There are 8 clinical trials
Peripheral neuropathies are diseases that affect the nervous system outside the brain and spinal cord, their prevalence is 1% in the general population, the causes are extremely varied with more than 200 identified causes; the main ones are diabetes, excessive alcohol consumption and chemotherapy. They may be sometimes disabling but generally preserve autonomy. Transthyretin amyloidosis is a rare multisystematic hereditary disease with autosomal dominant transmission. They present usually as a peripheral neuropathies (FAP). They are due to a point mutation of the transthyretin gene (chr 18q). FAP is secondary to endoneurial amyloid deposits and are characterized by a slowly progressive sensory, motor and autonomic. FAP is the most severe hereditary polyneuropathy of the adult are irreversible and fatal within 5 to 12 years from onset. Most frequent mutation of TTR gene is located on the second exon; but more than 100 mutations have been reported. Prevalence of FAP is 1 per 1 million inhabitants. They have been reported until 1990s' in four endemic areas North of Portugal, Sweden, Japan and Majorca. In these areas, diagnosis is facilitated because of the stereotypical presentation : a length-dependent polyneuropathy with predominant involvement of thermal and pain sensations and autonomic dysfunction, early onset in the third decade and a predominant Met30 TTR mutation. Positive family history is frequent 85% (one of the parents is affected). Diagnosis requires detection of TTR mutation by molecular biology (blood sample) and characterization of amyloid deposit on labial salivary gland biopsy.
Conversely to endemic areas, look for V30M mutation is not enough to exclude TTR-FAP, TTR gene sequencing is required. --- V30M ---
Description: Rate of amyloidogenic TTR mutation in progressive idiopathic polyneuropathy
Measure: Rate of amyloidogenic TTR mutation Time: 1 dayDescription: Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : disabling neuropathy (including ataxic).
Measure: To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy Time: 1 dayDescription: Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Measure: To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Time: 1 dayDescription: Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
Measure: To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy. Time: 1 dayThis study will examine whether Fx-1006A is effective in halting the progression of Familial Amyloid Polyneuropathy (FAP). Deposition of TTR amyloid is associated with a variety of human diseases. Deposition of amyloid fibrils of variant TTR (primarily V30M) in peripheral nerve tissue produces the condition called FAP. The prevention of the formation of amyloid by stabilization of the TTR native state should constitute an effective therapy for amyloid diseases. Therapeutic intervention with a TTR stabilizer drug, such as Fx-1006A, is hypothesized to stop progression of the disease in FAP patients. FAP is a uniformly fatal disease and Fx-1006A is intended to halt the relentless neurological deterioration FAP patients experience. This Phase 2/3 study will enroll early to mid-stage FAP patients in order to interrupt and stabilize the disease at a point in time where progression of motor and autonomic dysfunction can be maximally effected. Male and female patients with FAP with documented V30M TTR mutation will receive Fx-1006A or placebo once daily for a period of eighteen (18) months.
Deposition of amyloid fibrils of variant TTR (primarily V30M) in peripheral nerve tissue produces the condition called FAP. --- V30M ---
Male and female patients with FAP with documented V30M TTR mutation will receive Fx-1006A or placebo once daily for a period of eighteen (18) months. --- V30M ---
2. Documented V30M TTR mutation. --- V30M ---
Description: Response to treatment was indicated by either improvement (decrease from baseline) or stabilization (change from baseline of 0 to less than[<] 2) in NIS-LL score, based on mean of 2 scores in 1 week period. NIS-LL: assessed muscle weakness, reflexes, sensation. Each item scored separately for left, right limbs. Components of muscle weakness scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.
Measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 18 Time: Month 18Description: 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= -2 to 138, where higher score=worse quality of life.
Measure: Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 18 Time: Baseline, Month 18Description: NIS-LL: assessed muscle weakness, reflexes and 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) are scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.
Measure: Change From Baseline in Neuropathy Impairment Score- Lower Limb (NIS-LL) Score at Month 6, 12 and 18 Time: Baseline, Month 6, 12, 18Description: Response to treatment was indicated by either improvement (decrease from baseline) or stabilization (change from baseline of 0 to <2) in NIS-LL score, based on mean of 2 scores in 1 week period. NIS-LL: assessed muscle weakness, reflexes, sensation. Each item scored separately for left, right limbs. Components of muscle weakness scored on 0 (normal) to 4 (paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.
Measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 and 12 Time: Month 6, 12Description: 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= -2 to 138, where higher score=worse quality of life.
Measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 and 12 Time: Baseline, Month 6, 12Description: Norfolk QOL-DN:35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptom present, 0=symptom absent. Item 8-35: scored on 5-point Likert scale: 0=no problem, 4=severe problem (except item 32: -2=much better, 0=about same, 2=much worse). Norfolk QOL-DN summarized in 5 domains(score range):physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment, for each. Total score=-2 to138(higher score=worse QOL).
Measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, 12 and 18 Time: Baseline, Month 6, 12, 18Description: Summated 7 score: composite score included five Nerve Conduction Studies (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 Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function.
Measure: Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6, 12 and 18 Time: Baseline, Month 6, 12, 18Description: Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function.
Measure: Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6, 12 and 18 Time: Baseline, Month 6, 12, 18Description: BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation associated with malnutrition. A progressive decline in mBMI indicated worsening of disease severity.
Measure: Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, 12 and 18 Time: Baseline, Month 6, 12, 18Description: TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) 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.
Measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer Time: Week 8, Month 6, 12, 18Tafamidis has been developed as an oral specific stabilizer of transthyretin tetramer.
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 ---
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 weeksDescription: 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 78Description: 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 78Description: 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 78Description: 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 78Description: 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 StudyDescription: 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 78Description: 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 78Description: 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 78The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.
b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. --- Val30Met ---
Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: Standardized Uptake Values (SUV) in focal anatomical regions of the heart following 80-200 milligrams (mg) dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV in focal anatomical regions of the heart following an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV of whole heart following 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.
Measure: SUV of whole heart following an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.
Measure: Focal radioactivity uptake after 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.
Measure: Focal radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.
Measure: Total radioactivity uptake after 80-200 mg dose of anti-SAP mAb Time: Up to Day 6Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.
Measure: Total radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg Time: Up to Day 6Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Maximum concentration in plasma (Cmax) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Time associated with Cmax (Tmax) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Clearance of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Terminal half-life (T1/2) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.
Measure: Area under the concentration-time profile (AUC) of total mAb Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: Cmax of 89Zr- GSK2398852 pharmacokinetics of radioactivity (radio-PK) Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: Tmax of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: T1/2 of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.
Measure: AUC of 89Zr- GSK2398852 radio-PK Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-doseDescription: An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention.
Measure: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) Time: Up to Day 28Description: Rash will be graded as Grade 1 to Grade 4 based on symptoms and body surface area affected.
Measure: Number of subjects with skin rashes Time: Up to Day 28Description: Cardiovascular adverse events will include myocardial infarction/unstable angina, congestive heart failure, arrhythmias, valvulopathy, pulmonary hypertension, cerebrovascular events/stroke and transient ischemic attack, peripheral arterial thromboembolism, deep venous thrombosis/pulmonary embolism and revascularization.
Measure: Number of subjects with cardiac adverse events Time: Up to Day 28Description: Number of subjects with infusion related reactions will be summarized.
Measure: Number of subjects with infusion related reactions Time: Up to Day 28Description: The following hematology parameters will be assessed: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Measure: Number of subjects with abnormal hematology parameters Time: Up to Day 28Description: The following clinical chemistry parameters will be evaluated: blood urea nitrogen (BUN), creatinine, glucose (non-fasting), potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin.
Measure: Number of subjects with abnormal clinical chemistry parameters Time: Up to Day 28Description: The following parameters will be evaluated: specific gravity, potential hydrogen (pH), glucose, protein, blood and ketones by dipstick method. Urine microscopy will be performed if indicated.
Measure: Number of subjects with abnormal urine parameters Time: Up to Day 28Description: The following cardiac chemistry parameters will be evaluated: troponin T and N-terminal prohormone of brain natriuretic peptide (NT-ProBNP).
Measure: Number of subjects with cardiac safety parameters of clinical significance Time: Up to Day 28Description: 12-lead ECGs will be obtained in a semi-supine position using an automated ECG machine after approximately 5 minutes of rest for the subject.
Measure: Number of subjects with abnormal electrocardiogram (ECG) Time: Up to Day 28Description: Inpatient cardiac monitoring will be performed using inpatient lead II cardiac telemetry.
Measure: Number of subjects with abnormal inpatient cardiac telemetry Time: Up to Day 11Description: Outpatient cardiac monitoring will be performed using a non-implantable remote cardiac telemetry device.
