Retrospective Study Collecting Neurological Follow-up of Hereditary Transthyretin Amyloidosis (ATTRv) Patients Included in B3461028 and B3461045. (TRAMA)

Tafamidis 61mg, Outcomes in ATTR Amyloidosis With Neurologic and Multisystemic Involvement - TRAMA

A study of patients with hereditary transthyretin amyloidosis (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt) that have been enrolled in B3461028 and B3461045 studies in Spain - exposed to tafamidis 61mg for ≥12 months with polyneuropathy (PN) have kept going to their multisystemic follow-ups (neuro/ophthalmo/gastrointestinal) ≥12 months.

Study Overview

• Status: Completed
• Conditions: Polyneuropathy; Hereditary Transthyretin Amyloidosis (ATTRv)
• Intervention / Treatment: Drug: Tafamidis

• Study Type: Observational
• Enrollment (Actual): 5

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Palma de Mallorca, Spain, 07198
    • Hospital Son Llàtzer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Study population: retrospective cohort of patients with hereditary transthyretin amyloidosis (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt) that have been enrolled in B3461028 and B3461045 studies in Spain - exposed to tafamidis 61mg for ≥12 months with polyneuropathy have kept going to their multisystemic follow-ups (neuro/ophthalmo/gastrointestinal) ≥12 months

Description

Inclusion Criteria:

• Treatment with tafamidis 61 mg ≥ 12 months
• Neurological follow up ≥ 12 months
• Diagnosis of transthyretin amyloidosis with polyneuropathy (ATTR-PN) based on one of the following:
• Amplitude reduction in, at least, 2 nerves under normal value, excluding median nerve OR 50% amplitude reduction in, at least, 2 nerves on the basal value of the patient, excluding median nerve OR 2 abnormal tests detecting thin fibers alterations (through Sudo scan, RR Interval analysis, etc..)

Exclusion Criteria:

• Treatment with tafamidis 61 mg < 12 months
• Neurological follow up < 12 months
• Other diagnosis for polyneuropathy

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Retrospective cohort ATTRv and ATTRwt patients enrolled in B3461028 and B3461045 studies in Spain	Drug: Tafamidis; 61 milligrams (mg) as received in studies B3461028 and B3461045

