Transthyretin Amyloid Polyneuropathy (ATTR-PN) Clinical Trial
Official title:
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
| Verified date | February 2024 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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).
| Status | Completed |
| Enrollment | 15 |
| Est. completion date | February 12, 2023 |
| Est. primary completion date | February 12, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 80 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| China | Peking union hospital of Chinese academy of medical sciences | Beijing | |
| China | Peking union hospital of Chinese academy of medical sciences | Beijing | |
| China | Peking University First Hospital | Beijing | Beijing |
| China | Peking University Third Hospital | Beijing | Beijing |
| China | Tiantan Hospital Capital Medical University | Beijing | |
| China | Xuanwu Hospital Capital Medical University | Beijing | |
| China | The First Affiliated Hospital of Fujian Medical University | Fuzhou | Fujian |
| China | NanFang Hospital of Southern Medical University | Guangzhou | Guangdong |
| China | Huashan Hospital Fudan University | Shanghai | Shanghai |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer |
China,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 | |
| Secondary | 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 |