The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With V122I or Wild-Type (Transthyretin) TTR Amyloid Cardiomyopathy - Full Text View

Sponsor:	FoldRx Pharmaceuticals
Information provided by:	FoldRx Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00694161

Purpose

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

Condition	Intervention	Phase
Cardiomyopathy	Drug: Fx-1006A	Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With V122I or Wild-Type TTR Amyloid Cardiomyopathy

Resource links provided by NLM:

Genetics Home Reference related topics: transthyretin amyloidosis

MedlinePlus related topics: Cardiomyopathy

U.S. FDA Resources

Further study details as provided by FoldRx Pharmaceuticals:

Primary Outcome Measures:

The primary endpoint of this study is TTR stabilization at Week 6 compared with Baseline, as measured by a validated immunoturbidimetric assay [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The secondary endpoints of this study are TTR stabilization at Months 6 and 12 compared with Baseline, as measured by a validated immunoturbidimetric assay [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
Incidence of patients experiencing treatment-emergent adverse events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Incidence of patients experiencing treatment-emergent >/= Grade 3 AEs [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Incidence of patients with treatment-emergent echocardiography findings considered by the Investigator to be clinically significant [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Incidence of patients discontinuing from the study because of clinical or laboratory AEs [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
Change from Baseline in echocardiographic parameters [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
Change from Baseline in cardiac magnetic resonance imaging (MRI) parameters [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
Change from Baseline in 24-hour Holter monitoring parameters [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
Change from Baseline in the New York Heart Association (NYHA) Classification [ Time Frame: 6 Weeks, 3, 6, and 12 months ] [ Designated as safety issue: No ]
Change from Baseline in chest x-ray parameters [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]
Change from Baseline in the Patient Global Assessment [ Time Frame: 3, 6, 12 months ] [ Designated as safety issue: No ]
Change from Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score [ Time Frame: 3, 6, 12 months ] [ Designated as safety issue: No ]
Change from Baseline in the Short Form 36 (SF-36) [ Time Frame: 3, 6, 12 months ] [ Designated as safety issue: No ]
Change from Baseline in troponin I and T, and NT-pro-BNP levels [ Time Frame: 2 weeks, 6 weeks, 3, 6, 12 months ] [ Designated as safety issue: No ]
Change from Baseline in 6-Minute Walk Test [ Time Frame: 6 and 12 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	August 2008
Estimated Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Fx-1006A: Experimental	Drug: Fx-1006A Fx-1006A 20mg soft gelatin capsules once daily (at the same time each day) for 12 months

Detailed Description:

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

Ages Eligible for Study:	40 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patient is > 40 years-old.
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).
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.
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.
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-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.
Patient has a TTR mutation other than V122I.
Patient has primary or secondary amyloidosis.
Patient has received prior liver or heart transplantation.
Patient with positive results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV), and/or human immunodeficiency virus (HIV).
Patient has renal failure requiring dialysis.
Patient has moderate or severe hepatic impairment (assessed by Child-Pugh).
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 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.
Patient has a co-morbidity anticipated to limit survival to less than 12 months.
Patient received an investigational drug/device in another clinical investigational study within 60 days before Baseline (Day 0).
Patient had active alcohol or substance abuse within 60 days before Baseline (Day 0).
Patient has a history of documented noncompliance.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00694161

Locations

United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Harvard Vanguard Medical Associates
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Columbia University
New York, New York, United States, 10032

Sponsors and Collaborators

FoldRx Pharmaceuticals

More Information

No publications provided

Responsible Party:	FoldRx Pharmaceuticals, Inc. ( Jeff Packman, Vice President, Drug Development Operations )
Study ID Numbers:	Fx1B-201
Study First Received:	June 6, 2008
Last Updated:	March 30, 2009
ClinicalTrials.gov Identifier:	NCT00694161 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by FoldRx Pharmaceuticals:

Transthyretin
TTR
ATTR
TTR amyloidosis
cardiomyopathy

V122I
wild-type TTR
SSA
Patients with V122I or wild-type TTR amyloid cardiomyopathy

Additional relevant MeSH terms:

Amyloidosis
Heart Diseases
Metabolic Diseases
Cardiovascular Diseases
Cardiomyopathies

ClinicalTrials.gov processed this record on February 08, 2010