Deep brain stimulation targeting the fornix for mild Alzheimer dementia: design of the ADvance randomized controlled trial

Kathryn B Holroyd,1 Lisa Fosdick,2 Gwenn S Smith,1 Jeannie-Marie Leoutsakos,1 Cynthia A Munro,1 Esther S Oh,1 Kristen E Drake,2 Paul B Rosenberg,1 William S Anderson,1 Stephen Salloway,3–5 J Cara Pendergrass,6 Anna D Burke,7 David A Wolk,8 David F Tang-Wai,9–11 Francisco A Ponce,12 Wael F Asaad,13,14 Marwan N Sabbagh,15 Michael S Okun,16 Gordon Baltuch,17 Kelly D Foote,18 Steven D Targum,2,6 Andres M Lozano,10,11 Constantine G Lyketsos1 1Johns Hopkins University Memory and Alzheimer's Treatment Center, Baltimore, MD, 2Functional Neuromodulation Ltd, Minneapolis, MN, 3Department of Neurology, Butler Hospital, 4Department of Neurology, Rhode Island Hospital, 5Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, 6Clintara LLC, Boston, MA, 7Banner Alzheimer's Institute, Phoenix, AZ, 8Penn Memory Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; 9Department of Neurology, 10Department of Neurosurgery, University of Toronto, 11Division of Neurology, University Health Network Memory Clinic, Toronto, ON, Canada; 12Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, 13Department of Neurosurgery, Rhode Island Hospital, 14Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, RI, 15Banner Sun Health Research Institute, Sun City, AZ, 16Center for Movement Disorders and Neurorestoration, Department of Neurology, University of Florida – Gainsville, Gainsville, FL, 17Center for Functional and Restorative Neurosurgery, University of Pennsylvania, Philadelphia, PA, 18Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainsville, FL, USA Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS “off” or DBS “on” groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned “on” for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer's Disease Assessment Scale – cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test–retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up. Keywords: deep brain stimulation, Alzheimer disease, fornix, methods, clinical trials