Clinical trial NCT00694161: The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy
Official title: The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cardiomyopathy
Keywords: Transthyretin
TTR
ATTR
TTR amyloidosis
cardiomyopathy
V122I
wild-type TTR
SSA
Patients with V122I or wild-type TTR amyloid cardiomyopathy
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2008-06-10
Enrollment: 35
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Open-label, multicenter, international, single-treatment study designed to determine TTR stabilization as well as Fx-1006A safety and tolerability, and its effects on clinical outcomes in patients with V122I or wild-type TTR amyloid cardiomyopathy.

The study will be conducted in two parts. Part 1 will include a six-week dosing period during which all enrolled patients will self-administer 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 taking 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 (based on TTR stabilization data), the patient will be discontinued from the study. Safety and clinical outcomes will be evaluated during Part 2 of this study.

Two whole blood samples for pharmacodynamic assessments (TTR stabilization) and pharmacokinetic assessments (Fx-1006A concentrations as well as calculated steady-state parameters) will be collected at Baseline and Week 6. At Months 6 and 12, two whole blood samples will be collected for pharmacodynamic assessments, and four whole blood samples (two samples per time point) will be collected for pharmacokinetic assessments to be utilized in population pharmacokinetic modeling.

Echocardiography, chest x-ray, cardiac MRI, and 24-hour Holter monitoring will be conducted at Baseline, and Months 6 and 12. Six-minute walk test and quality of life utilizing the Patient Global Assessment, KCCQ, and SF-36 will be assessed at Baseline, and Months 3, 6, and 12. NYHA Classification will be assessed at Baseline, Week 6, and Months 3, 6, and 12. Serum markers of troponin I and T, and NT-pro-BNP levels will be assessed at each study visit.

Safety and tolerability will be assessed throughout the study. Vital signs, 12-lead ECG, blood and urine samples for clinical laboratory tests (serum chemistry, hematology, coagulation panel, and urinalysis), AEs, and concomitant medications (including diuretic usage) will be assessed at each study visit. Abbreviated physical examinations will be conducted at Baseline, Weeks 2 and 6, and Months 3 and 6, and a complete physical examination will be conducted at Month 12.

Clinic visits will be conducted during Screening (Days -30 to -1) and Baseline (Day 0); procedures scheduled for the Baseline visit may be conducted over a period of one week to accommodate patient scheduling. All Baseline procedures must be completed prior to the first self-administered dose on Day 1. Day 1 will be defined as administration of the first dose of study medication, which patients will self-administer at home. During treatment, clinic visits will be conducted at Week 2 (± 2 days), Week 6 (± 1 week), Month 3 (± 1 week), Month 6 (± 2 weeks), and Month 12 (± 2 weeks). Procedures scheduled for the Month 6 and 12 visits may occur over one week during the visit window to accommodate patient scheduling. Monthly telephone contacts (± 1 week of the scheduled date) will be made during months in which no clinical site visits are scheduled (Months 4, 5, 7, 8, 9, 10, and 11) for assessment of AEs and concomitant medications. A final telephone contact to assess AEs and concomitant medication usage will be made 30 days after the last dose of study medication for each patient.

Patients who discontinue from the study at any time 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:

1. Patient is \> 40 years-old.
2. Patient participated in FoldRx Study Fx-001 (TRACS) OR Patient has documented TTR amyloid cardiomyopathy and NYHA Classification of I or II.

   TTR amyloid cardiomyopathy is defined as:
   1. Variant TTR amyloid cardiomyopathy as defined as: V122I genotype and presence of amyloid in cardiac biopsy tissue (as determined by congo red stain, alcin blue stain, or immunohistochemical TTR analysis), or
   2. Variant TTR amyloid cardiomyopathy as defined as: V122I genotype, evidence of cardiac involvement by echocardiography with left ventricle wall thickness \> 12 mm and presence of amyloid in non-cardiac biopsy tissue (as determined by congo red stain, alcin blue stain, or immunohistochemical TTR analysis), or
   3. Wild-type TTR amyloid cardiomyopathy as defined as: normal TTR genotype and presence of TTR amyloid deposits in cardiac biopsy tissue (as determined by congo red stain and immunohistochemical TTR analysis), or
   4. Wild-type TTR amyloid cardiomyopathy as defined as: normal TTR genotype, evidence of cardiac involvement by echocardiography with left ventricle wall thickness \> 12 mm and presence of TTR amyloid deposits in non-cardiac biopsy tissue (as determined by congo red stain and immunohistochemical TTR analysis).
3. Patient's symptoms of congestive heart failure (CHF) have been optimally managed prior to baseline, as assessed by the Principal Investigator. Optimal CHF management includes stable drug regimen for ≥ 4 weeks prior to enrollment and stable dose of beta blocker for ≥ 3 months prior to enrollment.
4. If female, patient is post-menopausal. If male with a female partner of childbearing potential, willing to use an acceptable method of birth control for the duration of the study and for at least 3 months after the last dose of study medication.
5. 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:

1. Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs (NSAIDs), defined as greater than 3-4 times/month. The following NSAID are allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethicin, ketoprofen, nabumetone, naproxen, nimesulide, piroxicam, and sulindac.
2. Patient has a TTR mutation other than V122I.
3. Patient has primary or secondary amyloidosis.
4. Patient has received prior liver or heart transplantation.
5. Patient with positive results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV), and/or human immunodeficiency virus (HIV).
6. Patient has renal failure requiring dialysis.
7. Patient has moderate or severe hepatic impairment (assessed by Child-Pugh).
8. 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.
9. Patient has prior non-amyloid cardiac disease, such as myocardial infarction due to obstructive coronary artery disease, active non-amyloid cardiomyopathy (i.e., symptomatic left ventricular dysfunction from any cause other than amyloid), or symptomatic valvular heart disease that significantly contribute to the patient's underlying cardiac signs or symptoms.
10. Patient has a co-morbidity anticipated to limit survival to less than 12 months.
11. Patient received an investigational drug/device in another clinical investigational study within 60 days before Baseline (Day 0).
12. Patient had active alcohol or substance abuse within 60 days before Baseline (Day 0).
13. Patient has a history of documented noncompliance.

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 AEs
timeFrame: Baseline up to 30 days after the last dose
measure: Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings
timeFrame: Baseline up to Month 12
measure: Number of Participants Discontinuing From The Study Due to Clinically Significant Clinical or Laboratory Adverse Events (AEs)
timeFrame: Baseline up to Month 12
measure: Change From Baseline in Echocardiographic (ECHO) Parameters at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Mass (LVM) at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Ejection Fraction at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Doppler Data: E/A and E/e' Ratio at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Doppler Data: Mitral Deceleration Time at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Tissue Doppler- Septal and Lateral Velocity at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Pericardial Effusion at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Change From Baseline in Valvular Abnormalities at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Anteroseptal, Left Ventricular Inferolateral Wall Thickness and Right Ventricular End Diastolic Free Wall Thickness at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Mass, Mass of Left Ventricular Myocardium With Amyloidosis, Mass of Left Ventricular Myocardium With Fibrosis/Scar and Right Ventricular End Diastolic Mass at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricle End Diastolic Volume, Left Ventricle End Systolic Volume, Left Ventricle Stroke Volume, Right Ventricle End Diastolic Volume, Right Ventricle End Systolic Volume, Right Ventricle Stroke Volume at Month 6 and 12.
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Ejection Fraction and Right Ventricular Ejection Fraction at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Left Ventricular Cardiac Output and Right Ventricular Cardiac Output at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in Percentage of Left Ventricular Myocardial Mass With Amyloidosis and Left Ventricular Myocardial Mass With Fibrosis/Scar at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in 4 Chamber Interatrial Septal Thickness at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Change From Baseline in 4 Chamber Left Atrial Dimension and 4 Chamber Right Atrial Dimension at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Atrial Fibrillation/Flutter, Atrial Tachycardia, Non-Sustained Ventricular Tachycardia (NSVT) Beats), Sustained Ventricular Tachycardia (SVT), Sinus Pause at Month 6 and 12
timeFrame: Baseline, Month 6, Month 12
measure: 24-Hour Average Heart Rate and Maximium/Minimum Heart Rate
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Complete Heart Block
timeFrame: Baseline, Month 6, Month 12
measure: Heart Rate Variability (HRV)- Standard Deviation (SD) Parameters
timeFrame: Baseline, Month 6, Month 12
measure: Heart Rate Variability- Percentage of Successive R-R Intervals With Greater Than 50 Msec Difference Between Normal Beats (pNN50)
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Change From Baseline in New York Heart Association (NYHA) Classification at Week 6, Month 3, 6 and 12
timeFrame: Baseline, Week 6, Month 3, Month 6, Month 12
measure: Cardiothoracic (CT) Ratio
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Increased Interstitial Markings and Pleural Effusions
timeFrame: Baseline, Month 6, Month 12
measure: Number of Participants With Change in Patient Global Assessment (PtGA) at Month 3, 6 and 12
timeFrame: Baseline, Month 3, Month 6, Month 12
measure: Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score at Month 3, 6 and 12
timeFrame: Baseline, Month 3, Month 6, Month 12
measure: Change From Baseline in the Short Form 36 (SF-36) at Month 3, 6 and 12
timeFrame: Baseline, Month 3, Month 6, Month 12
measure: Change From Baseline in Troponin I and Troponin T at Week 2, 6, Month 3, 6 and 12
timeFrame: Baseline, Week 2, Week 6, Month 3, Month 6, Month 12
measure: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide(NT-proBNP) Levels at Week 2, 6, Month 3, 6 and 12
timeFrame: Baseline, Week 2, Week 6, Month 3, Month 6, Month 12
measure: Change From Baseline in 6-Minute Walk Test (6MWT) at Month 3, 6 and 12
timeFrame: Baseline, Month 3, Month 6, Month 12
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Harvard Vanguard Medical Associates
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Columbia University
state: New York
Study officials:
affiliation: FoldRx Pharmaceuticals, Inc
name: Jeff Packman, MBA
role: STUDY_DIRECTOR
References:
citation: Sultan MB, Gundapaneni B, Schumacher J, Schwartz JH. Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy. Clin Med Insights Cardiol. 2017 Sep 18;11:1179546817730322. doi: 10.1177/1179546817730322. eCollection 2017.
citation: Maurer MS, Grogan DR, Judge DP, Mundayat R, Packman J, Lombardo I, Quyyumi AA, Aarts J, Falk RH. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail. 2015 May;8(3):519-26. doi: 10.1161/CIRCHEARTFAILURE.113.000890. Epub 2015 Apr 14.