Measure: Number of subjects with abnormal outpatient cardiac telemetry Time: Up to Day 18Description: Temperature will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal temperature Time: Up to Day 28Description: Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal blood pressure Time: Up to Day 28Description: Pulse rate will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal pulse rate Time: Up to Day 28Description: Respiratory rate will be measured in a semi-supine position after 5 minutes of rest.
Measure: Number of subjects with abnormal respiratory rate Time: Up to Day 28Description: A brief physical examination will be performed, including assessments of the skin, lungs, cardiovascular system and abdomen (liver and spleen).
Measure: Number of subjects with abnormal physical examination findings Time: Up to Day 11The goal of this study is to investigate the prevalence of Transthyretin-Related Familial Amyloidotic Polyneuropathy (TTR-FAP) in a cohort of 500 subjects at risk for TTR-FAP, based on the subject's clinical presentation.
It accounts several thousand cases worldwide, with Val30Met mutation identified in most patients and with endemic foci in Portugal, Sweden and Japan. --- Val30Met ---
The most common mutation in TTR-FAP is a replacement of valine by methionine (TTR V30M). --- V30M ---
This study is an online (web-based) or paper-based survey for patients with transthyretin familial amyloidosis polyneuropathy (TTR-FAP) and caregivers. The results will be used to describe the emotional, physical, and financial impact of having TTR-FAP or caring for someone who has the disease.
In this outcome, number of participants with each type of resulted mutation type (Val30Met, wild type TTR, Phe64Leu, Ser77Tyr, Thr60Ala or other than these) were reported. --- Val30Met ---
Description: Main characteristics included were education level and employment status which were asked from all participants and caregivers. Type of job (full-time, part-time) was asked only from those participants and caregivers who provided their employment status as employed. Those who were unemployed reported their cause of unemployment, whether it was due to ATTR or not.
Measure: Demographical Characteristics of Participants Time: Baseline (Day 1)Description: Duration of disease was defined as the time from diagnosis of disease until baseline visit. This outcome measure was planned to be assessed for reporting arm of participants diagnosed with ATTR.
Measure: Disease Characteristics of Participants: Disease Duration Time: Baseline (Day 1)Description: Genetic mutation leads to misfolding of protein transthyretin (TTR) which results in ATTR. In this outcome, number of participants with each type of resulted mutation type (Val30Met, wild type TTR, Phe64Leu, Ser77Tyr, Thr60Ala or other than these) were reported. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.
Measure: Disease Characteristics of Participants: Mutation Type Time: Baseline (Day 1)Description: TTR protein is primarily synthesized in the liver. Liver transplantation was considered as one of the measure to eliminate the main source of variant TTR. In the study, participants who were diagnosed with ATTR were asked for their liver transplantation status (whether they had transplantation or not). In this outcome measure, number of participants with liver transplant status were reported. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.
Measure: Disease Characteristics of Participants: Liver Transplantation Status Time: Baseline (Day 1)Description: Family history of participants diagnosed with ATTR was assessed to determine whether family history of ATTR was a significant risk factor for ATTR or not. This outcome was planned to be assessed for reporting arm of participants diagnosed with ATTR.
Measure: Disease Characteristics of Participants: Number of Participants With Family History of ATTR Time: Baseline (Day 1)Description: Mobility, i.e., ability to walk was assessed as a part of loss of functioning in the participants diagnosed with ATTR. In this outcome, number of participants with their different mobility status along with the use of mobility aids (able to walk normally, some problems with feet but able to walk without difficulty, some difficulty walking but can walk without help, confined to bed all the time, need 1 cane or crutch to walk, need 2 canes/crutches or a walker to walk) were reported.
Measure: Disease Characteristics of Participants: Mobility Status Time: Baseline (Day 1)Description: SF-12 was a patient reported outcome survey that represented overall health status by measuring 8 health-related aspects of an individual: Body pain, general mental health, perception of general health, physical functioning, role limitations caused by mental condition, role limitations caused by a physical condition, social functioning, and vitality. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Responses on the SF-12 were also used to calculate 2 summary scores: Physical component score (PCS) and mental component score (MCS). The score range for each of these 2 summary scores was from 0 (poor health) to 100 (better health), where 100 indicated good health condition.
Measure: 12-Item Short-Form Health Survey (SF-12) Scores Time: Baseline (Day 1)Description: HADS: participant rated 14-item questionnaire with 2 subscales; HADS-anxiety scale (HADS-A) and HADS-depression scale (HADS-D). HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items and the participant responds as to how each item applies to him/her over the past week prior to baseline visit, on 4-point response scale. Separate scores were calculated for anxiety and depression with score ranges from 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score range was from 0 to 21 for each subscale; higher score indicating greater severity of anxiety and depression symptoms.
