The Effect Of Tafamidis Meglumine In Transthyretin Amyloid Polyneuropathy Patients

A SINGLE ARM, MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF ORALLY ADMINISTERED TAFAMIDIS MEGLUMINE IN TRANSTHYRETIN AMYLOID POLYNEUROPATHY PARTICIPANTS IN CHINA

This is a single-arm, open-label, multicenter study designed to evaluate the efficacy, safety, tolerability as well as pharmacodynamics of tafamidis meglumine in ATTR-PN participants in China.

Approximately 10-15 participants are planned to be enrolled. All enrolled participants will receive oral tafamidis meglumine 20 mg soft capsules once daily for 72 weeks (18 months).

Study Overview

• Status: Completed
• Conditions: Transthyretin Amyloid Polyneuropathy (ATTR-PN)
• Intervention / Treatment: Drug: tafamidis meglumine

Detailed Description

This is a single-arm, open-label, multicenter study designed to evaluate the efficacy, safety, tolerability as well as pharmacodynamics of tafamidis meglumine in ATTR-PN participants in China.

All enrolled participants will receive oral tafamidis meglumine 20 mg soft capsules once daily starting on Day 1. Clinical visits will be scheduled at Baseline (Day 1) and at Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60 and Week 72. At Week 36 and Week 60 site visit, assessment of adverse events, safety related lab testings, concomitant medications and investigational product compliance will be scheduled. Every 6 weeks (do not exceed 7 weeks since last confirmation) telephone contacts will be made during visits in which no investigative site visits are scheduled for assessment of adverse events, concomitant medications and investigational product compliance (between Week 12 and 24, between Week 24 and 36, between Week 36 and 48, between Week 48 and 60, and between Week 60 and 72).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100053
    • Xuanwu Hospital Capital Medical University
  • Beijing, China, 100070
    • Tiantan Hospital Capital Medical University
  • Beijing, China, 100730
    • Peking union hospital of Chinese academy of medical sciences
  • Beijing, China, 100005
    • Peking union hospital of Chinese academy of medical sciences
  • Beijing
    • Beijing, Beijing, China, 100034
      • Peking University First Hospital
    • Beijing, Beijing, China, 100191
      • Peking University Third Hospital
  • Fujian
    • Fuzhou, Fujian, China, 350005
      • The First Affiliated Hospital of Fujian Medical University
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital of Southern Medical University
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants between the ages of 18 and 80 years.
2. Participants have amyloid documented by biopsy
3. Participants must have a TTR mutation that is associated with ATTR-PN.
4. Participants have peripheral and/or autonomic neuropathy
5. Stages of disease according to symptom severity-stage I.

Exclusion Criteria:

1. Other acute or chronic medical or psychiatric condition including recent or active suicidal ideation or behavior or laboratory abnormality, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
2. Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs.

3. Use of diflunisal, tauroursodeoxycholate, doxycycline, inotersen, patisiran or any other TTR stabilizing agent, or experimental interventions for familial amyloidosis within 30 days prior to the study entry and/or during study participation. Participants who are taking or who have previously taken tafamidis.

   Prior/Concurrent Clinical Study Experience:

