ADvance DBS-f in Patients With Mild Probable Alzheimer's Disease (ADvance)

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ClinicalTrials.gov Identifier: NCT01608061

Recruitment Status : Completed

First Posted : May 30, 2012

Results First Posted : August 31, 2020

Last Update Posted : August 31, 2020

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Functional Neuromodulation Ltd

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Alzheimer Disease
Interventions	Device: DBS-f on Device: DBS-f off
Enrollment	42

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	DBS-f on	DBS-f Off
Arm/Group Description	DBS-f on ...	DBS-f off ...
Arm/Group Description	DBS-f on DBS-f on: deep brain stimulation of the fornix	DBS-f off DBS-f off: deep brain stimulation of the fornix turned off
Period Title: Blinded Period
Started	21	21
Completed	21	21
Not Completed	0	0
Period Title: Long Term Follow-Up
Started	21	21
Completed	14	16
Not Completed	7	5
Period Title: Extension Period
Started	14	16
Completed	14	14
Not Completed	0	2

Baseline Characteristics

Arm/Group Title		DBS-f on	DBS-f Off	Total
Arm/Group Description		DBS-f on ...	DBS-f off ...	Total of all reporting groups
Arm/Group Description		DBS-f on DBS-f on: deep brain stimulation of the fornix	DBS-f off DBS-f off: deep brain stimulation of the fornix turned off	Total of all reporting groups
Overall Number of Baseline Participants		21	21	42
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Median (Full Range) Unit of measure: Years
	Number Analyzed	21 participants	21 participants	42 participants
		68.1 (51.1 to 79.7)	71.3 (48.0 to 78.0)	69.9 (48.0 to 79.7)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	21 participants	21 participants	42 participants
	Female	10 47.6%	9 42.9%	19 45.2%
	Male	11 52.4%	12 57.1%	23 54.8%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	21 participants	21 participants	42 participants
	Hispanic or Latino	0 0.0%	2 9.5%	2 4.8%
	Not Hispanic or Latino	21 100.0%	19 90.5%	40 95.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	21 participants	21 participants	42 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	21 100.0%	20 95.2%	41 97.6%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	1 4.8%	1 2.4%
ADAS-Cog 11 ^[1] Median (Full Range) Unit of measure: Units on a scale
	Number Analyzed	21 participants	21 participants	42 participants
		17 (13 to 22)	17 (12 to 21)	17 (12 to 22)
		[1] Measure Description: Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11). The cognitive subscale (ADAS-Cog) includes 11 tasks that include both subject-completed tests and observer-based assessments.Together these tasks assess the cognitive domains of memory, language, and praxis. Single scale from 0 to 70 where a higher score indicates more advanced disease.
CDR ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	21 participants	21 participants	42 participants
0.5		13	15	28
1.0		8	6	14
		[1] Measure Description: Clinical Dementia Rating scale (CDR). The CDR is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. The necessary information to make each rating is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g., family member). Range is 0 to 3 with a higher score indicating more advanced disease.

Outcome Measures

1.Primary Outcome


Title	Acute Safety
Description	Acute safety will be assessed by estimating the rate of serious device...
Description	Acute safety will be assessed by estimating the rate of serious device (pulse generator or lead) or procedure related adverse events from the date of implant through the date of randomization, plus serious procedure related events through 30 days post-implant. All subjects undergoing an implant procedure will be included in these rate estimates. The rate and 95% confidence interval will be presented. Analysis is of a timepoint prior to randomization and thus all subjects are analyzed together.
Time Frame	30 days post implant

Outcome Measure Data

Analysis Population Description

All implanted subjects are used in this analysis. This analysis is of the entire population prior to randomization and thus cannot be analyzed per arm.


Arm/Group Title	All Implanted Subject
Arm/Group Description:	All implanted subjects are included...
Arm/Group Description:	All implanted subjects are included in this group.
Overall Number of Participants Analyzed	42
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: participants
	2 (0.6 to 16.2)

2.Primary Outcome


Title	Long Term Safety. Not Based on Formal Hypotheses.
Description	Long-term safety will be assessed by the rate of serious device or the...
Description	Long-term safety will be assessed by the rate of serious device or therapy related adverse events from the date of randomization through the date of the Month 12 visit. The rate and 95% confidence interval will be presented by randomization group. All subjects randomized will be included.
Time Frame	12 month

Outcome Measure Data

Analysis Population Description

All randomized subjects are included.