Measure: Hospital Anxiety and Depression Scale (HADS): Depression and Anxiety Subscale Scores Time: Baseline (Day 1)Description: EQ-5D-3L: participant rated questionnaire to assess generic health status in two parts: single utility score and visual analog scale. For utility score, participants rated their current health state on 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression with each dimension having three levels of function: 1 indicates no problem; 2 indicates some problem; 3 indicates extreme problem. Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score was transformed and results in a total score range of 0.05 to 1.00; higher scores indicating a better health state.
Measure: Euro Quality of Life (EQ-5D-3L)- Health State Profile Utility Score Time: Baseline (Day 1)Description: EQ-5D: participant rated questionnaire to assess generic health status in two parts: single utility score and visual analog scale. The VAS component rated the current health state on a scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicating a better health state.
Measure: Euro Quality of Life (EQ-5D-3L)- Visual Analog Scale (VAS) Score Time: Baseline (Day 1)Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asked about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Percentage of work time missed of participants were recorded and reported.
Measure: Work Productivity and Activity Impairment- Specific Health Version (WPAI-SH): Percent of Work Time Missed Time: Baseline (Day 1)Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asks about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.
Measure: Work Productivity and Activity Impairment- Specific Health Version: Percent Impairment While Working Time: Baseline (Day 1)Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asked about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.
Measure: Work Productivity and Activity Impairment- Specific Health Version: Percent Overall Work Impairment Time: Baseline (Day 1)Description: The WPAI assesses work productivity and impairment. It was a 6-item questionnaire used to assess the degree to which a specified health problem affected work productivity and regular activities over the past 7 days prior to baseline visit. The questionnaire asks about current employment status, hours worked, hours missed from work and degree to which a specified health problem (ATTR) or caregiving affected work productivity and regular activities. Component scores included percent work time missed due to the health problem; percent impairment while working due to problem; percent overall work impairment due to problem; and percent activity impairment due to problem. The computed percentage range for each sub-scale was from 0-100, where higher numbers indicating greater impairment and less productivity.
Measure: Work Productivity and Activity Impairment- Specific Health Version: Percent Activity Impairment Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).
Measure: Healthcare Resource Use Survey: Number of Outpatient Visits to Healthcare Providers Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).
Measure: Healthcare Resource Use Survey: Number of Hospitalizations Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR and caregivers was assessed by questions concerning a variety of different types of treatment and resources including outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (for example, costs of travel to receive care).
Measure: Healthcare Resource Use Survey: Number of Emergency Care Visits Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs. Number of participants (diagnosed with ATTR) who visited non-medical practitioners (nutrition consultant/dietician, chiropractor, acupuncturist, massage therapist, occupational therapist or other than these) for symptomatic treatments were reported.
Measure: Healthcare and Resource Use Survey: Symptomatic Treatment of Participants Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs. Number of visits of participants (diagnosed with ATTR) who visited non-medical practitioners (nutrition consultant/dietician, chiropractor, acupuncturist, massage therapist, occupational therapist or other than these) for symptomatic treatments were reported.
Measure: Healthcare Resource Use Survey: Number of Symptomatic Treatment Visits Time: Baseline (Day 1)Description: Healthcare resources use survey of participants diagnosed with ATTR was assessed by questions concerning a variety of treatments and resources included outpatient visits to healthcare providers, hospitalizations, emergency/urgent care visits, symptomatic treatments, and out-of-pocket costs (expenditure on nutritional supplements, non-prescription medications and travel to receive medical care).
Measure: Healthcare Resource Use Survey: Out-of-Pocket Costs Time: Baseline (Day 1)Description: Participants diagnosed with ATTR rated their pain due to the health condition based on 3 items: pain right now, average pain in the past week, and worst pain in the past week prior to baseline visit. All 3 items were rated on an 11-point numeric rating scale ranging from 0=none to 10=severe pain, where higher scores indicated severe pain.
Measure: Participants Pain Score Time: Baseline (Day 1)Description: Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of neuropathy on the quality of life of participants diagnosed with ATTR. Scoring was 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. This outcome measure was planned to be analyzed only for the reporting arm of participants diagnosed with ATTR.
Measure: Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL): Total Scores Time: Baseline (Day 1)Description: Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of neuropathy on the quality of life of participants diagnosed with ATTR. It was 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. This outcome measure was analyzed only for the participants diagnosed with ATTR.
