | Baseline | 38.09 units on a scale | Standard Deviation 31.89 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 | Change at Month 6 | -4.88 units on a scale | Standard Deviation 15.29 |
Primary
Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12
Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.
Time frame: Month 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis-Tafamidis | Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12 | 54.5 percentage of participants |
| Placebo-Tafamidis | Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12 | 60.0 percentage of participants |
Primary
Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6
Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.
Time frame: Month 6
Population: Intent-to-treat (ITT) population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis-Tafamidis | Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 | 62.2 percentage of participants |
| Placebo-Tafamidis | Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 | 68.8 percentage of participants |
Secondary
Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12
BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation. A progressive decline in mBMI indicated worsening of disease severity.
Time frame: Baseline, Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Baseline (n=38,33) | 23.94 (kilogram/square meter)*(gram/liter) | Standard Deviation 2.97 |
| Tafamidis-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Change at Month 6 (n=37,32) | -0.13 (kilogram/square meter)*(gram/liter) | Standard Deviation 0.81 |
| Tafamidis-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Change at Month 12 (n=33,30) | -0.12 (kilogram/square meter)*(gram/liter) | Standard Deviation 1.16 |
| Placebo-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Baseline (n=38,33) | 22.71 (kilogram/square meter)*(gram/liter) | Standard Deviation 5.15 |
| Placebo-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Change at Month 6 (n=37,32) | 0.42 (kilogram/square meter)*(gram/liter) | Standard Deviation 1.14 |
| Placebo-Tafamidis | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12 | Change at Month 12 (n=33,30) | 0.73 (kilogram/square meter)*(gram/liter) | Standard Deviation 1.45 |
Secondary
Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12
NIS-LL: assessed muscle weakness, reflexes and sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) are scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.
Time frame: Baseline, Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Baseline (n=38,33) | 8.38 units on a scale | Standard Deviation 13.23 |
| Tafamidis-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Change at Month 6 (n=37,32) | 0.93 units on a scale | Standard Deviation 3.65 |
| Tafamidis-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Change at Month 12 (n=33,30) | 1.36 units on a scale | Standard Deviation 4.77 |
| Placebo-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Baseline (n=38,33) | 17.50 units on a scale | Standard Deviation 20.82 |
| Placebo-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Change at Month 6 (n=37,32) | 1.89 units on a scale | Standard Deviation 4.55 |
| Placebo-Tafamidis | Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 | Change at Month 12 (n=33,30) | 1.60 units on a scale | Standard Deviation 8.2 |
Secondary
Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12
Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptoms present, 0=symptoms absent. Item 8-35:scored on 5-point Likert scale: 0=no problem,4=severe problem (except item 32: -2=much better, 0=about same, 2=much worse). Norfolk QOL-DN summarized in 5 domains(score range):physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment,for each. Total score=-2 to138(higher score=worse QOL).
Time frame: Baseline, Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: autonomic neuropathy (n=38,33) | 1.55 units on a scale | Standard Deviation 2.37 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: small fiber neuropathy(n=37,32) | -0.14 units on a scale | Standard Deviation 2.64 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: ADLs (n=38,33) | 2.21 units on a scale | Standard Deviation 4.38 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: autonomic neuropathy (n=37,32) | 0.19 units on a scale | Standard Deviation 1.33 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: physical functioning (n=37,32) | 0.14 units on a scale | Standard Deviation 4.08 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: physical functioning(n=32,30) | 1.84 units on a scale | Standard Deviation 6 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: small fiber neuropathy (n=38,33) | 2.50 units on a scale | Standard Deviation 3.85 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: ADLs (n=32,30) | 0.13 units on a scale | Standard Deviation 1.01 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: ADLs (n=37,32) | -0.30 units on a scale | Standard Deviation 1.45 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: symptoms (n=32,30) | -0.66 units on a scale | Standard Deviation 2.54 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: symptoms (n=38,33) | 5.34 units on a scale | Standard Deviation 4.43 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12:small fiber neuropathy(n=32,30) | 0.41 units on a scale | Standard Deviation 2.87 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: symptoms (n=34,32) | 0.00 units on a scale | Standard Deviation 3.18 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: autonomic neuropathy (n=32,30) | 0.53 units on a scale | Standard Deviation 1.46 |
| Tafamidis-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: physical functioning (n=38,33) | 9.45 units on a scale | Standard Deviation 11.43 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: autonomic neuropathy (n=32,30) | -0.30 units on a scale | Standard Deviation 1.66 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: physical functioning (n=38,33) | 19.88 units on a scale | Standard Deviation 17.44 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: ADLs (n=38,33) | 3.48 units on a scale | Standard Deviation 5.13 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: symptoms (n=38,33) | 7.48 units on a scale | Standard Deviation 5.48 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: small fiber neuropathy (n=38,33) | 4.42 units on a scale | Standard Deviation 4.23 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Baseline: autonomic neuropathy (n=38,33) | 2.82 units on a scale | Standard Deviation 3.12 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: physical functioning (n=37,32) | -3.00 units on a scale | Standard Deviation 8.08 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: ADLs (n=37,32) | -0.59 units on a scale | Standard Deviation 3.02 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: symptoms (n=34,32) | -0.75 units on a scale | Standard Deviation 4.27 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: small fiber neuropathy(n=37,32) | -0.09 units on a scale | Standard Deviation 2.32 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 6: autonomic neuropathy (n=37,32) | -0.44 units on a scale | Standard Deviation 2 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: physical functioning(n=32,30) | -0.83 units on a scale | Standard Deviation 9.62 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: ADLs (n=32,30) | -0.50 units on a scale | Standard Deviation 3.35 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12: symptoms (n=32,30) | -1.10 units on a scale | Standard Deviation 3.32 |
| Placebo-Tafamidis | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 | Change at Month 12:small fiber neuropathy(n=32,30) | 0.40 units on a scale | Standard Deviation 2.61 |
Secondary
Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12
NT-proBNP was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ LV wall stress).
