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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00409175
Recruitment Status : Completed
First Posted : December 8, 2006
Results First Posted : December 17, 2012
Last Update Posted : December 17, 2012
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE December 6, 2006
First Posted Date  ICMJE December 8, 2006
Results First Submitted Date  ICMJE November 16, 2012
Results First Posted Date  ICMJE December 17, 2012
Last Update Posted Date December 17, 2012
Study Start Date  ICMJE January 2007
Actual Primary Completion Date May 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2012)
  • Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 18 [ Time Frame: Month 18 ]
    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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 6, 2006)
  • Response to treatment at Month 18 as measured by the Neurologic Impairment Score - Lower Limb (NIS-LL)
  • Change from Baseline to 18 months in the Total Quality of Life (TQOL) score, as measured by the Norfolk QOL-DN.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2012)
  • 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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2006)
  • Change from Baseline through Month 18 in "+7 composite score" as measured by nerve conduction studies (NCS), vibration detection threshold (VDT) and heart rate response to deep breathing (HRDB)
  • Change from Baseline through Month 18 in heat pain and cooling thresholds as measured by Quantitative Sensory Testing (QST) utilizing CASE IV
  • Change from Baseline through Month 18 in modified Body Mass Index (mBMI)
  • TTR stabilization through Month 18.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis
Official Title  ICMJE Safety and Efficacy of Orally Administered Fx-1006A in Patients With Familial Amyloid Polyneuropathy (FAP): A Randomized, Double-blind, Placebo-controlled Study
Brief Summary

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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Familial Amyloid Polyneuropathy
Intervention  ICMJE
  • Drug: Fx-1006A
    Fx-1006A 20mg or matched placebo once daily (at the same time each day) for a period of 18 Months
  • Drug: Placebo
    Fx-1006A 20mg or matched placebo once daily (at the same time each day) for a period of 18 Months
Study Arms  ICMJE
  • Experimental: 1.
    Fx-1006A
    Intervention: Drug: Fx-1006A
  • Placebo Comparator: 2.
    Placebo
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 20, 2011)
128
Original Enrollment  ICMJE
 (submitted: December 6, 2006)
120
Actual Study Completion Date  ICMJE May 2009
Actual Primary Completion Date May 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Brazil,   France,   Germany,   Portugal,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00409175
Other Study ID Numbers  ICMJE FX-005
B3461020
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jeff Packman FoldRx Pharmaceuticals, Inc.
PRS Account Pfizer
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP