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

• ClinicalTrials.gov Identifier: NCT01435655
• Recruitment Status: Completed
• First Posted: September 16, 2011
• Results First Posted: September 9, 2015
• Last Update Posted: September 9, 2015
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: September 13, 2011
• First Posted Date: September 16, 2011
• Results First Submitted Date: February 24, 2015
• Results First Posted Date: September 9, 2015
• Last Update Posted Date: September 9, 2015
• Study Start Date: November 2011
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 10, 2015)

Number of Participants With Transthyretin (TTR) Stabilization at Week 8 Compared With Baseline as Measured by a Validated Immunoturbidimetric Assay [ Time Frame: 8 weeks ]

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%.

• Original Primary Outcome Measures (submitted: September 15, 2011): TTR stabilization at Week 8 compared with Baseline, as measured by a validated immunoturbidimetric assay. [ Time Frame: 8 weeks ]

Current Secondary Outcome Measures (submitted: August 10, 2015)

• 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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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%.

Original Secondary Outcome Measures (submitted: September 15, 2011)

• Change from baseline on the following scales: Neuropathy Impairment Score;QOL;"Σ7 NTs NDS" as measured by nerve conduction studies (NCS), vibration detection threshold (VDT) and heart rate response to deep breathing (HRDB); [ Time Frame: 3 years ]
• Change from baseline on the following scales: "Σ3 NTSF NDS" as measured by cooling and heat pain thresholds utilizing CASE IV and heart rate response to deep breathing (HRDB); mBMI; Ambulatory status. [ Time Frame: 3 years ]
• Transthyretin (TTR) stabilization at each follow up visit after Week 8. [ Time Frame: 3 years ]
• Blood samples for determination of plasma levels of tafamidis will be collected at Baseline and during the visits at Week 2. [ Time Frame: 2 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected at Week 4. [ Time Frame: 4 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected Week 8. [ Time Frame: 8 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected at Week 26. [ Time Frame: 26 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected at Week 52. [ Time Frame: 52 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected at Week 78. [ Time Frame: 78 weeks ]
• Blood samples for determination of plasma levels of tafamidis will be collected at End of study. [ Time Frame: 3 years ]

Current Other Pre-specified Outcome Measures (submitted: August 10, 2015)

Plasma Concentration of Tafamidis at Week 8, Week 26, Week 52 and Week 78 [ Time Frame: Week 8, Week 26, Week 52, Week 78 ]

Mean plasma concentration of tafamidis at 3 hours after administration

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effect Of Tafamidis For The Transthyretin Amyloid Polyneuropathy Patients With V30M Or Non-V30M Transthyretin
• 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
• Brief Summary: Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Transthyretin Familial Amyloid Polyneuropathy

Intervention

Drug: tafamidis

tafamidis meglumine 20 mg QD

Other Name: tafamidis meglumine

Study Arms

Experimental: open

tafamidis

Intervention: Drug: tafamidis

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 15, 2011): 10
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 2014
• Actual Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT01435655
• Other Study ID Numbers: B3461010
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: August 2015