The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy
Condition: Cardiomyopathy
MeSH terms: Cardiomyopathies
Intervention: Fx-1006A
Intervention description: Fx-1006A 20mg soft gelatin capsules once daily (at the same time each day) for 12 months
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Transthyretin; TTR; ATTR; TTR amyloidosis; cardiomyopathy; V122I; wild-type TTR; SSA; Patients with V122I or wild-type TTR amyloid cardiomyopathy

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.