SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation T60A

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 3 clinical trials

Clinical Trials


1 A Phase 4 Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of Hereditary Transthyretin-Mediated (ATTRv) Amyloidosis With a V122I or T60A Mutation

To evaluate the effectiveness of patisiran in patients with ATTRv amyloidosis with polyneuropathy who have a V122I or T60A mutation.

NCT04201418
Conditions
  1. Hereditary Transthyretin-mediated (ATTRv) Amyloidosis
  2. Polyneuropathy
Interventions
  1. Drug: Patisiran
MeSH:Polyneuropathies Amyloidosis
HPO:Amyloidosis Motor polyneuropathy Polyneuropathy

A Phase 4 Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of Hereditary Transthyretin-Mediated (ATTRv) Amyloidosis With a V122I or T60A Mutation. --- V122I --- --- T60A ---

A Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of ATTRv Amyloidosis With a V122I or T60A Mutation To evaluate the effectiveness of patisiran in patients with ATTRv amyloidosis with polyneuropathy who have a V122I or T60A mutation. --- V122I --- --- T60A ---

A Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of ATTRv Amyloidosis With a V122I or T60A Mutation To evaluate the effectiveness of patisiran in patients with ATTRv amyloidosis with polyneuropathy who have a V122I or T60A mutation. --- V122I --- --- T60A --- --- V122I --- --- T60A ---

PND Scores: Stage 0=No symptoms, Stage 1=Sensory disturbances but preserved walking capability, Stage 2=Impaired walking capacity, but ability to walk without a stick or crutches, Stage 3A/B=Walking with the help of 1 or 2 sticks or crutches, Stage 4=confined to wheel chair or bedridden.. Inclusion Criteria: - Diagnosed with ATTRv amyloidosis with polyneuropathy, with a documented V122I or T60A mutation - PND score of I-IIIB at baseline. --- V122I --- --- T60A ---

Exclusion Criteria: - New York Heart Association (NYHA) heart failure classification ≥3 - Karnofsky Performance Status (KPS) <60% - Unstable congestive heart failure (CHF) - Known primary amyloidosis (AL) or leptomeningeal amyloidosis - Prior major organ transplant - Previously received patisiran - Previous treatment with a TTR silencing therapy Inclusion Criteria: - Diagnosed with ATTRv amyloidosis with polyneuropathy, with a documented V122I or T60A mutation - PND score of I-IIIB at baseline. --- V122I --- --- T60A ---

Primary Outcomes

Description: PND Scores: Stage 0=No symptoms, Stage 1=Sensory disturbances but preserved walking capability, Stage 2=Impaired walking capacity, but ability to walk without a stick or crutches, Stage 3A/B=Walking with the help of 1 or 2 sticks or crutches, Stage 4=confined to wheel chair or bedridden.

Measure: Percentage of Participants with Stable or Improved Polyneuropathy Disability (PND) Score at 12 Months Relative to Baseline

Time: Baseline, Month 12

2 Cross-sectional, Non-interventional Burden Of Disease (Bod) Study In Patients With Transthyretin Familial Amyloidosis Polyneuropathy (Ttr-fap) Or Transthyretin Cardiomyopathy (ttr-cm) And Caregivers

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.

NCT01604122
Conditions
  1. Transthyretin Familial Amyloidosis Polyneuropathy (TTR-FAP)
  2. Transthyretin Cardiomyopathy (TTR-CM)
  3. Familial Amyloid Cardiomyopathy
  4. Senile Systemic Amyloidosis (SSA)
Interventions
  1. Other: No drug
  2. Other: No drug
MeSH:Polyneuropathies Amyloid Neuropathies Cardiomyopathies Amyloidosis, Familial Amyloidosis
HPO:Amyloidosis Cardiomyopathy Motor polyneuropathy Polyneuropathy

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 --- --- Phe64Leu --- --- Ser77Tyr --- --- Thr60Ala ---

Primary Outcomes

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)

3 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. 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.

NCT00630864
Conditions
  1. Transthyretin-associated Amyloidosis With Polyneuropathy
Interventions
  1. Drug: Fx-1006A
MeSH:Polyneuropathies Amyloidosis
HPO:Amyloidosis Motor polyneuropathy Polyneuropathy

- Patient has documentation of one of the following targeted TTR mutations: Ser77Tyr, Thr60Ala, Tyr114Cys, Leu58His, Glu89Gln, Ser77Phe, Thr49Ala, Ile107Val, Val30Ala, Gly47Ala, Gly47Glu, Leu55Arg, Lys70Asn, Ile84Thr, Ile107Met. --- Ser77Tyr --- --- Thr60Ala ---

Primary Outcomes

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 6

Secondary Outcomes

Description: 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 12

Other Outcomes

Description: 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 dose

Description: 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 dose

Description: 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 12

Description: 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 12

Description: 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 12

Measure: Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events

Time: Baseline up to Month 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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 12

