Tafamidis for transthyretin familial amyloid polyneuropathy
A randomized, controlled trial
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Abstract
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 (<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.
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.
GLOSSARY
- AE=
- adverse event;
- ANCOVA=
- analysis of covariance;
- ARR=
- absolute risk reduction;
- CI=
- confidence interval;
- DPN=
- diabetic polyneuropathy;
- EE=
- efficacy-evaluable;
- ITT=
- intent-to-treat;
- LS Mean=
- least-squares mean;
- mBMI=
- modified body mass index;
- NIS-LL=
- Neuropathy Impairment Score–Lower Limbs;
- NNT=
- number needed to treat;
- QOL=
- quality of life;
- QOL-DN=
- Quality of Life–Diabetic Neuropathy Questionnaire;
- TQOL=
- total quality of life;
- TTR-FAP=
- transthyretin familial amyloid polyneuropathy
Footnotes
Study funding: Funding information is provided at the end of the article.
Editorial, page 730
Supplemental data at www.neurology.org
Coinvestigators are listed on the Neurology® Web site at www.neurology.org.
- Received August 3, 2011.
- Accepted March 8, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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Letters: Rapid online correspondence
- Response to Merkies
- Teresa Coelho, Medical Director, Unidade Clinica de Paramiloidose,christine.masi@envisionpharma.com
- Joseph C Cappelleri, Michelle Stewart, Pedro E Huertas, Susanne Vidot
Submitted July 10, 2013 - Proper outcome measures evaluation in FAP should precede interventional trials
- Ingemar S.J. Merkies, neurologist and clinimetrician, Maastricht University Medical Centre and Spaarne Hosptial / Corresponding address: Dept Neurology -isjmerkies@planet.nl
Submitted September 07, 2012
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