4. Previous administration with an investigational drug within 30 days or 5 half lives preceding the first dose of investigational product used in this study (whichever is longer).
5. Participant has primary (light chain) or secondary amyloidosis.
6. If female, participant is pregnant or breast feeding, or plans to be pregnant or breast feeding in the next 18 months.
7. Participant has received prior liver or any other organ except cornea transplantation.
8. Participant requires significant assistance with ambulation or is wheel chair bound.
9. Participants with cardiomyopathy specific TTR mutations.
10. Participant has other causes of sensorimotor neuropathy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tafamidis treatment arm; Chinese patients diagnosed with ATTR-PN treated with tafamidis 20mg once daily oral administration for 72 weeks (18 months).	Drug: tafamidis meglumine; Tafamidis meglumine 20 mg, once daily, oral administration, for 72 weeks (18 months).; Other Names: Vyndaqel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Neuropathy Impairment Score-lower Limb (NIS-LL) Total Score at Week 72	NIS-LL: assess muscle weakness, reflexes, sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae); sensation (touch pressure, pin-prick, vibration, joint position) scored 0 = normal, 1 = decreased, or 2 = absent. Total possible NIS-LL score range 0-88, high score = more impairment. Components of muscle weakness are scored to eight levels: 0 = Normal, 1 = 25% Weak, 2 = 50% Weak, 3 = 75% Weak, 3.25 = Move against gravity, 3.5 = Movement, gravity eliminated, 3.75 = Muscle flicker, no movement, 4 = Paralysis.	Baseline, Week 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Neuropathy Impairment Score-lower Limb (NIS-LL) Total Score at Weeks 24, and 48	NIS-LL: assess muscle weakness, reflexes, sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) scored on scale 0 (normal) to 4 (paralysis), higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae); sensation (touch pressure, pin-prick, vibration, joint position) scored 0 = normal, 1 = decreased, or 2 = absent. Total possible NIS-LL score range 0-88, high score = more impairment. Components of muscle weakness are scored to eight levels: 0 = Normal, 1 = 25% Weak, 2 = 50% Weak, 3 = 75% Weak, 3.25 = Move against gravity, 3.5 = Movement, gravity eliminated, 3.75 = Muscle flicker, no movement, 4 = Paralysis.	Baseline, Week 24, Week 48
Change From Baseline in Total Quality of Life (TQOL) of Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) at Weeks 24, 48, and 72	Norfolk QOL-DN: 35-item participant-rated questionnaire assess the impact of neuropathy on the quality of life of participants diagnosed with transthyretin amyloid (ATTR). Scoring is based on 35 questions that yield a TQOL as well as 5 subscale scores: activities of daily living, large fiber neuropathy/physical functioning, small fiber neuropathy, autonomic neuropathy, and symptoms. TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.	Baseline, Week 24, Week 48, Week 72
Change From Baseline in 5 Domains of Norfolk QOL-DN at Weeks 24, 48, and 72	Norfolk QOL-DN: 35-item participant-rated questionnaire assess the impact of neuropathy on the quality of life of participants diagnosed with transthyretin amyloid (ATTR). It is summarized in 5 domains: (1) Activities of daily living (score ranges from 0 to 20, where higher score=worse quality of life); (2) Large fiber neuropathy/physical functioning (score ranges from -2 to 58, where higher score=worse condition); (3) Small fiber neuropathy (score ranges from 0 to 16, where higher score=worse condition); (4) Autonomic neuropathy (score ranges from 0 to 12, where higher score=worse condition) and (5) Symptoms (score ranges from 0 to 32, where higher score=less symptoms of disease). Total possible score range= -2 to 138, where higher score=worse quality of life.	Baseline, Week 24, Week 48, Week 72
Change From Baseline in Modified Body Mass Index (mBMI) at Weeks 4, 8, 12, 24, 36, 48, and 72	BMI is calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). mBMI is calculated by multiplying BMI by serum albumin levels [gram/liter (g/L)]. mBMI is measured as kg/m^2*g/L. A progressive decline in mBMI indicates worsening of disease severity.	Baseline, Weeks 4, 8, 12, 24, 36, 48, and 72
Change From Baseline in Physical Component Summary and Mental Component Summary of 36-Item Short Form Survey (SF-36) at Weeks 24, 48, and 72	The SF-36 is a participant administered scale assessing general quality of life. It consists of self-administered 36-item questionnaire that measured 8 health domains: physical function, role-physical, bodily pain, general health, vitality, social function, role-emotional, and mental health. These 8 domains are also summarized as physical and mental component scores. The score for each domain and component score is the mean of the individual question scores, which are scaled from 0 (minimum) to 100 (maximum), where high scores in each dimension and high overall scores indicate a better quality of life.	Baseline, Weeks 24, 48, and 72
