The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy

NCT ID: NCT00694161

Last Updated: 2013-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-08-31
• Study Completion Date: 2010-01-31

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.

Conditions

Cardiomyopathy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Fx-1006A

Group Type: EXPERIMENTAL

Fx-1006A

Intervention Type: DRUG

Fx-1006A 20mg soft gelatin capsules once daily (at the same time each day) for 12 months

Interventions

Fx-1006A

Fx-1006A 20mg soft gelatin capsules once daily (at the same time each day) for 12 months

Intervention Type: DRUG

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.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jeff Packman, MBA

Role: STUDY_DIRECTOR

FoldRx Pharmaceuticals, Inc

Locations

Emory University School of Medicine

Atlanta, Georgia, United States

University of Chicago

Chicago, Illinois, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Harvard Vanguard Medical Associates

Boston, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

Columbia University

New York, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 28951660 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25872787 (View on PubMed)

Other Identifiers

B3461025

Identifier Type: -

Identifier Source: secondary_id

FX1B-201

Identifier Type: -

Identifier Source: org_study_id