Time frame: Baseline, Week 6, Month 3, 6, 12
Population: Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Week 6 (n=33,33) | 6.0 picogram/milliliter (pg/mL) |
| Tafamidis-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 6 (n=33,33) | 9.0 picogram/milliliter (pg/mL) |
| Tafamidis-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 3 (n=33,34) | 11.0 picogram/milliliter (pg/mL) |
| Tafamidis-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 12 (n=30,29) | 15.0 picogram/milliliter (pg/mL) |
| Tafamidis-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Baseline (n=33,34) | 41.0 picogram/milliliter (pg/mL) |
| Placebo-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 12 (n=30,29) | -6.0 picogram/milliliter (pg/mL) |
| Placebo-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Baseline (n=33,34) | 75.0 picogram/milliliter (pg/mL) |
| Placebo-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Week 6 (n=33,33) | -1.0 picogram/milliliter (pg/mL) |
| Placebo-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 3 (n=33,34) | 1.0 picogram/milliliter (pg/mL) |
| Placebo-Tafamidis | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 | Change at Month 6 (n=33,33) | 0.0 picogram/milliliter (pg/mL) |
Secondary
Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12
Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function.
Time frame: Baseline, Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Baseline (n=38,33) | 4.78 units on a scale | Standard Deviation 4.33 |
| Tafamidis-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Change at Month 6 (n=36,32) | 0.43 units on a scale | Standard Deviation 1.51 |
| Tafamidis-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Change at Month 12 (n=32,30) | 0.59 units on a scale | Standard Deviation 1.28 |
| Placebo-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Baseline (n=38,33) | 7.08 units on a scale | Standard Deviation 4.39 |
| Placebo-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Change at Month 6 (n=36,32) | 0.38 units on a scale | Standard Deviation 1.08 |
| Placebo-Tafamidis | Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12 | Change at Month 12 (n=32,30) | 0.50 units on a scale | Standard Deviation 1.48 |
Secondary
Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12
Summated 7 score: composite score included five Nerve Conduction Studies (NCS) attributes (peroneal nerve distal motor latency, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, tibial nerve distal motor latency, and sural nerve sensory nerve action potential amplitude) along with Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function.
Time frame: Baseline, Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Baseline (n=38,33) | 6.68 units on a scale | Standard Deviation 8.51 |
| Tafamidis-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Change at Month 6 (n=37,32) | -0.01 units on a scale | Standard Deviation 2.99 |
| Tafamidis-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Change at Month 12 (n=33,30) | 0.64 units on a scale | Standard Deviation 3.23 |
| Placebo-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Baseline (n=38,33) | 10.06 units on a scale | Standard Deviation 10.68 |
| Placebo-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Change at Month 6 (n=37,32) | 1.38 units on a scale | Standard Deviation 3.58 |
| Placebo-Tafamidis | Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12 | Change at Month 12 (n=33,30) | 1.48 units on a scale | Standard Deviation 4.02 |
Secondary
Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12
Troponin I was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular \[LV\] wall stress).
