An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

NCT00791492 | Completed Phase 2 Results

• 2 other identifiers: FX-006B3461021
• Study Type: interventional
• Target: 86
• Locations: 6 countries
• Sites: 11

Brief Summary

This study is designed to determine the long-term safety and tolerability of Fx-1006A as well as the effects of Fx-1006A on clinical outcomes in patients with ATTR-PN. All patients who enroll in this extension study will receive once-daily oral 20 mg Fx-1006A for 12 months; therefore, patients randomized to placebo in Study Fx-005 will cross over to active drug (Fx-1006A 20 mg) during this study. However, patients and their families as well as clinical Investigators and their clinical site staff will remain blinded to the original Fx-005 treatment assignment. It is intended that there will be no interruption in study medication administration between the two studies. The majority of safety and clinical outcomes assessments will be identical to those evaluated in Study Fx-005. Additional assessments for this open-label extension study include 24-hour Holter monitoring and skin biopsy for IENF; patients will be required to provide written informed consent to participate in this open-label extension study prior to having these additional procedures performed. The values obtained from procedures and evaluations conducted during the Month 18 visit of Study Fx-005 will be used as the Baseline values for this open-label extension study. The Baseline assessments of IENF and Holter monitoring may be conducted at either day of the Month 18 visit days of Study Fx-005, but prior to the first Fx-1006A dose in this open-label extension study. Clinic Visits will be conducted at Week 6 (± 2 days), and Month 3 (± 1 week), Month 6 (± 2 weeks), and Month 12 (± 2 weeks). Monthly telephone contacts (± 1 week of the scheduled date) will be made during months in which no investigative site visits are scheduled (Months 2, 4, 5, 7, 8, 9, 10, and 11) for assessment of adverse events and concomitant medications. Neurological evaluation by NIS-LL will be performed at Months 6 and 12. The NIS-LL will be assessed by utilizing the average of two successive NIS-LL clinical assessment scores obtained at least 24 hours apart within a one week period for each study visit. A dedicated neurologist will be required to perform NIS-LL scoring across all time-points for each individual patient enrolled in the study. Quality of life utilizing the Norfolk QOL-DN will be assessed at Months 6 and 12 (based on the total score as well as the five individual domains of the questionnaire). QST (utilizing CASE IV), NCS, HRDB, mBMI, and echocardiography will be conducted at Months 6 and 12. Holter monitoring will be conducted at Baseline and Months 6 and 12. Biopsies for IENF will be obtained at Baseline only. Assessments of troponin I and NT-pro-BNP levels will be made at each study visit. Blood samples for pharmacokinetic assessments (Fx-1006A concentrations as well as calculated steady-state parameters) and pharmacodynamic assessments (TTR stabilization) will be collected at Week 6 and Months 6 and 12. 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, urinalysis, and urine pregnancy testing), adverse events, and concomitant medications will be assessed at each study visit. Eye examinations (including fundal photography) will be conducted at Months 6 and 12. Abbreviated physical examinations will be conducted at Week 6, and Months 3 and 6, and a complete physical examination will be conducted at Month 12. All patients will be contacted by telephone 30 days (± 1 week) after the last dose of study medication for assessment of adverse events and concomitant medications. Patients who complete the Month 12 visit of this open-label study may be allowed to continue receiving Fx-1006A under a compassionate use program. Patients who discontinue from the study at any time after enrollment (i.e., early termination) will have final safety assessments performed at the time of discontinuation. Any patient discontinuing after the Month 6 visit will have all safety and clinical outcomes assessments scheduled for the Month 12 visit performed.

Conditions

Familial Amyloid Polyneuropathy; ATTR-PN

Keywords

FAP; Familial Amyloid Polyneuropathy; ATTR-PN; transthyretin; TTR; amyloid; polyneuropathy; familial; hereditary; amyloidosis; FoldRx

Outcome Measures

Primary Outcomes (4)

• Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6

  Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.

  Month 6

• Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12

  Response to treatment indicated by either improvement(decrease from baseline) or stabilization(change from baseline of 0 to less than\[\<\] 2) in NIS-LL score,based on mean of 2 scores in 1 week period.NIS-LL assessed muscle weakness,reflexes,sensation.Each item scored separately for left,right limbs.Components of muscle weakness:0(normal)-4(paralysis),higher score=more weakness;reflexes,sensation:0=normal,1=decreased,or 2=absent.Total NIS-LL score range 0-88,higher score=more impairment. For tafamidis-tafamidis group, NIS-LL baseline value of previous study FX-005(NCT00409175) used as reference.

