Transthyretin-associated Amyloidosis With Polyneuropathy Clinical Trial
Official title:
The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis
| Verified date | January 2013 |
| Source | Pfizer |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | United States: Food and Drug Administration |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 21 |
| Est. completion date | January 2010 |
| Est. primary completion date | January 2010 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 75 Years |
| Eligibility |
Inclusion Criteria: - Patient has amyloid documented by biopsy (in accordance with institutional site standard of care). - 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. Patients with mutations other than those listed may be enrolled only after approval by the Sponsor. - Patient has peripheral and/or autonomic neuropathy and/or cardiomyopathy with a Karnofsky Performance Status = 50. - Patient is aged =18 to 75 years, inclusive. - If female, patient is post-menopausal, surgically sterilized, or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout the study and for 3 months from the end of the study. (A condom alone is not considered an acceptable method of birth control.) If male with a female partner of childbearing potential, willing to use two acceptable methods of birth control for the duration of the study. For both females and males, acceptable birth control must be used for at least 3 months after the last dose of study medication. - Patient is, in the opinion of the investigator, willing and able to comply with the study medication regimen and all other study requirements. Exclusion Criteria: - Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), defined as greater than 3-4 times/month (ibuprofen and nimesulide will be permitted). - Patient has primary or secondary amyloidosis. - Patient has TTR-associated amyloidosis with V30M mutation. - If female, patient is pregnant or breast feeding. - Patient has received prior liver transplantation. - Patient is expected to undergo liver transplantation within 12 months after enrollment. - Patient with positive results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV). - Patient has renal insufficiency (creatinine clearance < 30 ml/min). - Patient has liver function test abnormalities: alanine transaminases (ALT) and/or aspartate transaminases (AST) > 2 times upper limit of normal (ULN) that in the medical judgment of the investigator are due to reduced liver function or active liver disease. - Patient has a New York Heart Association (NYHA) Functional Classification = III. - Patient has other causes of sensorimotor neuropathy (B12 deficiency, Diabetes Mellitus, HIV treated with retroviral medications, thyroid disorders, alcohol abuse, and chronic inflammatory diseases). - Patient has prior non-amyloid cardiac disease such as: myocardial infarction due to obstructive coronary artery disease, active non-amyloid cardiomyopathy (e.g., symptomatic left ventricular dysfunction from any cause other than amyloid, patients with a primary diagnosis of symptomatic valvular heart disease) - Patient has a co-morbidity anticipated to limit survival to less than 12 months. - Patient has received an investigational drug/device and/or participated in another clinical investigational study within 60 days before Baseline (Day 0). |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| France | CHU de Bicetre | Paris | |
| Germany | Universitatsklinikum Munster, Transplant Hepatology | Munster | |
| Italy | Centro per lo Studio e la Cura delle Amiloidosi Sistemiche | IRCCS - Policlinico San Matteo | Pavia |
| United States | Johns Hopkins Hospital | Baltimore | Maryland |
| Lead Sponsor | Collaborator |
|---|---|
| Pfizer |
United States, France, Germany, Italy,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Number of Participants With Treatment-Emergent Adverse Events (AEs) | 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. | Baseline up to 30 days after the last dose | Yes |
| Other | Number of Participants With Greater Than or Equal to Grade 3 Treatment-Emergent Adverse Events | 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. | Baseline up to 30 days after the last dose | Yes |
| Other | Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings | 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). | Day 1 up to Month 12 | Yes |
| Other | Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings | 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. | Day 1 up to Month 12 | Yes |
| Other | Number of Participants With Clinically Significant Treatment-Emergent Holter Monitoring Findings | 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. | Day 1 up to Month 12 | Yes |
| Other | Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events | Baseline up to Month 12 | Yes | |
| Other | Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in the Neuropathy Impairment Score-Lower Limb (NIS-LL) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6, Month 12 | 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. | Month 6, Month 12 | No |
| Other | Change From Baseline in Total Quality of Life (TQOL) Score at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, Month 12 | 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). | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Nerve Conduction Studies (NCS) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Heart Rate Response to Deep Breathing (HRDB) at Month 6 and Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Overall Quality of Life and Individual Domains of the Short-form-36 (SF-36) at Month 6, Month 12 | 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). | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Echocardiography (ECHO) Parameters at Month 6, Month 12 | 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). | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Atrial Volume at Month 6, Month 12 | Left atrial volume was measured by echocardiography. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Ventricular (LV) End Systolic Volume, Left Ventricle (LV) Stroke Volume at Month 6, Month 12 | Cardiac MRI was done to measure left ventricular (LV) end systolic volume, left ventricle (LV) stroke volume. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Fractional Shortening at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Ventricular (LV) Ejection Fraction at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Ventricular Mass (LVM) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Isovolumetric Relaxation Time (IVRT), Mitral Deceleration Time at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Aortic Annulus Diameter at Month 6, Month 12 | The diameter at the base of the aortic root, the basal ring, is also called the aortic annulus diameter. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Tricuspid Peak Velocity at Month 6, Month 12 | Tricuspid peak velocity was measured by echocardiography. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Tricuspid Pulmonary Artery Systolic Pressure (PASP) at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Doppler Data at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | 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 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Ventricular (LV) Mass/Voltage Ratio at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Left Atrial (LA) Volume Index at Month 6, Month 12 | LA volume index (LAVI), was the value of LA volume divided by body surface area, to measure LA size. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) at Week 2, Week 6, Month 3, Month 6, Month 12 | 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. | Baseline, Week 2, Week 6, Month 3, Month 6, Month 12 | No |
| Other | Change From Baseline in Karnofsky Performance Status Scale at Month 6, Month 12 | 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. | Baseline, Month 6, Month 12 | No |
| Other | Change From Baseline in Troponin I Levels at Week 2, Week 6 , Month 3, Month 6, Month 12 | Troponin I is a cardiac injury biomarker. Higher concentrations of this marker in blood are associated with heart injury. | Baseline, Week 2, Week 6 , Month 3, Month 6, Month 12 | No |
| Primary | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Week 6 | 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. | Week 6 | No |
| Secondary | Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Month 6 and 12 | 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. | Month 6, Month 12 | No |