Deep brain stimulation targeting the fornix for mild Alzheimer dementia

Design of the ADvance randomized controlled trial

Kathryn B. Holroyd, Lisa Fosdick, Gwenn Smith, Jeannie-Marie S Leoutsakos, Cynthia Munro, Esther Oh, Kristen E. Drake, Paul B Rosenberg, William S Anderson, Stephen Salloway, J. Cara Pendergrass, Anna D. Burke, David A. Wolk, David F. Tang-Wai, Francisco A. Ponce, Wael F. Asaad, Marwan N. Sabbagh, Michael S. Okun, Gordon Baltuch, Kelly D. Foote & 3 others Steven D. Targum, Andres M. Lozano, Constantine G Lyketsos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)63-76
Number of pages14
JournalOpen Access Journal of Clinical Trials
Volume7
DOIs
StatePublished - Jul 10 2015

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Deep Brain Stimulation
Alzheimer Disease
Randomized Controlled Trials
Dementia
Brain Fornix
Placebos
Outcome Assessment (Health Care)
Neuroimaging
Positron-Emission Tomography
Patient Selection
Multicenter Studies
Canada
Psychiatry
Disease Progression
Animal Models
Public Health
Demography
Clinical Trials
Safety
Glucose

Keywords

  • Alzheimer disease
  • Clinical trials
  • Deep brain stimulation
  • Fornix
  • Methods

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
  • Pharmacology (medical)

Cite this

Deep brain stimulation targeting the fornix for mild Alzheimer dementia : Design of the ADvance randomized controlled trial. / Holroyd, Kathryn B.; Fosdick, Lisa; Smith, Gwenn; Leoutsakos, Jeannie-Marie S; Munro, Cynthia; Oh, Esther; Drake, Kristen E.; Rosenberg, Paul B; Anderson, William S; Salloway, Stephen; Pendergrass, J. Cara; Burke, Anna D.; Wolk, David A.; Tang-Wai, David F.; Ponce, Francisco A.; Asaad, Wael F.; Sabbagh, Marwan N.; Okun, Michael S.; Baltuch, Gordon; Foote, Kelly D.; Targum, Steven D.; Lozano, Andres M.; Lyketsos, Constantine G.

In: Open Access Journal of Clinical Trials, Vol. 7, 10.07.2015, p. 63-76.

Research output: Contribution to journalArticle

Holroyd, KB, Fosdick, L, Smith, G, Leoutsakos, J-MS, Munro, C, Oh, E, Drake, KE, Rosenberg, PB, Anderson, WS, Salloway, S, Pendergrass, JC, Burke, AD, Wolk, DA, Tang-Wai, DF, Ponce, FA, Asaad, WF, Sabbagh, MN, Okun, MS, Baltuch, G, Foote, KD, Targum, SD, Lozano, AM & Lyketsos, CG 2015, 'Deep brain stimulation targeting the fornix for mild Alzheimer dementia: Design of the ADvance randomized controlled trial', Open Access Journal of Clinical Trials, vol. 7, pp. 63-76. https://doi.org/10.2147/OAJCT.S81542
Holroyd, Kathryn B. ; Fosdick, Lisa ; Smith, Gwenn ; Leoutsakos, Jeannie-Marie S ; Munro, Cynthia ; Oh, Esther ; Drake, Kristen E. ; Rosenberg, Paul B ; Anderson, William S ; Salloway, Stephen ; Pendergrass, J. Cara ; Burke, Anna D. ; Wolk, David A. ; Tang-Wai, David F. ; Ponce, Francisco A. ; Asaad, Wael F. ; Sabbagh, Marwan N. ; Okun, Michael S. ; Baltuch, Gordon ; Foote, Kelly D. ; Targum, Steven D. ; Lozano, Andres M. ; Lyketsos, Constantine G. / Deep brain stimulation targeting the fornix for mild Alzheimer dementia : Design of the ADvance randomized controlled trial. In: Open Access Journal of Clinical Trials. 2015 ; Vol. 7. pp. 63-76.
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T1 - Deep brain stimulation targeting the fornix for mild Alzheimer dementia

T2 - Design of the ADvance randomized controlled trial

AU - Holroyd, Kathryn B.

AU - Fosdick, Lisa

AU - Smith, Gwenn

AU - Leoutsakos, Jeannie-Marie S

AU - Munro, Cynthia

AU - Oh, Esther

AU - Drake, Kristen E.

AU - Rosenberg, Paul B

AU - Anderson, William S

AU - Salloway, Stephen

AU - Pendergrass, J. Cara

AU - Burke, Anna D.

AU - Wolk, David A.

AU - Tang-Wai, David F.

AU - Ponce, Francisco A.

AU - Asaad, Wael F.

AU - Sabbagh, Marwan N.

AU - Okun, Michael S.

AU - Baltuch, Gordon

AU - Foote, Kelly D.

AU - Targum, Steven D.

AU - Lozano, Andres M.

AU - Lyketsos, Constantine G

PY - 2015/7/10

Y1 - 2015/7/10

N2 - 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.

AB - 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.

KW - Alzheimer disease

KW - Clinical trials

KW - Deep brain stimulation

KW - Fornix

KW - Methods

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