Arm/Group Title	DBS-f on	DBS-f Off
Arm/Group Description:	DBS-f on ...	DBS-f off ...
Arm/Group Description:	DBS-f on DBS-f on: deep brain stimulation of the fornix	DBS-f off DBS-f off: deep brain stimulation of the fornix turned off
Overall Number of Participants Analyzed	21	21
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: participants
	0 (0 to 16.1)	1 (0.1 to 23.8)

3.Secondary Outcome


Title	ADAS-Cog 13
Description	The mean change from baseline (pre-implant) to 12 months will be calcu...
Description	The mean change from baseline (pre-implant) to 12 months will be calculated in each treatment group. The differences between randomized groups in mean change will be calculated, along with corresponding 2-sided, 95% confidence intervals. Instrument is Alzheimer's Disease Assessment Scale - Cognitive subscale. Scores range from 0 to 85 with higher scores meaning worse outcome.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

All randomized subjects


Arm/Group Title	DBS-f on	DBS-f Off
Arm/Group Description:	DBS-f on ...	DBS-f off ...
Arm/Group Description:	DBS-f on DBS-f on: deep brain stimulation of the fornix	DBS-f off DBS-f off: deep brain stimulation of the fornix turned off
Overall Number of Participants Analyzed	21	21
Mean (Standard Error) Unit of Measure: score on a scale
	8.0 (2.2)	8.0 (1.9)

4.Secondary Outcome


Title	CDR-SB
Description	The mean change from baseline (pre-implant) to 12 months will be calcu...
Description	The mean change from baseline (pre-implant) to 12 months will be calculated in each treatment group. The differences between randomized groups in mean change will be calculated, along with corresponding 2-sided, 95% confidence intervals. The scale used is the Clinical Dementia Rating Scale and the score used is the sum of boxes. The scores for this measure range from 0 to 18 with a higher score indicating a worse outcome.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

All randomized subjects with available data. Two subjects in the ON group had missing CDR at 12 months.


Arm/Group Title	DBS-f on	DBS-f Off
Arm/Group Description:	DBS-f on ...	DBS-f off ...
Arm/Group Description:	DBS-f on DBS-f on: deep brain stimulation of the fornix	DBS-f off DBS-f off: deep brain stimulation of the fornix turned off
Overall Number of Participants Analyzed	19	21
Mean (Standard Error) Unit of Measure: score on a scale
	2.5 (0.4)	2.6 (0.7)

Adverse Events

Time Frame	Adverse events were collected from the time of consent until study exit for each subject. Maximum duration was 48 months.
Adverse Event Reporting Description	An independent Clinical Events Committee (CEC) reviewed all reported adverse events. The CEC was responsible for conducting a review of all adverse events reported for study subjects. The CEC will adjudicate and classify all events for relatedness to the study system, study procedure and study requirements. The CEC will determine if any serious device-related adverse event is an unanticipated adverse device effect (UADE).

Arm/Group Title	DBS-f on		DBS-f Off
Arm/Group Description	DBS-f on ...		DBS-f off ...
Arm/Group Description	DBS-f on DBS-f on: deep brain stimulation of the fornix		DBS-f off DBS-f off: deep brain stimulation of the fornix turned off
All-Cause Mortality
	DBS-f on		DBS-f Off
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/21 (4.76%)		0/21 (0.00%)
Serious Adverse Events Serious Adverse Events
	DBS-f on		DBS-f Off
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/21 (38.10%)		8/21 (38.10%)
Cardiac disorders
myocardial infarction with stent ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
Gastrointestinal disorders
Nausea and vomiting ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
General disorders
Headache ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
Infections and infestations
UTI ^† [1]	0/21 (0.00%)	0	1/21 (4.76%)	1
Skin infection ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
Bacteremia ^† [2]	1/21 (4.76%)	1	0/21 (0.00%)	0
Pneumonia ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
Device infection ^†	2/21 (9.52%)	3	1/21 (4.76%)	1
Musculoskeletal and connective tissue disorders
Increased rigidity ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
Nervous system disorders
Seizure ^†	1/21 (4.76%)	2	0/21 (0.00%)	0
Syncope ^†	1/21 (4.76%)	1	3/21 (14.29%)	4
Altered mental status ^†	1/21 (4.76%)	1	1/21 (4.76%)	1
Fall ^†	1/21 (4.76%)	1	2/21 (9.52%)	2
Psychiatric disorders
Agitation ^†	0/21 (0.00%)	0	1/21 (4.76%)	1
Depression ^†	0/21 (0.00%)	0	1/21 (4.76%)	1
Confusion ^†	0/21 (0.00%)	0	1/21 (4.76%)	1
Suicidal Ideation ^†	0/21 (0.00%)	0	1/21 (4.76%)	1
Surgical and medical procedures
Abnormal MRI ^†	0/21 (0.00%)	0	1/21 (4.76%)	1
Subdural hematoma ^† [3]	0/21 (0.00%)	0	1/21 (4.76%)	1
Lead misplacement ^†	1/21 (4.76%)	1	0/21 (0.00%)	0
† Indicates events were collected by systematic assessment [1] Urinary tract infection [2] suspected aortic valve endocarditis [3] bilateral subacute and chronic
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	DBS-f on		DBS-f Off
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/21 (90.48%)		17/21 (80.95%)
Gastrointestinal disorders
Diarrhea ^†	2/21 (9.52%)	2	3/21 (14.29%)	4
Fecal Incontinence ^†	1/21 (4.76%)	1	2/21 (9.52%)	2
Vomiting ^†	3/21 (14.29%)	3	1/21 (4.76%)	1
General disorders
Dizziness ^†	1/21 (4.76%)	1	2/21 (9.52%)	2
Epistaxis ^†	3/21 (14.29%)	3	0/21 (0.00%)	0
Fall ^†	2/21 (9.52%)	2	5/21 (23.81%)	17
Fatigue ^†	4/21 (19.05%)	4	4/21 (19.05%)	4
Headache ^†	6/21 (28.57%)	7	7/21 (33.33%)	7
Insomnia ^†	2/21 (9.52%)	2	4/21 (19.05%)	4
Lethargy ^†	0/21 (0.00%)	0	2/21 (9.52%)	2
Migraine ^†	2/21 (9.52%)	3	0/21 (0.00%)	0
Nausea ^†	4/21 (19.05%)	4	4/21 (19.05%)	4
Shortness of Breath ^†	2/21 (9.52%)	2	0/21 (0.00%)	0
Infections and infestations
Respiratory Infection ^†	5/21 (23.81%)	9	4/21 (19.05%)	6
Musculoskeletal and connective tissue disorders
Neck Pain ^†	1/21 (4.76%)	1	1/21 (4.76%)	1
Nervous system disorders
Agitation ^†	2/21 (9.52%)	2	2/21 (9.52%)	4
Anxiety ^†	2/21 (9.52%)	2	2/21 (9.52%)	6
Confusion ^†	3/21 (14.29%)	3	6/21 (28.57%)	7
Irritability ^†	2/21 (9.52%)	2	1/21 (4.76%)	1
Seizure ^†	2/21 (9.52%)	6	0/21 (0.00%)	0
Psychiatric disorders
Change in Mental Status ^†	1/21 (4.76%)	1	1/21 (4.76%)	1
Delerium ^†	1/21 (4.76%)	1	1/21 (4.76%)	1
Depression ^†	6/21 (28.57%)	6	4/21 (19.05%)	6
Paranoid Ideation ^†	1/21 (4.76%)	3	1/21 (4.76%)	1
visual Hallucinations ^†	1/21 (4.76%)	1	3/21 (14.29%)	5
Renal and urinary disorders
Urinary Tract Infection ^†	3/21 (14.29%)	3	1/21 (4.76%)	1
Urinary Retention ^†	1/21 (4.76%)	1	2/21 (9.52%)	2
Urinary Incontenance ^†	0/21 (0.00%)	0	2/21 (9.52%)	2
Skin and subcutaneous tissue disorders
Basal Cell Carcinoma ^†	0/21 (0.00%)	0	2/21 (9.52%)	2
Contact Dermatitis ^†	1/21 (4.76%)	1	1/21 (4.76%)	1
† Indicates events were collected by systematic assessment

Limitations and Caveats

While this feasibility trial was randomized it was not designed with formal hypotheses nor was it powered for analyses.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Todd Langevin
Organization:	Functional Neuromodulation
Phone:	7636071214
EMail:	todd@fxneuromod.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lozano AM, Fosdick L, Chakravarty MM, Leoutsakos JM, Munro C, Oh E, Drake KE, Lyman CH, Rosenberg PB, Anderson WS, Tang-Wai DF, Pendergrass JC, Salloway S, Asaad WF, Ponce FA, Burke A, Sabbagh M, Wolk DA, Baltuch G, Okun MS, Foote KD, McAndrews MP, Giacobbe P, Targum SD, Lyketsos CG, Smith GS. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease. J Alzheimers Dis. 2016 Sep 6;54(2):777-87. doi: 10.3233/JAD-160017.

Ponce FA, Asaad WF, Foote KD, Anderson WS, Rees Cosgrove G, Baltuch GH, Beasley K, Reymers DE, Oh ES, Targum SD, Smith GS, Lyketsos CG, Lozano AM; ADvance Research Group. Bilateral deep brain stimulation of the fornix for Alzheimer's disease: surgical safety in the ADvance trial. J Neurosurg. 2016 Jul;125(1):75-84. doi: 10.3171/2015.6.JNS15716. Epub 2015 Dec 18.

Layout table for additonal information

Responsible Party:	Functional Neuromodulation Ltd
ClinicalTrials.gov Identifier:	NCT01608061
Other Study ID Numbers:	FNMI-001
First Submitted:	May 21, 2012
First Posted:	May 30, 2012
Results First Submitted:	February 18, 2020
Results First Posted:	August 31, 2020
Last Update Posted:	August 31, 2020

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