The Fabrazyme® and Arbs and ACE Inhibitor Treatment (FAACET) Study
Condition: Fabry Disease; Proteinuria
MeSH terms: Fabry Disease; Proteinuria
Study type: Observational

Summary: 
      The primary hypothesis is that titration of ACE inhibitor and Angiotensin Receptor Blockers
      (ARBs)to reduce urine protein excretion to < 500 mg per day in Fabry Patients receiving
      agalsidase beta therapy at 1 mg/kg every two weeks will slow the progression rate of decline
      of glomerular filtration rate (GFR) compared to case controls drawn from the
      Genzyme-sponsored Phase III extension study (GFR 60 to 125 ml/min/1.73 m², urine protein > 1
      gram/day) or the Phase IV study (GFR 20 to 60 ml/min/1.73 m², urine protein > 0.5 gram/day).
      After a 3 month initial Evaluation Phase, the patients will be followed during a 24 month
      Observation Phase. FAACET is an open label, prospective observational study. The primary
      objective is reduction of first morning urine protein/creatinine ratio to < 0.5 gram/gram.
      The primary outcome measure is the regression slope of MDRD GFR with time in years
    

Detailed description: 
      TITLE: FABRAZYME® + ARBS + ACE INHIBITOR TREATMENT (FAACET) STUDY Multi-center, Open-label
      Study of the Safety and Efficacy of Control of Proteinuria with Angiotensin Receptors
      Blockers (ARBs) and Angiotensin Converting Enzyme Inhibitors (ACEIs) in Patients with Fabry
      Disease Who Are Receiving Fabrazyme®.

      PROTOCOL NO. UAB NEPHROLOGY 001-2006 SPONSOR: University of Alabama at Birmingham,
      Birmingham, AL 35294 NAME OF FINISHED PRODUCTS: Angiotensin Converting Enzyme Inhibitors,
      Angiotensin Receptor Blockers, Fabrazyme® INVESTIGATOR/STUDY CENTERS: Fourteen (14) study
      sites worldwide PRIMARY OBJECTIVE To determine whether decline of GFR can be slowed by
      titrating ACEI/ARB anti-proteinuric therapy to target urine protein/creatinine ratio of ≤
      0.5, or 50% reduction from baseline, in Fabry patients with significant kidney involvement
      (20 ≤ eGFRMDRD ≤ 60 ml/min/1.73 m²), and baseline urine protein/creatinine ratio > 0.5 (based
      on the last value obtained before initiating ACEI/ARB therapy or obtained at screening before
      the first Evaluation Visit of the FAACET Study), who are receiving standard of care treatment
      for Chronic Kidney Disease (CKD), and Fabry disease.

      SECONDARY OBJECTIVES

        1. To determine whether urine protein/creatinine ratio ≤ 0.5, or ≥ 50% reduction from
           baseline, can safely be achieved in Fabry patients with ACEI/ARB therapy.

        2. To determine whether urine protein/creatinine ratio ≤ 0. 5, or ≥ 50% reduction from
           baseline, result in a slower rate of GFR decline compared to patients who cannot achieve
           this target.

        3. To determine if GFR decline can be slowed by titrating ACEI/ARB therapy to target urine
           protein/creatinine ratio ≤ 0.5, or 50% reduction from baseline, in Fabry patients with
           definite kidney involvement (125 ≥ eGFRMDRD ≥ 60 ml/min/1.73 m²), and baseline urine
           protein/creatinine ratio > 1.0 (based on the last value obtained before initiating
           ACEI/ARB therapy or obtained at screening before the first Evaluation Visit of the
           FAACET Study) who are receiving standard of care treatment for Chronic Kidney Disease
           (CKD), and Fabry disease.

      METHODOLOGY This will be a multi-center, multinational, open-label study to confirm the
      safety and the effectiveness of ACE inhibitors and ARBs against proteinuria in patients with
      advanced Fabry disease who are receiving Fabrazyme® at 1 mg/kg every other week. Following an
      initial 3-month Evaluation Period, during which ACEI/ARB therapy will be titrated to reduce
      urinary protein/creatinine ratio to a target of 0.5, or 50% of baseline level, the patients
      will be followed for 24 months in an Observation Period with continued monitoring of their
      eGFRMDRD and protein excretion every 3 monthly for 24 months. ACEI/ARB therapy will continue
      to be titrated to maintain the proteinuria target in the Observation Period. The baseline
      urine protein/creatinine ratio is defined as the last value obtained in the individual
      patient before they began any ACEI/ARB therapy.

      STUDY SITES: 40 patients will be enrolled in the FAACET Study at 14 Study Sites.

      INCLUSION CRITERIA:

      The patient must provide written, informed consent, and be ≥ 19 yrs of age. The patient is
      already receiving Fabrazyme® at 1 mg/kg every two weeks at the time of enrollment.

      Patient has confirmed Fabry disease (plasma αGAL activity of < 1.5 nmol/hr/mL, or leukocyte
      αGAL activity of < 4 nmol/hr/mg), or a known mutation compatible with Fabry disease.

      Patients with either:

        1. eGFRMDRD ≥ 20 and ≤ 60 ml/min/1.73 m2, and documented baseline urine protein/creatinine
           ratio > 0.5, based on the last value obtained before initiating ACEI/ARB therapy or
           obtained at screening before the first Evaluation Visit of the FAACET Study; or

        2. eGFRMDRD ≤ 125 ml/min/1.73 m2 and > 60 ml/min/1.73 m2 with documented baseline urine
           protein/creatinine ratio > 1, based on the last value obtained before initiating
           ACEI/ARB therapy or obtained at screening before the first Evaluation Visit of the
           FAACET Study.

      EXCLUSION CRITERIA:

      The patient has undergone kidney transplantation or is currently on dialysis, or is planning
      on receiving a kidney transplant during the first year of the study.

      The patient has diabetic nephropathy or the presence of another, confounding kidney disease
      unless there is kidney biopsy confirmation that the patient does not have diabetic
      nephropathy or another, confounding kidney disease.

      The patient has a clinically significant organic disease, or other condition that in the
      opinion of the investigator would preclude participation in the full extent of the trial.

      The patient is unwilling to comply with the requirements of the protocol, including
      continuing on Fabrazyme® at 1 mg/kg body weight every two weeks.

      Patients who have documented allergies to ACE inhibitors and to ARBs are not eligible to
      participate in the FAACET Study.

      The patient is pregnant or intends to become pregnant during the course of the study.

      TREATMENT REGIMEN During the Evaluation Period, the patients will be titrated with ACEI/ARBs
      to reduce their first morning urine protein/creatinine ratio to ≤ 0.5, or 50% of the baseline
      level. During the Observation Period, the ACEI/ARB therapy will be dose-adjusted, as
      tolerated, to maintain their urine protein/creatinine ratio at target level. Patients will
      continue to receive Fabrazyme® intravenously every 2 weeks throughout the study. Unless there
      is a compelling clinical indication, patients in the FAACET study should avoid all
      potentially nephrotoxic agents (e.g., NSAIDs, aminoglycoside antibiotics, X-ray contrast
      agents, etc.) STUDY DURATION: 3 month Evaluation Period, followed by 24-month Observation
      Period.

      CRITERIA FOR EVALUATION Efficacy: Change in renal function will be assessed with the eGFRMDRD
      for the FAACET patients, and compared to the Phase IV patient population (AGAL008 and
      AGAL025) to assess the additional impact of ACEI/ARB therapy on the decline in eGFRMDRD in
      patients receiving Fabrazyme® therapy. Patients who every received Fabrazyme for at least 12
      months in AGAL008/AGAL025 or Phase III/extension study will be included in the Control
      Cohorts: a). if eGFRMDRD ≤ 60 ml/min/1.73 m² and urine protein/creatinine ratio > 0.5 at
      Baseline before initiating treatment with Fabrazyme®, OR b). Baseline eGFRMDRD ≤ 125 and ≥ 60
      ml/min/1.73 m², and urine protein/creatinine ratio > 1.0 at Baseline before initiating
      treatment with Fabrazyme®. These patients will be used in analyses for comparison to the
      FAACET Study patients based on their characteristics before initiating Fabrazyme®.

      Safety: Safety will be monitored in terms of adverse experiences, vital sign parameters,
      physical examinations, laboratory safety parameters, concomitant medications and antibody
      formation.

      DSMP and DSMB: A Data Safety Monitoring Plan has been developed for the FAACET Study, and the
      Steering Committee will assume the responsibilities usually attributed to a Data Safety
      Monitoring Board. A summary log will be kept of all adverse events reported to the UAB IRB.

      STATISTICAL METHODS Efficacy: The primary efficacy analysis will be the change in renal
      function assessed as eGFRMDRD for the patient group that reaches and maintains their urine
      protein/creatinine ratio ≤ 0.5, or ≤ 50% of their baseline, to assess the impact of ACEI/ARB
      therapy on decline of eGFRMDRD in patients receiving Fabrazyme® therapy. A secondary efficacy
      analysis will be carried out on the change in eGFRMDRD for the patient group that cannot
      maintain their urine protein/creatinine ratio ≤ 0.5, or less than 50% of their baseline. The
      Phase III/Phase III extension and Phase IV/Phase IV extension patients, who met the Criteria
      for evaluation listed above, will serve as the Control Cohorts for comparison to the FAACET
      patients in the various analyses.

      The Control Cohort will be defined a priori before FAACET enrollment begins. The age, gender,
      baseline eGFRMDRD, systolic blood pressure, and baseline proteinuria, as well as duration of
      Fabrazyme® therapy versus the appropriate mixed models with random slopes for individual
      patients. The mixed model analyses will be adjusted as needed for the covariates assumed to
      be most important in determining the rate of decline in kidney function (i.e. age, gender,
      baseline eGFRMDRD, systolic blood pressure, baseline proteinuria, and duration of Fabrazyme®
      therapy).

      Safety: Adverse events and serious adverse events will be summarized by body system and
      preferred term using a standardized coding dictionary (MedDRA). The severity and relationship
      of treatment to adverse events will be summarized. Clinically significant laboratory values,
      and physical exam findings will be summarized. Overall antibody status, including
      seroconversion rates, and titer levels will be summarized. Concomitant medications will be
      detailed at each study visit.
    

Intervention name(s): enalapril and other angiotensin converting enzyme inhibitors; losartan and other angiotensin receptor blockers
Intervention type(s): Drug
Intervention description(s): 10 mg by mouth every day; 25 mg by mouth every day
Other intervention name(s): agalsidase beta
Intervention MeSH terms: Losartan; Enalapril; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Enzyme Inhibitors
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Adult patients with confirmed diagnosis of Fabry disease, who are receiving enzyme
        replacement therapy with agalsidase beta
      
Keywords: Definition: Fabry disease; Definition: Progression; Definition: MDRD GFR; Definition: Chronic Kidney Disease; Definition: Proteinuria; Definition: Enzyme Replacement Therapy; Definition: Anti-proteinuric therapy