title: Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).
  
  
  METHODS
  In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.
  
  
  RESULTS
  There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.
  
  
  CONCLUSIONS
  Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.
  
  
  METHODS
  This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.
authors: Hospital de Santo António, Porto, Portugal. tcoelho@netcabo.pt
authors: Teresa
authors: T
authors: Coelho
authors: Luis F
authors: LF
authors: Maia
authors: Ana
authors: A
authors: Martins da Silva
authors: Marcia
authors: M
authors: Waddington Cruz
authors: Violaine
authors: V
authors: Planté-Bordeneuve
authors: Pierre
authors: P
authors: Lozeron
authors: Ole B
authors: OB
authors: Suhr
authors: Josep M
authors: JM
authors: Campistol
authors: Isabel Maria
authors: IM
authors: Conceição
authors: Hartmut H-J
authors: HH
authors: Schmidt
authors: Pedro
authors: P
authors: Trigo
authors: Jeffery W
authors: JW
authors: Kelly
authors: Richard
authors: R
authors: Labaudinière
authors: Jason
authors: J
authors: Chan
authors: Jeff
authors: J
authors: Packman
authors: Amy
authors: A
authors: Wilson
authors: Donna R
authors: DR
authors: Grogan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001583:Benzoxazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism; D011788:Quality of Life; D012720:Severity of Illness Index
chemical_list: D001583:Benzoxazoles; D018696:Neuroprotective Agents; D011228:Prealbumin; C547076:tafamidis