Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00409175
First received: December 6, 2006
Last updated: November 16, 2012
Last verified: November 2012
  Purpose

This study will examine whether Fx-1006A is effective in halting the progression of Familial Amyloid Polyneuropathy (FAP).

Deposition of TTR amyloid is associated with a variety of human diseases. Deposition of amyloid fibrils of variant TTR (primarily V30M) in peripheral nerve tissue produces the condition called FAP.

The prevention of the formation of amyloid by stabilization of the TTR native state should constitute an effective therapy for amyloid diseases. Therapeutic intervention with a TTR stabilizer drug, such as Fx-1006A, is hypothesized to stop progression of the disease in FAP patients. FAP is a uniformly fatal disease and Fx-1006A is intended to halt the relentless neurological deterioration FAP patients experience.

This Phase 2/3 study will enroll early to mid-stage FAP patients in order to interrupt and stabilize the disease at a point in time where progression of motor and autonomic dysfunction can be maximally effected. Male and female patients with FAP with documented V30M TTR mutation will receive Fx-1006A or placebo once daily for a period of eighteen (18) months.


Condition Intervention Phase
Familial Amyloid Polyneuropathy
Drug: Fx-1006A
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Orally Administered Fx-1006A in Patients With Familial Amyloid Polyneuropathy (FAP): A Randomized, Double-blind, Placebo-controlled Study

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 18 [ Time Frame: Month 18 ] [ Designated as safety issue: No ]
    Response to treatment was 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 scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.

  • Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 18 [ Time Frame: Baseline, Month 18 ] [ Designated as safety issue: No ]
    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 symptom 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.


Secondary Outcome Measures:
  • Change From Baseline in Neuropathy Impairment Score- Lower Limb (NIS-LL) Score at Month 6, 12 and 18 [ Time Frame: Baseline, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    NIS-LL: assessed muscle weakness, reflexes and sensation; scored separately for left and right limbs. Components of muscle weakness (hip and knee flexion, hip and knee extension, ankle dorsiflexors, ankle plantar flexors, toe extensors, toe flexors) are scored on 0(normal) to 4(paralysis) scale, higher score=greater weakness. Components of reflexes (quadriceps femoris, triceps surae) and sensation (touch pressure, pin-prick, vibration, joint position) were scored 0 = normal, 1= decreased, or 2 = absent. Total possible NIS-LL score range 0-88, higher score=greater impairment.

  • Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 and 12 [ Time Frame: Month 6, 12 ] [ Designated as safety issue: No ]
    Response to treatment was indicated by either improvement (decrease from baseline) or stabilization (change from baseline of 0 to <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 scored on 0 (normal) to 4 (paralysis) scale, higher score=greater weakness. Components of reflexes, sensation scored 0=normal, 1=decreased, or 2=absent. Total NIS-LL score range 0-88, higher score=greater impairment.

  • Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 and 12 [ Time Frame: Baseline, Month 6, 12 ] [ Designated as safety issue: No ]
    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 symptom 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.

  • Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6, 12 and 18 [ Time Frame: Baseline, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    Norfolk QOL-DN:35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptom present, 0=symptom absent. Item 8-35: scored on 5-point Likert scale: 0=no problem, 4=severe problem (except item 32: -2=much better, 0=about same, 2=much worse). Norfolk QOL-DN summarized in 5 domains(score range):physical functioning/large fiber neuropathy(-2 to 58), activities of daily living(ADLs) (0 to 20), symptoms(0 to 32), small fiber neuropathy(0 to 16), autonomic neuropathy(0 to 12); higher score=greater impairment, for each. Total score=-2 to138(higher score=worse QOL).

  • Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6, 12 and 18 [ Time Frame: Baseline, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    Summated 7 score: composite score included five Nerve Conduction Studies (NCS) attributes (peroneal nerve distal motor latency, peroneal nerve compound muscle action potential, peroneal nerve motor conduction velocity, tibial nerve distal motor latency, and sural nerve sensory nerve action potential amplitude) along with Vibration Detection Threshold (VDT) obtained in great toes, and Heart Rate Response to Deep Breathing (HRDB) value. Score was determined through reference to normal values for age, sex and height. Total score range= -26 to 26, where higher score=worse nerve function.

  • Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6, 12 and 18 [ Time Frame: Baseline, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    Summated 3 Nerve Tests Small Fiber Normal Deviates Score (NTSFnds) included cooling threshold for the lower limbs, heat pain threshold for the lower limbs and HRDB. Total score range= -11.2 to 11.2, where higher score=worse nerve function.