Measure: Norfolk Quality of Life-Diabetic Neuropathy Total Quality of Life: Subscale Scores Time: Baseline (Day 1)Description: KCCQ was a 23-item participant-completed questionnaire that assessed health status and health-related quality of life (HRQoL) in participants with heart failure. It was quantified in to following 10 summary scores: physical limitation, symptom frequency, symptom severity, and symptom stability, total symptoms, quality of life, social interference, self-efficacy, overall summary and clinical summary. Each summary score was scaled to range from 0 (minimum) to 100 (maximum), with higher scores representing greater disability. Total score ranged from 0 to 100, where higher scores indicated better functioning, fewer symptoms, and better disease specific quality of life.
Measure: Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores Time: Baseline (Day 1)Description: ZBI was a 22-item questionnaire designed to evaluate five broad aspects of caregiver burden in terms of personal and role strain associated with caregiving. Five broad aspects were: burden in the relationship, emotional well-being, social and family life, finances, loss of control over one's life. Each item rated on a 5 point scale anchored at 0 for "never" and 4 for "nearly always." Total score ranges from 0-88 with higher scores indicating increased burden of care.
Measure: Zarit Burden Interview (ZBI): Total Scores Time: Baseline (Day 1)Description: A questionnaire designed to evaluate aspects of caregiver burden in terms of personal and role strain associated with caregiving. Total score of ZBI scale ranges from 0-88 with higher scores indicating increased burden of care. Five subscale scores were also calculated: (1) Burden in the relationship (consist of 6-items, ranging from 0 to 24 where higher scores indicating increased burden in relationship); (2) Emotional well-being (consisting of 7-items, ranging from 0 to 28 where higher scores indicating worse condition; (3) Social and family life (consisting of 4-items, ranging from 0 to 16 where higher scores indicating worse life condition); (4) Finances (consisting of a single item, scored from 0 to 4 where higher scores indicating worse financial condition); and (5) Loss of control over one's life (consisting of 4-items, ranging from 0 to 16 where higher scores indicating worse control over life).
Measure: Zarit Burden Interview: Subscale Scores Time: Baseline (Day 1)Description: Caregivers completed a series of questions related to the number of hours per week spent on providing care and support to the participants diagnosed with ATTR.
Measure: Caregiver Burden Items Assessment: Number of Hours Per Week Spent in Care of the Participants With ATTR Time: Baseline (Day 1)Description: Caregivers completed a series of questions related to the loss in their working time while providing care and support to the participants diagnosed with ATTR.
Measure: Caregiver Burden Items Assessment: Work Time Lost Time: Baseline (Day 1)Description: Caregivers completed a series of questions related to the total cost spent on providing healthcare support to participants diagnosed with ATTR.
Measure: Caregiver Burden Items Assessment: Total Cost Time: Baseline (Day 1)Development of a new MS-based biomarker for the early and sensitive diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy from blood
Even though more than 100 point mutations are known to cause the disease, the most common amino acid change is V30M. --- V30M ---
Description: New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.
Measure: Development of a new MS-based biomarker for the early and sensitive diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy from blood Time: 24 monthsDescription: the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.
