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Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease

Primary Purpose

Prodromal Alzheimer's Disease, Cerebral Vascular Disorder, Mild Cognitive Impairment

Status

Recruiting

Phase

Not Applicable

Locations

Israel

Study Type

Interventional

Intervention

Hyperbaric oxygen therapy

Sham

About this trial

This is an interventional treatment trial for Prodromal Alzheimer's Disease

Eligibility Criteria

60 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of Mild cognitive impairment (MCI) due to AD or mixed AD and vascular dementia pathology
MMSE score of 20 and above
Stable psychological and pharmacological treatment for more than three months prior to inclusion.
Caregiver that is seeing the patient at least twice per week and is willing to participate and accompany the patient and fill questionnaires
Subject willing and able to read, understand and sign an informed consent

Exclusion Criteria:

Inability to attend scheduled clinic visits and/or comply with the study protocol
History of traumatic brain injury, brain tumors, brain surgery, chronic subdural haemorrhages, Epilepsy
Active malignancy
Substance use at baseline, except for prescribed cannabis if vaporized or taken PO as tincture
History of other neurodegenerative diseases including Parkinson's disease (PD), Lewy body dementia (LBD), Frontotemporal dementia (FTD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Creutzfeld Jacob disease (CJD), Multisystem atrophy (MSA), Pseudobulbar palsy (PSP), Corticobasal degeneration (CBD), Wernicke Korsakoff syndrome
Chronic use of medications that may compromise cognitive function and cannot be stopped: Anticonvulsants, Anticholinergics, antiparkinsonian, corticosteroids, Benzodiazepines
Moderate to severe sleep apnea with no use of CPAP
Diagnosis of a psychiatric disorder including: major depression, schizophrenia, bipolar disorder
Serious suicidal ideation
Renal or liver insufficiency, electrolyte imbalances
Chronic heart failure with ejection fraction of 35 or less
HBOT for any reason prior to study enrolment
Chest pathology incompatible with pressure changes (including active asthma or COPD)
Ear or Sinus pathology incompatible with pressure changes (above 3 otolaryngologist visits a year)
An inability to perform an awake brain MRI or Amyloid PET
An inability to perform computerized cognitive tests (Neurotrax)
MMSE score below 20
No evidence of amyloid in the brain PET
No evidence of vascular related lesions in the brain MRI
Active smoking
Participation in another study

Sites / Locations

Shamir Medical Center (Assaf Harofeh)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Sham Comparator

Arm Label

Hyperbaric Oxygen Therapy active arm

Sham active arm

Arm Description

The protocol comprises of 60 consecutive hyperbaric oxygen treatment (HBOT) sessions, 5 sessions per week within a three months' period. Then there will be a maintenance period for 6 months in which the participants will receive HBOT twice a week.

The protocol comprises of 60 consecutive Sham sessions, 5 sessions per week within a three months' period. Then there will be a maintenance period for 6 months in which the participants will receive Shan sessions twice a week.

Outcomes

Primary Outcome Measures

Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)

Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.

Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)

Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.

Secondary Outcome Measures

Brain amyloid PET using Flumetamol (Vizamyl) tracer

Brain amyloid assessment using PET scan with Flumetamol (Vizamyl) tracer will be used to assess change in amyloid burden

Whole-brain quantitative perfusion imaging

Whole-brain quantitative perfusion imaging will be performed using Dynamic susceptibility contrast (DSC)-MRI technique

Brain microstructure MRI evaluation

Fractional anisotropy (FA) and Mean diffusivity (MD) will be evaluated using diffusion tensor imaging (DTI) MRI protocol

Brain volume MRI evaluation

Gray matter and hippocampal volumetric measurement using high-resolution MP-RAGE 3D MRI

Brain functional connectivity imaging

Resting state functional MRI

Full Information

NCT ID

NCT05349318

First Posted

March 21, 2022

Last Updated

July 24, 2022

Sponsor

Assaf-Harofeh Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT05349318

Brief Title

Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease

Official Title

Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease: A Prospective, Randomized, Double Blind Study

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

March 31, 2022 (Actual)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assaf-Harofeh Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

Alzheimer´s disease is a devastating illness that effects the patients as well as their family members. Its prevalence increases exponentially and the burden on the healthcare system is enormous. AD neuropathology begins 15-20 years before the occurrence of cognitive symptoms, which ranges from preclinical stage to mild cognitive impairment (MCI) to dementia. Prodromal AD is an early stage of the disease which is characterized by positive biomarkers and MCI. To this day, there is no medication that can cure or halt the progression of the disease and most studies focus on finding reversible risk factors and changing their influence. Several aetiologies have been proposed, like the deposition of amyloid and tau proteins, neuroinflammation and cerebral ischemia due to cerebrovascular factors. The Amyloid deposition, which serves as the biological marker of AD, was originally thought to be the main cause of the disease, however, recent data suggests that it is not the cause and that it might actually has a protective role. On the other hand, it is known today that vascular changes with related tissue ischemia and neuroinflammation have a crucial role in the development of AD in many patients. These pathologies, ischemia & neuroinflammation, can be improved by the use of hyperbaric oxygen therapy (HBOT). The goal of this study is to explore the potential beneficial effect of HBOT on prodromal AD.

Detailed Description

Alzheimer disease is characterised by cognitive, mental and functional disability that is expected to progress until the patient is fully dependent on others for activities of daily living. The pathology begins many years until the cognitive symptoms appear. Prodromal Alzheimer's disease is a state where a person has mild cognitive impairment and Amyloid deposition, which is seen on brain Amyloid PET or in lumbar puncture. To date, there has been neither a cure nor a therapy that can significantly halt or relieve symptoms for most patients. This study offers a new biological therapeutic approach aimed to induce neuroplasticity and improve neurological and cognitive functions. Pre -clinical as well as clinical data indicate that HBOT can be beneficial for those patients who suffer from MCI due to Alzheimer's disease and also to patients with cerebral vascular disease. HBOT is a well-known treatment used in clinical practice for other indications and is considered to be safe with relative rare mild and reversible side effect .The study is designed as a prospective, randomized, sham controlled double blinded study. Subjects will be enrolled up to a total of 100 subjects, age 60-85, diagnosed with MCI and positive Amyloid PET and vascular changes on brain MRI. Eligible patients will be randomized to the two study groups at a ratio of 6:6 (in clusters of 6 patients). The HBOT/sham treatment includes 60 daily sessions of 90 minutes each, five days per week. After the treatment period, there will be a maintenance period of HBOT/sham sessions twice a week for 6 months. All assessments with be done on baseline, after the treatment period and after the maintenance period. The primary endpoint includes improvement in cognitive scores in neurocognitive evaluations (Neurotrax). Secondary and tertiary endpoints include changes in cognitive, physiological, physical, imaging, lab tests and self report questionaires.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Prodromal Alzheimer's Disease, Cerebral Vascular Disorder, Mild Cognitive Impairment, Vascular Cognitive Impairment

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Upon consent and evaluation, eligible participants will be randomized with equal probability into one of two arms: HBOT or SHAM. The evaluation procedure will be performed at baseline, after the treatment and after a maintenance period.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Eligible candidates will be randomized with equal probability to the HBOT and sham interventions. Randomization will be performed using a computer software based on patients' code. Since the HBOT chamber can hold six subjects, the randomization will be done in clusters of six patients. After randomization, when a cluster of six subjects from one of the arms will be filled, the intervention for that cluster will begin. Three study technicians will be the only unblinded staff who have the key for the group assignment of each subject. They will exclusively activate the HBOT/sham protocol during session times. All subjects and other clinic staff will remain blinded to the group assignments.

Allocation

Randomized

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Hyperbaric Oxygen Therapy active arm

Arm Type

Active Comparator

Arm Description

Arm Title

Sham active arm

Arm Type

Sham Comparator

Arm Description

Intervention Type

Device

Intervention Name(s)

Hyperbaric oxygen therapy

Intervention Description

Each session will include exposure of 90 minutes to 100% at 2 ATA, with 5 minutes air breaks every 20 minutes

Intervention Type

Device

Intervention Name(s)

Sham

Intervention Description

Each session will include exposure of 90 minutes to 21% at 1.2 ATA during the first five minutes of the session with the noise of circulating air, and then decrease slowly during the next five minutes to 1.03 ATA

Primary Outcome Measure Information:

Title

Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)

Description

Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.

Time Frame

At baseline, 3 months

Title

Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)

Description

Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.

Time Frame

9 months

Secondary Outcome Measure Information:

Title

Brain amyloid PET using Flumetamol (Vizamyl) tracer

Description

Brain amyloid assessment using PET scan with Flumetamol (Vizamyl) tracer will be used to assess change in amyloid burden

Time Frame

At baseline, 3 months, 9 months

Title

Whole-brain quantitative perfusion imaging

Description

Whole-brain quantitative perfusion imaging will be performed using Dynamic susceptibility contrast (DSC)-MRI technique

Time Frame

At baseline, 3 months, 9 months

Title

Brain microstructure MRI evaluation

Description

Fractional anisotropy (FA) and Mean diffusivity (MD) will be evaluated using diffusion tensor imaging (DTI) MRI protocol