Description: 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


HPO Nodes


HP:0001638: Cardiomyopathy
Genes 753
DSP UBR1 TRNK DSP PET100 ND6 CSRP3 TOP3A PEX3 NDUFS4 PEX6 COL7A1 TREX1 ACTN2 BAG3 PSEN1 ACADS LMNA NDUFAF4 AHCY MYBPC3 WARS2 GTF2IRD1 EPG5 DOLK GSN INSR ERCC6 POMGNT1 TTN COL7A1 SDHA CAVIN1 D2HGDH SLC25A4 ATP6V1A LAMA3 FANCM FKRP DSG2 ND1 ITPA BMP2 DSG2 TTR NBAS NDUFA2 HADHA GAA POLG TMEM43 LMNA ACTA1 LMNA PRKAG2 MYL3 SYNE1 ABCC9 PPCS RAD51C FKRP FHL1 GNPTAB CLIP2 COA5 JUP LAMA4 TAZ ANKRD11 SDHA TPM1 TARS1 NF1 RAF1 BAG3 SLC25A4 BRIP1 MYOZ2 DES TKFC PMM2 CRYAB NRAS TPM2 BRAF EMD COX1 SCO2 TXNRD2 FIG4 ELN DSG2 HJV SLC19A2 TCAP TWNK EYA4 ARSB FANCG NDUFV2 NDUFAF5 HFE DLD TERT GNS SLC40A1 SURF1 USP9X SHOC2 ND4 POLG SLC25A20 NDUFS8 MLYCD CHKB TTR TPM2 SPEG LAMP2 SDHAF1 MYH6 TXNRD2 SHOC2 KRAS XYLT1 HAMP SUFU TRNW NEB ADCY5 MRAP PIGT FHL1 PTPN11 POMT2 PSEN2 BCS1L TPM2 MRPS22 NDUFB11 PCCA RNU4ATAC GLA CLN3 RAF1 HSD17B10 TNNT2 GNE MYBPC3 MTO1 ATP5F1D FANCD2 GATA5 FKTN MAP2K2 AGL JUP GPC4 MYOCD H19-ICR TRNV NAGA RMND1 TMEM70 NDUFAF6 FAH MEFV ACAD8 PYGM NDUFB10 MAP3K20 POMT1 FKTN NF1 CSRP3 ERCC8 GYS1 FANCL KRAS MAP2K2 NDUFB11 SLC25A4 ENPP1 NDUFA11 NDUFS3 GSN MYOT HJV ACADVL HRAS CAP2 MRPL3 COX10 TAPT1 EPB42 VPS33A VPS13A LDB3 NAGA XYLT2 MYH6 COX15 NDUFA12 HRAS XK TTN SLC25A20 TRNS1 TRNH PTPN11 SDHA TPM1 AGPAT2 TREX1 SCO2 LMNA AIP STAR ND2 ND5 IFIH1 DES FHL1 USP8 LMNA FANCF ND1 ACADVL BRCC3 ND4 LAMA4 LDB3 TKFC FOXRED1 MICOS13 PCCB KIF20A GTPBP3 TMEM126A UQCRFS1 GPR101 PPARG MYH7 TRNQ ATP5MK ATP6 PLN PCCA TCAP KCNH1 TRNN SLC19A3 MYLK2 PEX13 NDUFB11 FLAD1 RBCK1 HNRNPA2B1 MYL2 RNASEH2B TRNE FIG4 XRCC4 COA6 NDUFAF8 AHCY ATPAF2 ND3 ACAD9 TRNK LAMA2 SLC4A1 PDHA1 GUSB ADCY5 FBXL4 MMACHC BRAF HADHB DES FANCI NUP107 SLC22A5 NDUFS2 GMPPB HACD1 HBB HADH MYBPC3 NEXN TTN SELENON ABCC6 TAZ TNNT2 MRPS14 TRNF LMNA ALMS1 VCP CDKN1C ECHS1 IDUA KANSL1 NDUFV1 HMGCL MIB1 LAMP2 ABCC9 GPC3 DTNA NDUFS2 PEX14 RNASEH2A TRNS2 SPTB TIMMDC1 AGPAT2 RBM20 SGCB NDUFA13 LMNA NDUFA4 TGFB3 ND1 FANCA DLD IDUA GATAD1 VCL PTPN11 MYH7 RMRP TTN TNNC1 NNT NPPA PEX7 ABHD5 NDUFAF3 MYPN KCNQ1OT1 MGME1 EPG5 TNNI3 ATP5F1E NDUFS4 SLC25A3 TACO1 DSP ANK1 ANKRD1 SYNE2 PPP1CB MMUT POLG2 POLG JPH2 PEX7 ACTA1 NDUFS3 PHYH LIPT1 PHYH FASTKD2 MYSM1 TRNL1 IDS MYH7 PLN MC2R BSCL2 ATAD3A LIMS2 CRYAB ACTC1 TNNT2 JUP CAV1 BRAF SGCD RTL1 FXN SCN5A NDUFA11 TSFM INSR TNNT2 NDUFB9 WFS1 NDUFA10 ND2 PEX7 PMM2 PPA2 CDH23 TTPA EYA4 KAT6B DPM3 CRYAB YARS2 SLC2A10 NDUFS8 NDUFB8 SMC1A TNNC1 SLC30A10 CPT2 NDUFS7 NDUFS6 PALB2 TRNK POMT1 GMPPB IL12B FKTN VCL COQ4 TBL2 PIGT RRM2B SYNE2 FLNC NDUFS8 FANCE SDHD PDGFRA HCCS HCCS TGFB1 DCAF8 PNPLA2 POMT1 LMNA NDUFAF5 NDUFB11 MPLKIP PLN RFC2 GYG1 LAMC2 SDHB RNASEH1 NDUFS1 GATA4 RNASEH2C MYH6 LMNA KLHL41 FANCC PYGL RRM2B LMNA LIMK1 DMD NDUFA10 FLNC DSP SDHAF1 MYO18B GTPBP3 NEB POMK TPM3 SDHA TWNK TRNT SURF1 NDUFAF1 ATAD3A RIT1 BRCA1 NDUFA6 TANGO2 GATC MYH6 SGCD ACTC1 TMPO NDUFS2 FKTN SPTA1 MLX VAC14 DMD ND3 HAND2 KLF1 TAZ ANKS6 BRCA2 FOXRED1 TPM3 NUP107 IDS MYOT RNF113A BRAF RAF1 FKRP TNNI3K PEX16 FXN TRNS1 TNNT2 FOXRED1 TRIP4 DNAJC19 MAP2K1 CISD2 CPT2 PRDM16 POLG PRKAG2 FLNC NDUFS7 MRPL44 MYPN NDUFA1 ITGA7 NUBPL ERCC2 TAF1A RAB3GAP2 TK2 BSCL2 PPCS COX15 COX2 COQ2 NDUFA2 TNNI3 HADHA NF1 DES ACTN2 ACTA1 TNNC1 DSP NDUFB3 COX3 PEX12 TNNI3 TMEM126B GPC3 AGK HADH NDUFV2 GATAD1 ACAD9 GNPTAB IDUA ACTA1 HBB GBE1 RERE TFR2 POLG HADHB TPM1 MAD2L2 PRDM16 LTBP4 NEU1 SKI AIP NDUFAF3 NDUFAF2 TNNI3 RBM20 FANCB MYH7 TRNW PEX2 PEX10 MTFMT SDHD SLX4 SLC25A4 BAG3 GLB1 ALMS1 KRAS PGM1 COX7B ANO5 PARS2 TNNI3 DPM3 BBS2 FHL2 GABRD LMNA SOS1 HAMP NDUFAF2 DMPK PEX26 MYH7 CRYAB PNPLA2 SURF1 RYR2 SGCA NDUFS1 SAMHD1 C1QBP HPS1 NDUFV1 KBTBD13 TREX1 RAF1 MGME1 ABCC6 UBE2T CENPE GTF2I WARS2 MYH7 DMD COG7 TWNK HGSNAT LAMB3 DSC2 KCNQ1 TMEM126B KANSL1 GTF2H5 NEK8 FHL1 FTO CLPB LDB3 OPA1 NDUFB10 ALG1 PRKAG2 TWNK RYR1 DNAJC19 PSEN2 HADHA COX14 HADHA MAP2K1 RNU4ATAC HFE AIP NDUFS2 ELAC2 CPT1A MAP2K1 TMEM70 SELENON PCCB NDUFAF4 NEXN ERCC4 ERBB3 VCL NEXN RAD51 ATAD3A AARS2 TRNT1 QRSL1 NDUFA9 MMUT HSD17B10 SCN5A XRCC2 MYH7 PEX19 NAGLU TRNL1 ACTC1 PEX5 ADA2 DOLK HNRNPA1 TPM3 CPT2 MYPN ADAR DMD SLC25A3 MYL2 MEN1 RFWD3 NDUFV2 ND5 HSD17B10 GPC4 SARDH COX6B1 ND6 FOS HLA-B MMP1 BOLA3 TNNI3 GMPPB MEG3 NDUFS4 PRDM16 AGK KCNJ8 IDH2 DLK1 PEX11B TPI1 LIAS PPARG NAXD PSEN1 WFS1 GTF2E2 ACAD8 PKP2 SGSH MYPN ABCC9 MYPN IGF2 BAZ1B VHL JUP ALG1 NDUFAF1 POMT1 RAF1 MIPEP PEX1 COX7B CPT2 ATP6 NEBL LDB3 ERCC3 COA8 CAV3 CSRP3 DMD SGCB KCNAB2 TMEM43 VPS33A POMT2 GJA5 TRNL1 SDHA