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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: An Open-Label Extension Of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy

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.

Detailed Summary:
Sponsor: Pfizer

Current Primary Outcome:

  • Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6 [ Time Frame: 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.
  • Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12 [ Time Frame: 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.
  • Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6 [ Time Frame: Baseline, Month 6 ]

    Original Primary Outcome:

    • Response to treatment at Months 6 and 12, as indicated by either improvement (decrease from Baseline) or stabilization (change from baseline of 0 to < 2) in the Neurologic Impairment Score - Lower Limb (NIS-LL) score. The NIS-LL score for each visit will [ Time Frame: 12 months ]
    • Change from Baseline to Months 6 and 12 in the Total Quality of Life (TQOL) score, as measured by the Norfolk QOL-DN. [ Time Frame: 12 months ]


    Current Secondary Outcome:

    • Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12 [ Time Frame: Baseline, Month 6, 12 ]
      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 scale 0 (normal) to 4 (paralysis), 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.
    • Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12 [ Time Frame: Baseline, Month 6, 12 ]
      Norfolk QOL-DN: 35-item participant-rated questionnaire to assess impact of DN on QOL; Item 1-7:scored as 1=symptoms present, 0=symptoms 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 and 12 [ Time Frame: Baseline, Month 6, 12 ]
      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 and 12 [ Time Frame: Baseline, Month 6, 12 ]
      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 and 12 [ Time Frame: Baseline, Month 6, 12 ]
      BMI was calculated by weight divided by height squared. mBMI was calculated by multiplying BMI by serum albumin levels to compensate for edema formation. A progressive decline in mBMI indicated worsening of disease severity.
    • Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12 [ Time Frame: Baseline, Week 6, Month 3, 6, 12 ]
      Troponin I was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ left ventricular [LV] wall stress).
    • Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12 [ Time Frame: Baseline, Week 6, Month 3, 6, 12 ]
      NT-proBNP was biomarker of cardiac stress (myocardial necrosis and increased filling pressures/ LV wall stress).
    • Intraepidermal Nerve Fiber (IENF) Density [ Time Frame: Baseline ]
      IENF density was quantified in 3 millimeter (mm) immunostained skin punch biopsies containing epidermis and superficial dermis to evaluate the amount and morphological appearance of small diameter nerve fibers, both somatic and autonomic, in sensory neuropathies. It is used in diagnosing various neuropathic conditions.
    • Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer [ Time Frame: Month 6, 12 ]
      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:

    • Change from Baseline to Months 6 and 12 in NIS-LL [ Time Frame: 12 months ]
    • Change from Baseline to Months 6 and 12 in the five domains of the Norfolk QOL-DN [ Time Frame: 12 months ]
    • Change from Baseline to Months 6 and 12 in "+7 composite score" as measured by nerve conduction studies (NCS), vibration detection threshold (VDT) and heart rate response to deep breathing (HRDB) [ Time Frame: 12 months ]
    • Change from Baseline to Months 6 and 12 in heat, pain and cooling thresholds as measured by Quantitative Sensory Testing (QST) utilizing CASE IV [ Time Frame: 12 months ]
    • Change from Baseline to Months 6 and 12 in modified Body Mass Index (mBMI) [ Time Frame: 12 months ]
    • Change from Baseline to Week 6 and Months 3, 6, and 12 in troponin I and NT-pro-BNP levels [ Time Frame: 12 months ]
    • IENF density at Baseline [ Time Frame: 12 months ]
    • TTR stabilization at Months 6 and 12, as measured by a validated immunoturbidimetric assay [ Time Frame: 12 months ]


    Information By: Pfizer

    Dates:
    Date Received: November 13, 2008
    Date Started: July 2008
    Date Completion:
    Last Updated: November 16, 2012
    Last Verified: November 2012