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Neuropathy Impairment Score (NIS) at Month 12 for ATTRv	NIS (Neuropathy Impairment Score) is a clinically important, sensitive measure of individual neurological function, assessing sensory function, reflexes, and muscle weakness. NIS score ranged from 0 to 244, with higher score indicating greater disability or impairment. The rate of change was calculated from last follow-up.	Baseline and Month 12 (data collected and analyzed over 22 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NIS for ATTRv	NIS (Neuropathy Impairment Score) is a clinically important, sensitive measure of individual neurological function, assessing sensory function, reflexes, and muscle weakness. NIS score ranged from 0 to 244, with higher score indicating greater disability or impairment. The rate of change was calculated from last follow-up.	Baseline, Month 6, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in Neuropathy Impairment Score - Lower Limbs (NIS-LL) for ATTRv	NIS-LL (Neuropathy Impairment Score Lower Limbs) is a clinically important, sensitive measure of neurological function in individuals, assessing sensory function, reflexes, and muscle weakness of the lower limbo. NÍS-LL assessed muscle weakness, reflexes, sensation. Each item is scored separately for left and right limbs. Components of muscle weakness:0(normal) to4(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. The rate of change was calculated from last follow-up.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in Norfolk Quality of Life- Diabetic Neuropathy (Norfolk QOL-DN) for ATTRv	Norfolk Quality of Life Questionnaire for Diabetic Neuropathy is a standardized and validated instrument that assesses the effect of polyneuropathy on the functionality and quality of life of the individual. Norfolk QOL-DN: 35-item participant-rated questionnaire is 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 symptom 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= -4 to 138, where higher score=worse quality of life.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in COMPASS-31 for ATTRv	COMPASS-31 (Composite Autonomic Symptom Score 31) is a questionnaire designed to assess the severity and functional ability in participants with autonomic dysfunction. COMPASS-31 total score ranged from 0 to 100; where 0=Lesser severity of dysautonomia and 100=Greater severity of dysautonomia.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in Familial Amyloid Polyneuropathy Specific Rasch-Built Overall Disability Scale (FAP-RODs) for ATTRv	FAP-RODS is a questionnaire that assessed the effect of neuropathy on daily activities. FAP-RODS total score ranged from 0 to 68; where, 0=Lower ability to perform daily activities and 68=Greater ability to perform daily activities.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants According to Familiar Amyloidotic Polyneuropathy Stage (FAP) for ATTRv	FAP is a stage system based on symptom severity and disease progression. FAP stages included: Asymptomatic; Free ambulation (walking without support): stage 1; Supportive ambulation (walking with support): stage 2; Wheelchair-bound or bedridden: stage 3.	Month 18, 24 and 30 months after the start of treatment (data collected and analyzed over 22 days)
Percentage of Participants Who do Not Have Stage Progression in the PND Score for ATTRv	PND is a staging system that assess the degree of neuropathic dysfunction and its impact on ambulation. PND stages included: Asymptomatic; Stage I: Sensory disturbances, normal gait; Stage II: Sensory disturbances, altered gait not requiring support; IIIA: Gait requiring one support; IIIB: Gait requiring two supports; IV: Wheelchair or bedside. Participants who did not change to higher stages compared to the start of treatment was reported as Unchanged and those who progressed to higher stages were reported under Staging up.	From Baseline to Month 30 (data collected and analyzed over 22 days)
Percentage of Responders to Treatment for ATTRv	Percentage of responders to treatment at Month 12 was defined as participants who achieved the change from baseline of less than 4 points in the NIS and participants who achieved the change from baseline of less than 2 points in the NIS-LL were reported in this outcome measure.	Month 12 (data collected and analyzed over 22 days)
Number of Participants With R-R Interval Variability for ATTRv	Number of participants with R-R interval variability (altered/unaltered) was reported in this outcome measure.	Month 18, 24 and 30 (data collected and analyzed over 22 days)
Modified Body Mass Index (mBMI) for ATTRv	BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). mBMI was calculated by multiplying BMI by serum albumin levels [gram/liter (g/L)].	Month 18, 24 and 30 after start of treatment (data collected and analysed over 22 days)
Ulnar/Sural Sensory Nerve Action Potential Amplitude (SNAP) for ATTRv	Sural sensory nerve action potential amplitude (in microvolts) was measured using electromyography of the left lower limb.	Month 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Ulnar/Peroneal Compound Muscle Action Potential Amplitude (CMAP) for ATTRv	Peroneal motor nerve compound muscle action potential amplitude was measured using electromyography of the left lower limb.	Month 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Change in NIS for ATTRwt	NIS (Neuropathy Impairment Score) was a clinically important, sensitive measure of individual neurological function, assessing sensory function, reflexes, and muscle weakness. NIS score ranged from 0 to 244, with higher score indicating greater disability or impairment. The rate of change was calculated from last follow-up.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in NIS-LL for ATTRwt	NIS-LL (Neuropathy Impairment Score Lower Limbs) was clinically important, sensitive measure of neurological function in individuals, assessing sensory function, reflexes, and muscle weakness of the lower limbo. NÍS-LL assessed muscle weakness, reflexes, sensation. Each item scored separately for left and right limbs. Components of muscle weakness:0(normal) to4(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. The rate of change was calculated from last follow-up.