Time frame: Baseline, Week 6, Month 3, 6, 12
Population: Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tafamidis-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Week 6 (n=28,29) | 0.0 nanogram/milliliter (ng/mL) |
| Tafamidis-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 6 (n=29,30) | 0.0 nanogram/milliliter (ng/mL) |
| Tafamidis-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 3 (n=29,30) | 0.0 nanogram/milliliter (ng/mL) |
| Tafamidis-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 12 (n=26,28) | 0.0 nanogram/milliliter (ng/mL) |
| Tafamidis-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Baseline (n=29,30) | 0.2 nanogram/milliliter (ng/mL) |
| Placebo-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 12 (n=26,28) | 0.0 nanogram/milliliter (ng/mL) |
| Placebo-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Baseline (n=29,30) | 0.2 nanogram/milliliter (ng/mL) |
| Placebo-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Week 6 (n=28,29) | 0.0 nanogram/milliliter (ng/mL) |
| Placebo-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 3 (n=29,30) | 0.0 nanogram/milliliter (ng/mL) |
| Placebo-Tafamidis | Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 | Change at Month 6 (n=29,30) | 0.0 nanogram/milliliter (ng/mL) |
Secondary
Intraepidermal Nerve Fiber (IENF) Density
IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. It is used in diagnosing various neuropathic conditions.
Time frame: Baseline
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis-Tafamidis | Intraepidermal Nerve Fiber (IENF) Density | Left distal leg | 8.2 fibers/mm | Standard Deviation 9.8 |
| Tafamidis-Tafamidis | Intraepidermal Nerve Fiber (IENF) Density | Left proximal thigh | 16.1 fibers/mm | Standard Deviation 12.6 |
| Placebo-Tafamidis | Intraepidermal Nerve Fiber (IENF) Density | Left proximal thigh | 15.3 fibers/mm | Standard Deviation 11.9 |
| Placebo-Tafamidis | Intraepidermal Nerve Fiber (IENF) Density | Left distal leg | 8.0 fibers/mm | Standard Deviation 9.2 |
Secondary
Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer
TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI.
Time frame: Month 6, 12
Population: ITT population included all participants who received at least one dose of study medication and had no more than 2 months interruption between studies FX-005 and FX-006. 'N' (number of participants analyzed) signifies participants evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tafamidis-Tafamidis | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer | Month 6 | 94 percentage of participants |
| Tafamidis-Tafamidis | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer | Month 12 | 94 percentage of participants |
| Placebo-Tafamidis | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer | Month 6 | 97 percentage of participants |
| Placebo-Tafamidis | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer | Month 12 | 93 percentage of participants |
Other Pre-specified
Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events
An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Baseline up to Month 12
Population: Safety population included participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis-Tafamidis | Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events | 0 participants |
| Placebo-Tafamidis | Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events | 0 participants |
Other Pre-specified
Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings
Clinically significant ECHO findings included: LV posterior wall thickness greater than or equal to (\>=)13 mm, LV septal thickness \>= 13 mm, right ventricular thickness \>= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) \>= 2, prime septal (E/E) \>15, ejection fraction \< 50 percent (%), E deceleration time \<= 150 millisecond (ms), isovolumic relaxation time (IVRT) \<= 70 ms, any valve thickening (\> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion.
Time frame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
Population: Safety population included participants who received at least one dose of study medication. 'N' (number of participants analyzed) signifies participants evaluable for this measure. 'n' signifies participants evaluable for this measure at the specified time point for each arm group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings | Baseline (n=38,34) | 23 participants |
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings | Anytime on-treatment (n=21,23) | 16 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings | Baseline (n=38,34) | 18 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings | Anytime on-treatment (n=21,23) | 13 participants |
Other Pre-specified
Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings
Clinically significant ECG findings included: corrected QT (QTc) \> 450 ms, QTc \>500 ms, change in QTc between 30 and 60 ms, change in QTc greater than or equal to 60 ms.
Time frame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
Population: Safety population included participants who received at least one dose of study medication. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings | Baseline (n=44,41) | 16 participants |
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings | Anytime on-treatment (n=28,24) | 6 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings | Baseline (n=44,41) | 17 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings | Anytime on-treatment (n=28,24) | 6 participants |
Other Pre-specified
Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings
Clinically significant Holter monitor findings included: atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (\<30 beats), sustained ventricular tachycardia (\>= 30 beats), sinus pause (RR \>2.0 second, where RR=60/heart rate), ventricular premature contractions.
Time frame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
Population: Safety population included participants who received at least one dose of study medication. 'n' signifies participants for this measure at specified time point for each arm group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings | Baseline (n=44,41) | 20 participants |
| Tafamidis-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings | Anytime on-treatment (n=24,20) | 8 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings | Baseline (n=44,41) | 21 participants |
| Placebo-Tafamidis | Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings | Anytime on-treatment (n=24,20) | 7 participants |
Other Pre-specified
Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3
AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent events=between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline up to 30 days after last dose of study medication
Population: Safety population included participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis-Tafamidis | Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3 | 6 participants |
| Placebo-Tafamidis | Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3 | 4 participants |
Other Pre-specified
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
An Adverse Event (AE) was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug, up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline up to 30 days after last dose of study medication
Population: Safety population included participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis-Tafamidis | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) | 5 participants |
| Placebo-Tafamidis | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) | 4 participants |