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Report for Clinical Trial NCT01435655

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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.

NCT01435655 Transthyretin Familial Amyloid Polyneuropathy
MeSH: Polyneuropathies Amyloid Neuropathies Amyloid Neuropathies, Familial Amyloidosis
HPO: Amyloidosis Lattice corneal dystrophy Motor polyneuropathy Polyneuropathy

1 Interventions

Name: tafamidis

Description: tafamidis meglumine 20 mg QD

Type: Drug

open


Primary Outcomes

Description: 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%.

Measure: Number of Participants With Transthyretin (TTR) Stabilization at Week 8 Compared With Baseline as Measured by a Validated Immunoturbidimetric Assay

Time: 8 weeks

Secondary Outcomes

Description: 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.

Measure: 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: Baseline, Week 26, Week 52, Week 78

Description: 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.

Measure: 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: Baseline, Week 26, Week 52, Week 78

Description: 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.

Measure: 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: Baseline, Week 26, Week 52, Week 78

Description: 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.

Measure: 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: Baseline, Week 26, Week 52, Week 78

Description: 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.

Measure: Change From Baseline in Modified Body Mass Index (mBMI) at Week 8, Week 26, Week 52 and End of Study

Time: Baseline, Week 8, Week 26, Week 52, End of Study

Description: 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.

Measure: Change From Baseline in Ambulatory Status at Week 26, Week 52 and Week 78

Time: Baseline, Week 26, Week 52, Week 78

Description: 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%.

Measure: 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: Baseline, Week 26, Week 52, Week 78

Other Outcomes

Description: Mean plasma concentration of tafamidis at 3 hours after administration

Measure: Plasma Concentration of Tafamidis at Week 8, Week 26, Week 52 and Week 78

Time: Week 8, Week 26, Week 52, Week 78

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V30M

The Effect Of Tafamidis For The Transthyretin Amyloid Polyneuropathy Patients With V30M Or Non-V30M Transthyretin Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer. --- V30M ---

The Effect Of Tafamidis For The Transthyretin Amyloid Polyneuropathy Patients With V30M Or Non-V30M Transthyretin Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer. --- V30M --- --- V30M ---

Inclusion Criteria: - Transthyretin amyloid polyneuropathy with V30M or non-V30M transthyretin mutation. --- V30M ---

Inclusion Criteria: - Transthyretin amyloid polyneuropathy with V30M or non-V30M transthyretin mutation. --- V30M --- --- V30M ---



HPO Nodes


HPO:
Amyloidosis
Genes 30
LIG4 TNFRSF1A APOA1 NLRP1 SLC7A7 CST3 MEFV GSN SAA1 OSMR PSEN2 TTR B2M RET ITM2B MEFV NLRP3 NLRP3 IL31RA LYZ ITM2B CCND1 APP PRNP POLA1 CST3 APP APOE FGA NLRP3
Lattice corneal dystrophy
Genes 6
OSMR TGFBI TGFBI GSN TGFBI GSN
Motor polyneuropathy
Genes 26
AGRN SLC12A6 SCO2 TFG SLC18A3 SYT2 CTDP1 SLC25A1 REEP1 SNAP25 SPG11 CHAT PPOX GARS1 GJC2 TRPV4 BSCL2 HINT1 SLC5A7 ARL6IP1 COL13A1 ALDH18A1 ALDH18A1 VAMP1 SELENOI MYO9A
Polyneuropathy
Genes 59
GCLC NAGS SLC12A6 ERCC6 AIFM1 C12ORF65 PSAP CYP7B1 COX3 PEX11B ATP6 ARL6IP1 COQ7 OPA1 PIK3R5 SH3TC2 LDB3 PEX12 ALAD ABHD12 FAM126A EDNRB NGLY1 ND2 ABCD1 CYTB PEX7 RPIA GSN TBC1D24 GRM1 SNAP29 TTR ND5 PDK3 ND4 GSN DGUOK PMM2 ND4L DHH ND1 TTR SEPTIN9 FUCA1 DARS2 PRPS1 SETX SLC25A19 PDYN ATP7B ERCC8 DHH DMXL2 MYOT MYD88 ARL6IP1 CD59 ND6