Change From Baseline in EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) Index Score at Weeks 24, 48, and 72	EQ-5D-5L: standardized participant (aged >17 years) completed questionnaire consists of 2 components: a health state profile and an optional VAS. EQ-5D health state profile has 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Responses to 5 dimensions comprise a health state/a single utility index value. E.g. if a participant responds "no problems" for each 5 dimensions, then health state was coded as "11111" with a predefined index value to it. Every health state (coded as combination of responses on each of 5 dimensions) has a unique predefined utility index value assigned to it, by EuroQol. Chinese value sets (with all possible health states) is used for adults in the study, range from -0.391 to 1. Higher (positive) scores = better health state.	Baseline, Weeks 24, 48, and 72
Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	An adverse event is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment emergent adverse event is defined as any adverse event started after the first dose. The TEAEs were collected until Week 77.	Baseline up to Week 77
Number of Participants With Categorical Vital Signs Data	Vital signs categorical criteria: 1) pulse rate <40 beats per minute (bpm), or >120 bpm; 2) standing diastolic blood pressure (BP) <50 mmHg, or increase ≥20 mmHg, or decrease ≥20 mmHg; 3) standing systolic BP <90 mmHg, or increase ≥30 mmHg, or decrease ≥30 mmHg; 4) supine diastolic BP <50 mmHg, or increase ≥20 mmHg, or decrease ≥20 mmHg; 5) supine systolic BP <90 mmHg, or increase ≥30 mmHg, or decrease ≥30 mmHg.	Baseline up to Week 72
Number of Participants With Categorical Electrocardiogram (ECG) Data	ECG categorical criteria: 1) ECG mean heart rate <40 beats/minute, or >120 beats/minute; 2) PR interval not otherwise specified ≥300 milliseconds (msec), or baseline >200 msec and %increase ≥25%/ baseline ≤200 msec and %increase ≥50% (% change ≥25/50%); 3) QRS interval not otherwise specified ≥140 msec, or %change ≥50%; 4) QT interval not otherwise specified ≥500 msec; 5) corrected QT (QTc) interval not otherwise specified ≥450 and <480 msec, or ≥480 and <500 msec, or ≥500 msec; or change ≥30 and <60 msec, or change ≥60 msec.	Baseline up to Week 72
Number of Participants With Clinically Significant Echocardiography (ECHO) Value Related to Primary Diagnosis (Transthyretin Amyloidosis [ATTR]) at Baseline, Weeks 24, 48, and 72	Clinically significant ECHO findings include: left ventricular (LV) posterior wall thickness greater than or equal to (>=)13 mm, LV septal thickness >= 13 mm, right ventricular thickness >= 7 mm, ratio of peak mitral early diastolic and atrial contraction velocity (E/A ratio) >= 2, prime septal (E/E) >15, ejection fraction < 50 percent (%), E deceleration time <= 150 millisecond (ms), isovolumic relaxation time (IVRT) <= 70 ms, any valve thickening (> trace regurgitation in mitral, aortic, pulmonary, or tricuspid valves), abnormal respiratory variation of inferior vena cava, pericardial effusion.	Baseline, Weeks 24, 48, and 72
Number of Participants With Clinical Laboratory Abnormalities	Protocol-required safety laboratory assessments include: Lymphocytes <0.8 × LLN; Neutrophils <0.8 × LLN, or >1.2 × ULN; Basophils >1.2 × ULN; Activated Partial Thromboplastin Time >1.1 × ULN; Prothrombin Time >1.1 × ULN; Prothrombin International Normalized Ratio >1.1 × ULN; Bilirubin >1.5 × ULN; Urate > 1.2 × ULN; Cholesterol >1.3 × ULN; Potassium <0.9 × LLN; Phosphate >1.2 × ULN; Bicarbonate >1.1 × ULN; Thyroid Stimulating Hormone >1.2 × ULN; URINE Protein ≥1; URINE Hemoglobin ≥1; Nitrite ≥1; URINE Erythrocytes ≥20; Epithelial Cells ≥6; and Casts >1.	Baseline up to Week 72
Transthyretin (TTR) Concentrations on Day 1 (Baseline), and at Weeks 8, 12, 24, 48, and 72	The TTR (also referred to as pre-albumin) concentrations were determined as pharmacodynamic (PD) biomarkers.	Baseline, Weeks 8, 12, 24, 48, and 72
TTR Stabilization and Percentage and 95% CI of Responders in TTR Stabilization at Post Baseline Visit	The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration (post-denaturation) to the measured TTR concentration (pre-denaturation). Percent Stabilization (%) is the difference between the dosed FOI and the baseline FOI expressed as a percentage of the baseline FOI. Responder was the participant who achieved TTR stabilization (ie, who had been TTR stabilized). Percentage of responders was number of responders / number of evaluable (i.e., analyzed) participants.	Weeks 8, 12, 24, 48, and 72

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): April 28, 2021
• Primary Completion (Actual): February 12, 2023
• Study Completion (Actual): February 12, 2023

Study Registration Dates

• First Submitted: March 17, 2021
• First Submitted That Met QC Criteria: March 30, 2021
• First Posted (Actual): April 2, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: tafamidis meglumine
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Amyloidosis; Polyneuropathies; Amyloid Neuropathies
• Other Study ID Numbers: B3461078

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• 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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes