Clinical trial NCT00630864: The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis
Official title: The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Transthyretin-associated Amyloidosis With Polyneuropathy
Keywords: Transthyretin, TTR, amyloidosis, TTR amyloidosis, polyneuropathy
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2008-03-07
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Week 6
timeFrame: Week 6
Secondary outcomes:
measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Month 6 and 12
timeFrame: Month 6, Month 12
Other outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs)
timeFrame: Baseline up to 30 days after the last dose
measure: Number of Participants With Greater Than or Equal to Grade 3 Treatment-Emergent Adverse Events
timeFrame: Baseline up to 30 days after the last dose
measure: Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings
timeFrame: Day 1 up to Month 12
measure: Number of Participants With Clinically Significant Treatment-Emergent Electrocardiogram (ECG) Findings
timeFrame: Day 1 up to Month 12
measure: Number of Participants With Clinically Significant Treatment-Emergent Holter Monitoring Findings
timeFrame: Day 1 up to Month 12
measure: Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events
timeFrame: Baseline up to Month 12
measure: Change From Baseline in the Neuropathy Impairment Score (NIS) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in the Neuropathy Impairment Score-Lower Limb (NIS-LL) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6, Month 12
timeFrame: Month 6, Month 12
measure: Change From Baseline in Total Quality of Life (TQOL) Score at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Nerve Conduction Studies (NCS) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Heart Rate Response to Deep Breathing (HRDB) at Month 6 and Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Overall Quality of Life and Individual Domains of the Short-form-36 (SF-36) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Echocardiography (ECHO) Parameters at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Atrial Volume at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular (LV) End Systolic Volume, Left Ventricle (LV) Stroke Volume at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Fractional Shortening at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular (LV) Ejection Fraction at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Mass (LVM) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Isovolumetric Relaxation Time (IVRT), Mitral Deceleration Time at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Aortic Annulus Diameter at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Tricuspid Peak Velocity at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Tricuspid Pulmonary Artery Systolic Pressure (PASP) at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Doppler Data at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
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
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular (LV) Mass/Voltage Ratio at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Atrial (LA) Volume Index at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) at Week 2, Week 6, Month 3, Month 6, Month 12
timeFrame: Baseline, Week 2, Week 6, Month 3, Month 6, Month 12
measure: Change From Baseline in Karnofsky Performance Status Scale at Month 6, Month 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Troponin I Levels at Week 2, Week 6 , Month 3, Month 6, Month 12
timeFrame: Baseline, Week 2, Week 6 , Month 3, Month 6, Month 12
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Paris
country: France
facility: CHU de Bicetre
city: Munster
country: Germany
facility: Universitatsklinikum Munster, Transplant Hepatology
city: IRCCS - Policlinico San Matteo
country: Italy
facility: Centro per lo Studio e la Cura delle Amiloidosi Sistemiche
state: Pavia
Study officials:
References:
citation: Merlini G, Coelho T, Waddington Cruz M, Li H, Stewart M, Ebede B. Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years. Neurol Ther. 2020 Jun;9(1):105-115. doi: 10.1007/s40120-020-00180-w. Epub 2020 Feb 27.
citation: Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019 Dec;26(4):203-209. doi: 10.1080/13506129.2019.1643714. Epub 2019 Jul 27.
citation: Gundapaneni BK, Sultan MB, Keohane DJ, Schwartz JH. Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy. Eur J Neurol. 2018 Mar;25(3):464-468. doi: 10.1111/ene.13510. Epub 2017 Dec 26.
citation: Merlini G, Plante-Bordeneuve V, Judge DP, Schmidt H, Obici L, Perlini S, Packman J, Tripp T, Grogan DR. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res. 2013 Dec;6(6):1011-20. doi: 10.1007/s12265-013-9512-x. Epub 2013 Oct 8.