  • Change From Baseline in Modified Body Mass Index (mBMI) at Month 6, 12 and 18 [ Time Frame: Baseline, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation associated with malnutrition. A progressive decline in mBMI indicated worsening of disease severity.

  • Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer [ Time Frame: Week 8, Month 6, 12, 18 ] [ Designated as safety issue: No ]
    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.


Enrollment: 128
Study Start Date: January 2007
Study Completion Date: May 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1.
Fx-1006A
Drug: Fx-1006A
Fx-1006A 20mg or matched placebo once daily (at the same time each day) for a period of 18 Months
Placebo Comparator: 2.
Placebo
Drug: Placebo
Fx-1006A 20mg or matched placebo once daily (at the same time each day) for a period of 18 Months

Detailed Description:

Deposition of TTR amyloid is associated with a variety of human diseases. Deposition of amyloid fibrils of variant TTR (primarily V30M) in peripheral nerve tissue produces the condition called FAP.

The prevention of the formation of amyloid by stabilization of the TTR native state should constitute an effective therapy for amyloid diseases. Therapeutic intervention with a TTR stabilizer drug, such as Fx-1006A, is hypothesized to stop progression of the disease in FAP patients. FAP is a uniformly fatal disease and Fx-1006A is intended to halt the relentless neurological deterioration FAP patients experience.

This Phase 2/3 study will enroll early to mid-stage FAP patients in order to interrupt and stabilize the disease at a point in time where progression of motor and autonomic dysfunction can be maximally effected. Male and female patients with FAP with documented V30M TTR mutation will receive Fx-1006A or placebo once daily for a period of eighteen (18) months.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Amyloid documented by biopsy.
  2. Documented V30M TTR mutation.
  3. Peripheral and/or autonomic neuropathy with a Karnofsky Performance Status ≥50.
  4. Patient is 18-75 years old.
  5. If female, patient is post-menopausal, surgically sterilized, or willing to use 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, birth control must be used for at least 3 months after the last dose of study medication.
  6. 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-steroidal anti-inflammatory drugs (NSAIDs).
  2. Primary amyloidosis.
  3. If female, patient is pregnant or breast feeding.
  4. Prior liver transplantation.
  5. No recordable sensory threshold for vibration perception in both feet, as measured by CASE IV.
  6. Positive results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV).
  7. Renal insufficiency or liver function test abnormalities.
  8. New York Heart Association (NYHA) Functional Classification ≥III.
  9. Other causes of sensorimotor neuropathy (B12 deficiency, Diabetes Mellitus, HIV treated with retroviral medications, thyroid disorders, alcohol abuse, and chronic inflammatory diseases).
  10. Co-morbidity anticipated to limit survival to less than 18 months.
  11. Patient received an investigational drug/device and/or participated in another clinical investigational study within 60 days before Baseline.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00409175

Locations
United States, Massachusetts
MGH Neuropathy Laboratory
Boston, Massachusetts, United States, 02114
Argentina
FLENI-Hepatology and Organ Transplant Dept.
Ciudad de Buenos Aires, Buenos Aires Province, Argentina, C1428AQK
Brazil
Hospital Universitário Prof. Clementino Fraga Filho-UFRJ
Rio de Janeiro, Southeast, Brazil, Cep 21945-560
France
CHU de Bicetre
Le Kremlin Bicêtre, Ile de France, France, 94275
Germany
Universitatsklinikum Munster, Transplant Hepatology
Munster, Nordrhein-Westfalen, Germany, 48149
Portugal
Serviço de Neurologia-Hospital de Santa Maria
Lisboa, Lisbon, Portugal, 1649-035
Unidade Clinica de Paramiloidose-Hospital Santo Antonio
Porto, Norte, Portugal, 4099-001
Spain
Hospital Clinic de Barcelona
Barcelona, Catalunya, Spain, 08036
Sweden
Umea University Hospital
Umea, Vasterbotten County, Sweden, SE-901 85
United Kingdom
Kings College Hospital
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Jeff Packman FoldRx Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00409175     History of Changes
Other Study ID Numbers: FX-005, B3461020
Study First Received: December 6, 2006
Results First Received: November 16, 2012
Last Updated: November 16, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
hereditary
FAP
Fx-1006A
transthyretin
TTR
amyloid
polyneuropathy
V30M
familial
amyloidosis
FoldRx

Additional relevant MeSH terms:
Amyloid Neuropathies, Familial
Amyloid Neuropathies
Amyloidosis
Polyneuropathies
Amyloidosis, Familial
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on July 09, 2014