Measure: Number of correctly identified patients with Transthyretin-Related Familial Amyloidotic Polyneuropathy Time: 36 monthsThis is an open-label, multicenter, international study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with non-V30M TTR amyloidosis. Strong pre-clinical and clinical evidence support a daily dose of 20 mg of Fx-1006A to be the optimum dose to achieve stabilization of tetrameric TTR in ATTR-PN patients. Since disease presentation is similar between V30M and non-V30M TTR mutations associated with ATTR-PN and Fx-1006A has been shown to stabilize wild-type and V30M TTR in vitro and ex vivo, the present study is being conducted to determine the effects of Fx-1006A on TTR stabilization in ATTR-PN patients with TTR mutations other than V30M. Safety and exploratory efficacy of Fx-1006A administered once daily for 12 months will also be evaluated in this patient population. This is an open-label, multicenter, international study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with non-V30M TTR amyloidosis. The study will be conducted in two parts. Part 1 will include a six-week dosing period during which all enrolled patients will receive oral Fx-1006A 20 mg soft gelatin capsules once daily for six weeks. At Week 6, blood samples will be collected from each patient to determine TTR stabilization. Patients who complete the Week 6 visit will continue receiving daily oral Fx-1006A 20 mg for up to a total of 12 months during Part 2 of this study. If it is determined that a patient is not stabilized at Week 6, the patient will be discontinued from the study. During Part 2, clinical outcomes will be measured at Months 6 and 12, based on NIS, Norfolk QOL-DN, mBMI, NCS, HRDB, SF-36, Karnofsky score, and echocardiography; NT-pro-BNP and troponin I levels will be measured at Baseline, Weeks 2 and 6, and Months 3, 6, and 12. Pharmacokinetic measurements will be made using samples collected at Baseline, Week 6, and Months 6 and 12. Safety and tolerability will be assessed throughout the study based on vital signs, physical examinations, ECG, echocardiography, 24-hour Holter monitoring, clinical laboratory tests (hematology, serum chemistry, and urinalysis), and monitoring adverse events and concomitant medication use. Day 1 will be defined as administration of the first dose of study drug. Clinic Visits will be conducted during Screening (Days -30 to -1) and at Baseline (Day 0), and Week 2, and Week 6, and Months 3, 6, and 12 (± 2 weeks of the scheduled date for post-Baseline visits). Monthly telephone contacts (+ 1 week of the scheduled date) will be made during months in which no investigative site visits are scheduled (Months 4, 5, 7, 8, 9, 10, and 11) for assessment of adverse events and concomitant medications. A final telephone contact to assess adverse events and concomitant medication usage will be made 30 days after the last dose of study drug. Patients who discontinue from the study at any time following enrollment will have a final visit performed, including all safety assessments, at the time of discontinuation. Any patient discontinuing after the Month 6 visit will also have all exploratory assessments performed.
The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis. --- V30M ---
The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis This is an open-label, multicenter, international study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with non-V30M TTR amyloidosis. --- V30M ---
The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis This is an open-label, multicenter, international study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with non-V30M TTR amyloidosis. --- V30M --- --- V30M ---
Since disease presentation is similar between V30M and non-V30M TTR mutations associated with ATTR-PN and Fx-1006A has been shown to stabilize wild-type and V30M TTR in vitro and ex vivo, the present study is being conducted to determine the effects of Fx-1006A on TTR stabilization in ATTR-PN patients with TTR mutations other than V30M. --- V30M ---
Since disease presentation is similar between V30M and non-V30M TTR mutations associated with ATTR-PN and Fx-1006A has been shown to stabilize wild-type and V30M TTR in vitro and ex vivo, the present study is being conducted to determine the effects of Fx-1006A on TTR stabilization in ATTR-PN patients with TTR mutations other than V30M. --- V30M --- --- V30M ---
Since disease presentation is similar between V30M and non-V30M TTR mutations associated with ATTR-PN and Fx-1006A has been shown to stabilize wild-type and V30M TTR in vitro and ex vivo, the present study is being conducted to determine the effects of Fx-1006A on TTR stabilization in ATTR-PN patients with TTR mutations other than V30M. --- V30M --- --- V30M --- --- V30M ---
Since disease presentation is similar between V30M and non-V30M TTR mutations associated with ATTR-PN and Fx-1006A has been shown to stabilize wild-type and V30M TTR in vitro and ex vivo, the present study is being conducted to determine the effects of Fx-1006A on TTR stabilization in ATTR-PN patients with TTR mutations other than V30M. --- V30M --- --- V30M --- --- V30M --- --- V30M ---
This is an open-label, multicenter, international study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with non-V30M TTR amyloidosis. --- V30M ---
- Patient has TTR-associated amyloidosis with V30M mutation. --- V30M ---
Description: TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) 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.
Measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Week 6 Time: Week 6Description: TTR tetramer was assessed using a validated immunoturbidimetric assay. The FOI 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.
Measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Month 6 and 12 Time: Month 6, Month 12Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) Time: Baseline up to 30 days after the last doseDescription: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. On the basis of intensity, grade 3 was referred as severe, grade 4 as life-threatening and grade 5 as death.
Measure: Number of Participants With Greater Than or Equal to Grade 3 Treatment-Emergent Adverse Events Time: Baseline up to 30 days after the last doseDescription: ECHO: investigator assessed test to assess cardiac function. ECHO abnormality criteria: any abnormality, valvular abnormality, pericardial effusion, abnormal regional wall motion, inferior vena cava respiratory variation, posterior (P) left ventricular (LV) wall/septal (S) thickness, right ventricular thickness, ejection fraction, ratio of early (E) diastolic transmitral flow and atrial(A) contraction velocity (E/A), ratio of 'E'to lateral/septal mitral annular velocity (e') (E/e'prime lateral, E/e'prime septal), E deceleration time (DT), isovolumic relaxation time (IVRT).
