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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01435655
First received: September 13, 2011
Last updated: August 10, 2015
Last verified: August 2015
  Purpose
Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer.

Condition Intervention Phase
Transthyretin Familial Amyloid Polyneuropathy
Drug: tafamidis
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With Transthyretin (TTR) Stabilization at Week 8 Compared With Baseline as Measured by a Validated Immunoturbidimetric Assay [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    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%.


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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.

  • 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. [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Modified Body Mass Index (mBMI) at Week 8, Week 26, Week 52 and End of Study [ Time Frame: Baseline, Week 8, Week 26, Week 52, End of Study ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Ambulatory Status at Week 26, Week 52 and Week 78 [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: Baseline, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    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%.


Other Outcome Measures:
  • Plasma Concentration of Tafamidis at Week 8, Week 26, Week 52 and Week 78 [ Time Frame: Week 8, Week 26, Week 52, Week 78 ] [ Designated as safety issue: No ]
    Mean plasma concentration of tafamidis at 3 hours after administration


Enrollment: 10
Study Start Date: November 2011
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: open
tafamidis
Drug: tafamidis
tafamidis meglumine 20 mg QD
Other Name: tafamidis meglumine

  Eligibility

Ages Eligible for Study:   20 Years to 75 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01435655

Locations
Japan
Kumamoto University Hospital/Department of Neurology
Kumamoto-shi, Kumamoto, Japan, 860-8556
Shinshu University Hospital/Department of Medicine (Neurology and Reumatology)
Matsumoto-shi, Nagano, Japan, 390-8621
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01435655     History of Changes
Other Study ID Numbers: B3461010 
Study First Received: September 13, 2011
Results First Received: February 24, 2015
Last Updated: August 10, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Amyloid Neuropathies
Amyloid Neuropathies, Familial
Amyloidosis
Polyneuropathies
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Amyloidosis, Familial
Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on August 29, 2016