Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial.
OBJECTIVE
To determine whether the tumor necrosis factor α inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia.


METHODS
In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and ClinicalTrials.gov (NCT01068353).


RESULTS
Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function.


CONCLUSIONS
This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients.


METHODS
This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia.
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Joseph
J
Butchart
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Laura
L
Brook
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Vivienne
V
Hopkins
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Jessica
J
Teeling
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Ursula
U
Püntener
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
David
D
Culliford
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Richard
R
Sharples
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Saif
S
Sharif
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Brady
B
McFarlane
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Rachel
R
Raybould
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Rhodri
R
Thomas
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
Peter
P
Passmore
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.
V Hugh
VH
Perry
From the Faculty of Medicine, Clinical Experimental Sciences (J.B., L.B., D.C., C.H.), and Faculty of Natural and Environmental Science, Centre for Biological Sciences (J.T., U.P., V.H.P.), University of Southampton; Memory Assessment and Research Centre (J.B., L.B., V.H., R.S., S.S., C.H.), Moorgreen Hospital, Southern Health Foundation Trust, Southampton; Becton Health Centre (B.M.), Southern Health Foundation Trust, New Milton; Centre for Public Health (P.P.), Queens University Belfast; MRC Centre for Neuropsychiatric Genetics and Genomics (R.R., R.T.), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK. c.holmes@soton.ac.uk.
Clive
C
Holmes
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004311:Double-Blind Method; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept