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ADvance II: A 12-month Double-blind, Randomized, Controlled Study to Evaluate the Safety and Efficacy of Deep Brain Stimulation of the Fornix (DBS-f) in Patients With Mild Probable Alzheimer’s Disease


Brief Summary:

The primary efficacy objective of this study is to test the hypothesis that DBS-f stimulation
(ON) will slow cognitive and functional progression of AD, as compared to no stimulation
(OFF), by measuring baseline (pre-implantation) to 12-month change in the integrated
Alzheimer’s disease rating scale (iADRS).


Inclusion Criteria:

1. Informed consent signed by the subject and caregiver.

2. At least 65 years old

3. Probable Alzheimer’s disease according to the National Institute of Aging Alzheimer’s
disease Association criteria.

4. Mild dementia according to the Clinical Dementia Rating (CDR) global rating of 0.5 or
1 at screening.

5. ADAS-cog-11 score of 10-24 inclusive at screening AND baseline (with a score ≥ 4 on
ADAS-cog item 1).

6. Confirmation of Alzheimer’s disease based on CSF biomarkers.

7. The patient has an available caregiver or other appropriate knowledgeable informant
who can reliably report on daily activities and function and signs the informed
consent for participation as such.

8. Patient must be a good surgical candidate for placement of a deep brain stimulator as
judged by the DBS surgical team.

9. Fluency (oral and written) in the language in which standardized tests will be

10. The patient is either

1. taking a stable dose of cholinesterase inhibitor (AChEI) medication (donepezil,
galantamine, or rivastigmine) for at least 60 days prior to signing the informed
consent form OR

2. the patient has previously had an intolerance/failure to cholinesterase inhibitor
medications that can be documented AND there is no intention to modify the dose
over the course of the study (NOTE: These medications may NOT be initiated,
discontinued or modified during the 12-month control period).

Exclusion Criteria:

1. NPI total score ≥ 10 or score ≥ 4 in any NPI domain (clinically significant
neuropsychiatric symptoms). Apathy score ≥ 4 acceptable.

2. Modified Hachinski ischemia scale score > 4 at screening.

3. At risk for suicide in the opinion of the investigator or the subject answers “yes” to
“Suicidal Ideation” Item 4 or 5 on the C-SSRS (at the time of evaluation) at the
screening visit or attempted suicide within the last 2 years.

4. Suffers from a major psychiatric disorder such as schizophrenia, bipolar disorder or
major depressive disorder, or has current alcohol or substance abuse based on
psychiatric consultation at screening visit.

5. History of moderate or more severe traumatic brain injury in the 2 years prior to
signing the consent to participate in the study.

6. History of brain tumor, subdural hematoma, or other clinically significant (in the
judgment of the investigator) space-occupying lesion on CT or MRI.

7. History of seizure disorder.

8. Contraindications for PET scanning (e.g., insulin dependent diabetes).

9. Contraindications for MRI scanning, including implanted metallic devices (e.g.
non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins;
surgical clips; or other implanted metal parts), or claustrophobia or discomfort in
confined spaces.

10. Radiation exposure in the 1 year prior to signing the informed consent form that, in
combination with the radiation exposure from this study, would exceed 5 rem.

11. Abnormal cardiovascular or neurovascular disorder that, in the opinion of the
investigator would preclude participation in the study.

12. Currently prescribed any non-AD medications that, in the opinion of the investigator
would preclude participation in the study.

13. Is unable or unwilling to comply with protocol follow-up requirements.

14. Has a life expectancy of < 1 year. 15. Is actively enrolled in another concurrent clinical trial.


  • University of Southern California, Los Angeles, California, United States, 90033
  • Stanford University, Stanford, California, United States, 94305
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