  Month 12

• Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6

  Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.

  Baseline, Month 6

• Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12

  Norfolk QOL-DN: 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy; Item 1 to 7: related to symptoms and presence of symptoms was assessed as 1 and absence was assessed as 0. Item 8-35: related to activities of daily living and scored on a 5-point Likert scale, where 0= no problem and 4= severe problem (except item 32, where -2= much better, 0=about the same, 2=much worse). TQOL= sum of all the items, total possible score range= -2 to 138, where higher score=worse quality of life.

  Baseline, Month 12

Secondary Outcomes (9)

• Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12

  Baseline, Month 6, 12

• Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12

  Baseline, Month 6, 12

• Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12

  Baseline, Month 6, 12

• Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12

  Baseline, Month 6, 12

• Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12

  Baseline, Month 6, 12

Other Outcomes (6)

• Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)

  Baseline up to 30 days after last dose of study medication

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

  Baseline up to 30 days after last dose of study medication

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

  Baseline, Day 1 up to Month 12 (anytime on-treatment)

Study Arms (1)

Fx-1006A

EXPERIMENTAL

Drug: Fx-1006A

Interventions

Fx-1006A DRUG

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

Fx-1006A

Eligibility Criteria

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

You may qualify if:

• Male and non-pregnant female patients meeting all of the following criteria are eligible for enrollment in this study:
• Patient has completed the Month 18 visit of Study Fx-005.
• If female, patient is post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout 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 an acceptable method 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.
• Patient agrees not to participate in another investigational drug or device study while participating in this open-label extension study.

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).
• If female, patient is pregnant or breast feeding.
• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (11)

FLENI Departamento de Hepatología y Transplante de Organos

Buenos Aires, Argentina

Location

FLENI-Hepatology and Organ Transplant Dept.

Ciudad de Buenos Aires, C1428AQK, Argentina

Location

Hospital Universitario Clementino Fraga Filho

Rio de Janeiro, Brazil

Location

Service de Neurologie, CHU Henri Mondor

Paris, France

Location

Universitatsklinikum Munster, Transplant Hepatology

Münster, Germany

Location

Serviço de Neurologia-Hospital de Santa Maria

Lisbon, 1649-035, Portugal

Location

Servicio de Neurologica Piso 7, Hospital de Santa Maria

Lisbon, Portugal

Location

Unidade Clinica de Paramiloidose-Hospital Santo Antonio

Porto, 4099-001, Portugal

Location

Unidade Clinica de Paramiloidose, Hospital Geral de Santo Antonio, Largo Prof Abdel Salazar

Porto, Portugal

Location

Umea University Hospital

Umeå, SE-901 85, Sweden

Location

FAP-Teamet Familjar Amyloids, Norrlands universitetssjukhus

Umeå, Sweden

Location

Related Publications (5)

• 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

• Amass L, Li H, Gundapaneni BK, Schwartz JH, Keohane DJ. Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy. Orphanet J Rare Dis. 2018 Dec 17;13(1):225. doi: 10.1186/s13023-018-0947-7.

  PMID: 30558645 DERIVED

• Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016 Sep;23(3):178-183. doi: 10.1080/13506129.2016.1207163. Epub 2016 Aug 5.

  PMID: 27494299 DERIVED

• Coelho T, Maia LF, da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I, Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Grogan DR. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013 Nov;260(11):2802-14. doi: 10.1007/s00415-013-7051-7. Epub 2013 Aug 22.

  PMID: 23974642 DERIVED

MeSH Terms

Conditions

Amyloid Neuropathies, Familial; Alzheimer Disease; Polyneuropathies; Amyloidosis

Interventions

tafamidis

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Amyloid Neuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amyloidosis, Familial; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Proteostasis Deficiencies; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurocognitive Disorders; Mental Disorders

Limitations and Caveats

Instead of intended endpoint 'heat pain and cooling threshold', results of 'summated 3 score for small nerve fiber function' were reported. Designation of outcomes as primary and secondary was based on study team input as study did not specify this.

Results Point of Contact

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

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Jeff Packman

  FoldRx Pharmaceuticals, Inc.

  STUDY DIRECTOR

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: November 13, 2008
• First Posted: November 14, 2008
• Study Start: July 1, 2008
• Primary Completion: August 1, 2008
• Study Completion: October 1, 2010
• Last Updated: December 17, 2012
• Results First Posted: December 17, 2012

Record last verified: 2012-11

Locations

PT (4); SE (2); DE (1); FR (1); AR (2); BR (1)