The Effects of Fx-1006A on Transthyretin Stabilization and Clinical Outcome Measures in Patients With Non-V30M Transthyretin Amyloidosis

NCT00630864 | Completed Phase 2 Results

• 2 other identifiers: FX1A-201B3461022
• Study Type: interventional
• Target: 21
• Locations: 4 countries
• Sites: 4

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.

Conditions

Transthyretin-associated Amyloidosis With Polyneuropathy

Keywords

Transthyretin, TTR, amyloidosis, TTR amyloidosis, polyneuropathy

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Week 6

  TTR tetramer was assessed using a validated immunoturbidimetric assay. The Fraction of Initial (FOI) is the ratio of the measured TTR tetramer concentration after denaturation to the measured TTR tetramer concentration before denaturation. TTR tetramer stabilization is based on the difference between the on-treatment FOI and the baseline FOI expressed as a percentage of the baseline FOI.

  Week 6

Secondary Outcomes (1)

• Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer at Month 6 and 12

  Month 6, Month 12

Other Outcomes (32)

• Number of Participants With Treatment-Emergent Adverse Events (AEs)

  Baseline up to 30 days after the last dose

• Number of Participants With Greater Than or Equal to Grade 3 Treatment-Emergent Adverse Events

  Baseline up to 30 days after the last dose

• Number of Participants With Clinically Significant Treatment-Emergent Echocardiography (ECHO) Findings

  Day 1 up to Month 12

Study Arms (1)

1

EXPERIMENTAL

Fx-1006A 20mg soft gelatin capsules once daily for 12 months

Drug: Fx-1006A

Interventions

Fx-1006A DRUG

During Part 1, patients will receive Fx-1006A 20mg soft gelatin capsules once daily (at the same time each day) for two weeks. During Part 2, patients will receive Fx-1006A 20mg soft gelatin capsules once daily to complete a total of 12 months of dosing

1

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Pfizer: lead

Study Sites (4)

Johns Hopkins Hospital

Baltimore, Maryland, 21205, United States

Location

CHU de Bicetre

Paris, France

Location

Universitatsklinikum Munster, Transplant Hepatology

Münster, Germany

Location

Centro per lo Studio e la Cura delle Amiloidosi Sistemiche

Irccs - Policlinico San Matteo, Pavia, 19 - 27100, Italy

Location

Related Publications (4)

• 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.

  PMID: 32107748 DERIVED

• 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.

  PMID: 31353964 DERIVED

• 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.

  PMID: 29115008 DERIVED

• 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.

  PMID: 24101373 DERIVED

MeSH Terms

Conditions

Amyloidosis; Polyneuropathies

Interventions

tafamidis

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2008
• First Posted: March 7, 2008
• Study Start: June 1, 2008
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: January 18, 2013
• Results First Posted: December 17, 2012

Record last verified: 2013-01

Locations

DE (1); FR (1); US (1); IT (1)