The Effect Of Tafamidis For The Transthyretin Amyloid Polyneuropathy Patients With V30M Or Non-V30M Transthyretin

The Effect On Transthyretin Stabilization, Safety, Tolerablity, Efficacy And Pharmacokinetics Of Orally Administered Tafamidis In Transthyretin Amyloid Polyneuropathy Patients With V30m Or Non-v30m Transthyretin: A Phase Iii, Open-label Study

Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer.

Study Overview

• Status: Completed
• Conditions: Transthyretin Familial Amyloid Polyneuropathy
• Intervention / Treatment: Drug: tafamidis

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Kumamoto
    • Kumamoto-shi, Kumamoto, Japan, 860-8556
      • Kumamoto University Hospital/Department of Neurology
  • Nagano
    • Matsumoto-shi, Nagano, Japan, 390-8621
      • Shinshu University Hospital/Department of Medicine (Neurology and Reumatology)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Transthyretin amyloid polyneuropathy with V30M or non-V30M transthyretin mutation.
• Subject had amyloid documented by biopsy in accordance with institutional site standard of care.

Exclusion Criteria:

• Primary amyloidosis and secondary amyloidosis.
• History of liver transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: open; tafamidis	Drug: tafamidis; tafamidis meglumine 20 mg QD; Other Names: tafamidis meglumine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Transthyretin (TTR) Stabilization at Week 8 Compared With Baseline as Measured by a Validated Immunoturbidimetric Assay	TTR tetramer level for each plasma sample was assessed using a validated immunoturbidimetric assay before and after urea denaturation. The Fraction of Initial (FOI) tetramer concentration is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer average 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. A patient who has the "TTR stabilization" is defined as the patient whose percent stabilization is equal to or more than 32%.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Neuropathy Impairment Score (NIS); NIS (Total), NIS-LL (Lower Limb) and NIS-UL (Upper Limb) at Week 26, Week 52 and Week 78	The NIS provides a total body single score of neuropathic deficits (score range: 0-122, higher score = more deficit), comprising subset scores for cranial nerves, muscle weakness, reflexes, and sensation (based on mean of 2 scores in 1 week period; each item scored separately for left and right). The NIS-LL is a subscale that provides a score for the lower limbs functions (muscle weakness, reflexes and sensation in great toe) and has a score range of 0-44 (higher score = more deficit). The NIS-UL is a subscale that provides a score for the upper body functions (muscle weakness [including cranial nerves], reflexes and sensation in finger) and has a score range of 0-78 (higher score = more deficit). The components for cranial nerves and muscle weakness are scored from 0 (Normal) to 4 (Paralysis), and those for reflexes and sensation from 0 (Normal) to 2 (Absent). For all items, higher scores indicate greater impairment.	Baseline, Week 26, Week 52, Week 78
Change From Baseline in Scores of the Total Quality of Life (TQOL) and 5 Domains as Measured by the Norfolk QOL - Diabetic Neuropathy (Norfolk QOL-DN) at Week 26, Week 52 and Week 78.	Norfolk QOL-DN is a 35-item participant-rated questionnaire. It consists of 5 domains: Physical Functioning/Large Fiber [score range: -4 - 56] , Activities of Daily Living (ADL) [0 - 20], Symptoms [0 - 32], Small Fiber [0 - 16] and Autonomic [0 - 12]. Total of quality of life (TQOL) score is the sum of all five domains with a range of -4 to 136 (Pfizer Data Standards). Higher scores on each item of the Norfolk QOL-DN TQOL indicate worse quality of life.	Baseline, Week 26, Week 52, Week 78
Change From Baseline in Summated 7 Nerve Tests Normal Deviate Score (∑ 7 NTs Nds) as Measured by Nerve Conduction Studies (NCS), Vibration Detection Threshold (VDT) and Heart Rate Response to Deep Breathing (HRDB) at Week 26, Week 52, and Week 78	The Σ7 NTs nds measures primarily large-fiber function. It is a composite score derived from five 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 VDT obtained in great toes by Quantitative Sensory Testing (QST), and HRDB value. It is defined as 7 times the mean of non-missing values of, the five normal deviates of NCS, HRDB, and average normal deviate for VDT of toes. Score was determined through reference to normal values for age, sex, height and abnormalities scored. Total score range is approximately -26 to 26, where higher score=worse nerve function.	Baseline, Week 26, Week 52, Week 78
Change From Baseline in Summated 3 Nerve Tests Small Fiber Normal Deviate Score (∑ 3 NTSF Nds) as Measured by Cooling and Heat Pain Thresholds by QST and HRDB at Week 26, Week 52 and Week 78	The Σ3 NTSF nds measures small-fiber function. It is a composite score defined as 3 times the mean of non-missing values of normal deviates of cooling threshold for lower limbs, heat pain intermediate response for lower limbs, and HRDB. The total score range is approximately -11.2 to 11.2, with a higher score demonstrating worse nerve function.	Baseline, Week 26, Week 52, Week 78
Change From Baseline in Modified Body Mass Index (mBMI) at Week 8, Week 26, Week 52 and End of Study	The mBMI was calculated by multiplying the BMI (the weight in kilograms divided by the square of the height in meters) by serum albumin level (gram/liter). Change in mBMI was calculated as the mBMI at the given week minus the Baseline mBMI.	Baseline, Week 8, Week 26, Week 52, End of Study
Change From Baseline in Ambulatory Status at Week 26, Week 52 and Week 78	Ambulatory status was evaluated using walking ability scale in polyneuropathy disability score. The ambulatory status was evaluated as: 0=Good, 1=Sensory disturbances in the feet but able to walk without difficulty, 2=Some difficulties with walking but can walk without aid, 3a=Able to walk with 1 stick or crutch, 3b=Able to walk with 2 sticks or crutches, 4=Not ambulatory, confined to a wheelchair or bedridden.	Baseline, Week 26, Week 52, Week 78
Number of Participants With Transthyretin (TTR) Stabilization at Week 26, Week 52, and Week 78 Compared With Baseline as Measured by a Validated Immunoturbidimetric Assay	TTR tetramer was assessed using a validated immunoturbidimetric assay. The TTR tetramer level for each plasma sample was measured before and after urea denaturation. The Fraction of Initial (FOI) tetramer concentration 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. A patient who has the "TTR stabilization" is defined as the patient whose percent stabilization is equal to or more than 32%.	Baseline, Week 26, Week 52, Week 78

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of Tafamidis at Week 8, Week 26, Week 52 and Week 78	Mean plasma concentration of tafamidis at 3 hours after administration	Week 8, Week 26, Week 52, Week 78

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019 Dec;26(4):203-209. doi: 10.1080/13506129.2019.1643714. Epub 2019 Jul 27.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): February 1, 2014
• Study Completion (ACTUAL): February 1, 2014

Study Registration Dates

• First Submitted: September 13, 2011
• First Submitted That Met QC Criteria: September 15, 2011
• First Posted (ESTIMATE): September 16, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): September 9, 2015
• Last Update Submitted That Met QC Criteria: August 10, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis, Familial; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: B3461010