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in Norfolk QOL-DN for ATTRwt	Norfolk Quality of Life Questionnaire for Diabetic Neuropathy was a standardized and validated instrument that assesses the effect of polyneuropathy on the functionality and quality of life of the individual. 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 symptom 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= -4 to 138, where higher score=worse quality of life.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Change in COMPASS-31 for ATTRwt	COMPASS-31 (Composite Autonomic Symptom Score 31) was a questionnaire designed to assess the severity and functional ability in participants with autonomic dysfunction. COMPASS-31 total score ranged from 0 to 100; where 0=Lesser severity of dysautonomia and 100=Greater severity of dysautonomia.	Baseline, Month 6, 12, 18, 24 and 36 after treatment initiation
Change in FAP-RODs for ATTRwt	FAP-RODS is a questionnaire that assessed the effect of neuropathy on daily activities. FAP-RODS total score ranged from 0 to 68; where, 0=Lower ability to perform daily activities and 68=Greater ability to perform daily activities.	Baseline, Month 6, 12, 18, 24 and 36 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants According to FAP Stage for ATTRwt	FAP stage is a staging system based on symptom severity and disease progression. FAP stages included: Asymptomatic; Free ambulation (Walking without support): stage 1; Supportive ambulation (Walking with support): stage 2; Wheelchair-bound or bedridden: stage 3.	Month 18, 24 and 30 months after the start of treatment (data collected and analyzed over 22 days)
Percentage of Participants Who do Not Have Stage Progression in the PND Score for ATTRwt	PND was a simple staging system according to the degree of neuropathic dysfunction and its impact on ambulation. PND stages included: Asymptomatic: I Sensory disturbances, normal gait: II Sensory disturbances, altered gait not requiring support: IIIA Gait requiring one support: IIIB Gait requiring two supports: IV Wheelchair or bedside). Participants who did not change to higher stages compared to the start of treatment was reported as Unchanged and those who progressed to higher stages were reported under Staging up.	From Baseline to Month 30 (data collected and analysed over 22 days)
Percentage of Responders to Treatment for ATTRwt	Percentage of responders to treatment was defined as participants who achieved the change from baseline of less than 4 points in the NIS and participants who achieved the change from baseline of less than 2 points in the NIS-LL were reported in this outcome measure.	Month 12 (data collected and analyzed over 22 days)
Number of Participants With R-R Interval Variability for ATTRwt	Number of participants with R-R interval variability (altered/unaltered) was reported in this outcome measure.	Month 18, 24 and 30 (data collected and analyzed over 22 days)
mBMI for ATTRwt	BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2).	Month 18, 24 and 30 after start of treatment (data collected and analysed over 22 days)
Ulnar/Sural SNAP Score for ATTRwt	Sural sensory nerve action potential amplitude (in microvolts) was measured using electromyography of the left lower limb.	Month 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Ulnar/Peroneal CMAP Score for ATTRwt	Peroneal motor nerve compound muscle action potential amplitude (in millivolts) was measured using electromyography of the left lower limb.	Month 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Carpal Tunnel Syndrome	Number of participants with carpal tunnel syndrome were reported in this outcome measure.	At baseline (data collected and analyzed over 22 days)
Number of Participants With Lumbar Stenosis	Number of participants with lumbar stenosis were reported in this outcome measure.	At baseline (data collected and analyzed over 22 days)
Number of Participants With Gastrointestinal Disturbances	Number of participants with gastrointestinal disturbances were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Unintentional Weight Loss	Number of participants with unintentional weight loss were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Urological Disturbances	Number of participants with urological disturbances were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Ophthalmological Disturbances	Number of participants with ophthalmological disturbances were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Central Nervous System (CNS) Disturbances	Number of participants with CNS disturbances were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Symptoms of Autonomic Neuropathy	Number of participants with symptoms of autonomic neuropathy including impaired sweating, sexual dysfunction, orthostatic hypotension were reported in this outcome measure.	Month 18, 24 and 30 after the start of treatment (data collected and analyzed over 22 days)
Number of Participants With Symptoms of Peripheral Neuropathy	Number of participants with symptoms of peripheral neuropathy (allodynia and paresthesia) were reported in this outcome measure.	At baseline (data collected and analyzed over 22 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2022
• Primary Completion (Actual): November 15, 2022
• Study Completion (Actual): November 15, 2022

Study Registration Dates

• First Submitted: September 26, 2022
• First Submitted That Met QC Criteria: September 26, 2022
• First Posted (Actual): September 29, 2022

Study Record Updates

• Last Update Posted (Actual): May 13, 2024
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

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; Amyloid Neuropathies; Amyloidosis; Polyneuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: B3461104; TRAMA (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No