Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).

Objectives: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 (Ͻ2-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 ϭ 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n ϭ 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 ϭ 0.068) and change in TQOL (2.0 vs 7.2; p ϭ 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 ϭ 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p ϭ 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p Ͻ 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. Classification of evidence: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. Neurology® 2012;79:785-792 GLOSSARY AE ϭ adverse event; ANCOVA ϭ analysis of covariance; ARR ϭ absolute risk reduction; CI ϭ confidence interval; DPN ϭ diabetic polyneuropathy; EE ϭ efficacy-evaluable; ITT ϭ intent-to-treat; LS Mean ϭ least-squares mean; mBMI ϭ modified body mass index; NIS-LL ϭ Neuropathy Impairment Score-Lower Limbs; NNT ϭ number needed to treat; QOL ϭ quality of life; QOL-DN ϭ Quality of Life-Diabetic Neuropathy Questionnaire; TQOL ϭ total quality of life; TTR-FAP ϭ transthyretin familial amyloid polyneuropathy.