Measure: Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings Time: Day 1 up to Month 12Description: ECG: investigator assessed test to assess cardiac function. ECG abnormality criteria: any abnormality, arrhythmia, rhythm, conduction, morphology, myocardial infarction, ST segment, T waves and abnormal U waves.
Measure: Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings Time: Day 1 up to Month 12Description: Holter monitoring recorded heart rhythm. Holter monitoring abnormality criteria: any abnormality, atrial fibrillation/flutter, atrial tachycardia, non-sustained ventricular tachycardia (VT), sustained VT and sinus pause.
Measure: Number of Participants With Clinically Significant Treatment-Emergent Holter Monitoring Findings Time: Day 1 up to Month 12Description: NIS assessed cranial nerves(nerve 3,6; facial, palate and tongue weakness),muscle weakness (respiratory; neck, elbow(E), wrist(W), finger(F), hip, knee(K) flexion; shoulder, thumb abduction; brachioradialis; E, W, hip, K extension; F spread; toe, dorsal and plantar ankle flexors; toe extensors); score: 0-4, higher score=more weakness, reflexes(biceps and triceps brachii; brachioradialis; quadriceps femoris; triceps surae), index F and great toe sensation(touch pressure, pin-prick, vibration, joint position)score:0=normal,1=decreased or 2=absent. Total score=0-244, higher score=more impairment.
Measure: Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: NIS-LL: assessed muscle weakness, reflexes and 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) are scored on 0 to 4 scale, higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.
Measure: Change From Baseline in the Neuropathy Impairment Score-Lower Limb (NIS-LL) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Response to treatment was indicated by either improvement (decrease from baseline) or stabilization (change from baseline of 0 to less than [<] 2) in Neuropathy Impairment Score- Lower Limb (NIS-LL) score, based on mean of 2 scores in 1 week period. NIS-LL: assessed muscle weakness, reflexes, sensation. Each item scored separately for left, right limbs. Components of muscle weakness scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.
Measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6, Month 12 Time: Month 6, Month 12Description: TQOL= sum of all Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) items,a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on QOL of participants with DN; 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). Total TQOL score=-2 to 138;higher score=worse quality of life.
Measure: Change From Baseline in Total Quality of Life (TQOL) Score at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Norfolk QOL-DN:35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7: scored as 1=symptom present, 0=symptom absent. Item 8-35: scored on 5-point Likert scale:0=no problem, 4=severe problem(except item 32: -2=much better, 0=about same, 2=much worse).Norfolk QOL-DN summarized in 5 domains (score range): physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptom(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12);higher score=greater impairment, for each. Total score=-2 to 138 (higher score=worse QOL).
Measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: NCS: quantitative measures of peripheral nerve dysfunction consists of 5 attributes: peroneal nerve (PN) motor distal latency, PN compound muscle action potential, PN motor conduction velocity, tibial nerve distal motor latency, sural nerve sensory nerve action potential. Normal deviates (Z-score) summated into composite score (higher score=worsened nerve fiber function). Z-score is the defined position of the result in normal probability distribution with a mean of 0 and standard deviation (std) of 1 and describes how far a score is (in std) from the mean.
Measure: Change From Baseline in Nerve Conduction Studies (NCS) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: HRDB test was used to evaluate the cardio-vagal response. Participant took a series of 8 deep breaths and average heart rate difference was measured and compared to normative data. The main factor affecting HRDB is age, with older patients showing less heart rate variability. R-R (time between two consecutive R waves in the electrocardiogram) response to deep breathing was reported as the normal deviates (Z-score), the defined position of the result in normal probability distribution with a mean of 0 and standard deviation (std) of 1 and describes how far a score is (in std) from the mean.
Measure: Change From Baseline in Heart Rate Response to Deep Breathing (HRDB) at Month 6 and Month 12 Time: Baseline, Month 6, Month 12Description: 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)]. mBMI was measured as kg/m^2*g/L. A progressive decline in mBMI indicated worsening of disease severity.
Measure: Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health and two total scores (physical component summary [PCS] and mental component summary [MCS]. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).
Measure: Change From Baseline in Overall Quality of Life and Individual Domains of the Short-form-36 (SF-36) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Echocardiography was used to measure interventricular septal thickness (IVST), posterior left ventricular wall thickness (PLVWT), right ventricular wall thickness (RVWT), left atrial diameter (LAD): anterior-posterior (ant-post), medio-lateral, superior-inferior (sup-inf) and left ventricular end diastolic diameter (LVED), relative LV wall thickness (RLVWT).
Measure: Change From Baseline in Echocardiography (ECHO) Parameters at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Left atrial volume was measured by echocardiography.
Measure: Change From Baseline in Left Atrial Volume at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Cardiac MRI was done to measure left ventricular (LV) end systolic volume, left ventricle (LV) stroke volume.
Measure: Change From Baseline in Left Ventricular (LV) End Systolic Volume, Left Ventricle (LV) Stroke Volume at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Fractional shortening (FS) is the fraction of any diastolic dimension that is lost in systole. Percent of FS was calculated as difference between end-diastolic dimension (EDD) and end-systolic dimension (EDS) divided by EDD.
Measure: Change From Baseline in Fractional Shortening at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Cardiac MRI was done to measure left ventricular ejection fraction (LVEF) which was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction.
Measure: Change From Baseline in Left Ventricular (LV) Ejection Fraction at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: LV mass was calculated from the product of the myocardial volume and specific gravity of heart muscle, estimated by echocardiography. Increased LVM was associated with cardiovascular morbidity and mortality.
Measure: Change From Baseline in Left Ventricular Mass (LVM) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. IVRT is the time between the closure of the aortic valve and the opening of the mitral valve. Mitral deceleration time (MDT) was the time taken from the maximum E point wave to baseline. E wave arises due to early diastolic filling.
Measure: Change From Baseline in Isovolumetric Relaxation Time (IVRT), Mitral Deceleration Time at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: The diameter at the base of the aortic root, the basal ring, is also called the aortic annulus diameter.
Measure: Change From Baseline in Aortic Annulus Diameter at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Tricuspid peak velocity was measured by echocardiography.
Measure: Change From Baseline in Tricuspid Peak Velocity at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Systolic right ventricular pressure can be estimated on echocardiography by adding right atrial pressure (RAP) to the trans-tricuspid gradient derived from the tricuspid regurgitation velocity.
Measure: Change From Baseline in Tricuspid Pulmonary Artery Systolic Pressure (PASP) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. Doppler principle was used to measure the mitral peak early (E) diastolic transmitral flow, mitral peak atrial (A) contraction velocity and annular velocities at the lateral and septal areas of the mitral annulus. s': systolic velocity during ejection, e': early diastolic mitral annular velocity, a': late diastolic mitral annular velocity.
Measure: Change From Baseline in Doppler Data at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Doppler echocardiography was a procedure which used ultrasound technology to examine the heart. Ratio of early (E) diastolic transmitral flow velocity and atrial (A) contraction velocity (E/A) and ratio of the early (E) diastolic transmitral flow velocity to the mitral annular velocity (e') (E/e') were estimated.
Measure: Change From Baseline in e:e' Lateral Ratio , Ratio of Peak Mitral Early Diastolic and Atrial Contraction Velocity (E/A Ratio) at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: LV mass was calculated from the product of the myocardial volume and specific gravity of heart muscle, estimated by echocardiography. QRS score (the sum of QRS voltages in the peripheral leads) was used as an index of "electrical" LV mass.
Measure: Change From Baseline in Left Ventricular (LV) Mass/Voltage Ratio at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: LA volume index (LAVI), was the value of LA volume divided by body surface area, to measure LA size.
Measure: Change From Baseline in Left Atrial (LA) Volume Index at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: NT-proBNP was a cardiac marker which had the prognostic value for participants with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage.
Measure: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) at Week 2, Week 6, Month 3, Month 6, Month 12 Time: Baseline, Week 2, Week 6, Month 3, Month 6, Month 12Description: Karnofsky performance score is used to quantify participant's general well-being and activities of daily life and participants are classified based on their functional impairment. Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (no evidence of disease). Higher score means higher ability to perform daily tasks.
Measure: Change From Baseline in Karnofsky Performance Status Scale at Month 6, Month 12 Time: Baseline, Month 6, Month 12Description: Troponin I is a cardiac injury biomarker. Higher concentrations of this marker in blood are associated with heart injury.
Measure: Change From Baseline in Troponin I Levels at Week 2, Week 6 , Month 3, Month 6, Month 12 Time: Baseline, Week 2, Week 6 , Month 3, Month 6, Month 12