Time Frame

At baseline, 3 months, 9 months

Title

Brain volume MRI evaluation

Description

Gray matter and hippocampal volumetric measurement using high-resolution MP-RAGE 3D MRI

Time Frame

At baseline, 3 months, 9 months

Title

Brain functional connectivity imaging

Description

Resting state functional MRI

Time Frame

At baseline ,3 months, 9 months

Other Pre-specified Outcome Measures:

Title

Quality of life SF-36 questionnaire

Description

Self reported SF-36 quality of life questionnaire

Time Frame

At baseline, 3 months, 9 months

Title

The Pittsburgh Sleep Quality Index (PSQI) questionnaire

Description

Self reported quality of sleep questionnaire

Time Frame

At baseline, 3 months, 9 months

Title

The Depression, Anxiety and Stress Scale-21 (DASS-21)

Description

Self reported questionnaire of depression, anxiety and stress

Time Frame

At baseline, 3 months, 9 months

Title

Advanced Activities of Daily Function (a-ADL)

Description

Questionnaire of activities of daily living for the patient and the informant

Time Frame

At baseline, 3 months, 9 months

Title

Clinical Dementia Rating (CDR) scale - sum of boxes

Description

Cognitive assessment of 6 cognitive and functional domains, based on an interview of the patient and a reliable informant

Time Frame

At baseline, 3 months, 9 months

Title

Montreal Cognitive Assessment (MOCA)

Description

Neurocognitive assessment

Time Frame

At baseline, 3 months, 9 months

Title

Mini Mental State Exam (MMSE)

Description

Neurocognitive assessment

Time Frame

At baseline, 3 months, 9 months

Title

Serum inflammatory markers

Description

Serum inflammatory markers include: IL-1, IL-6, tumor necrosis factor-alpha, hsCRP

Time Frame

At baseline, 3 months, 9 months

Title

Alzheimer's disease (AD) biomarkers: Abeta 42/40

Description

Plasma will be tested for Abeta 42/40

Time Frame

At baseline, 3 months, 9 months

Title

Alzheimer's disease (AD) biomarkers: P-tau181

Description

Plasma will be tested for P-tau181

Time Frame

At baseline, 3 months, 9 months

Title

Alzheimer's disease (AD) biomarkers: P-tau231

Description

Plasma will be tested for P-tau 231

Time Frame

At baseline, 3 months, 9 months

Title

Alzheimer's disease (AD) biomarkers: neurofilament light (NfL)

Description

Plasma will be tested for neurofilament light (NfL)

Time Frame

At baseline, 3 months, 9 months

Title

Alzheimer's disease (AD) biomarkers: plasma glial fibrillary acidic protein (GFAP)

Description

Plasma will be tested for plasma glial fibrillary acidic protein (GFAP)

Time Frame

At baseline, 3 months, 9 months

Title

Vascular biomarker- Vascular endothelial growth factor (VEGF)

Description

Serum will be tested for VEGF

Time Frame

At baseline, 3 months, 9 months

Title

Passive behavioral monitoring using BHQ smartphone application

Description

An application will be installed on the participants' smartphones for continuous passive monitoring of human behavior

Time Frame

Through study completion, up to one year

Title

Cardiopulmonary exercise test (CPET)

Description

CPET determines the anaerobic threshold that is expected to change through the intervention

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation - Static balance

Description

Static balance will be assessed by the Balance Error Scoring System (BESS)

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation- Timed Up and Go test

Description

Dynamic balance and risk of falling will be assessed by the Timed Up and Go test (TUG)

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation - 10 meter walk

Description

Dynamic balance and risk of falling will be assessed by 10-meter walk (10MW).

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation - Sit to Stand test

Description

Muscle function will be assessed by the sit to stand (STS) test for the leg strength and endurance

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation - Hand held dynamometery

Description

Muscle function will be assessed by the hand-held dynamometry (HHD) for the isometric grip strength.

Time Frame

At baseline, 3 months, 9 months

Title

Neuro-physical evaluation - 6 minute walk

Description

The sub-maximal aerobic capacity and endurance will be assessed by the 6-minute walk test (6MWT).

Time Frame

At baseline, 3 months, 9 months

Title

Event-related synchronization (ERS) change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Event-related desynchronization (ERD) change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Grand average P300 ERP change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Alpha band power change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Beta band power change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Gamma band power change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Delta band power change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

Theta to alpha bands power ratio change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

Title

N-back match/no match percentage change - EEG

Description

The EEG will include a three-level visual N-back task, and go-no-go task

Time Frame

At baseline, 3 months, 9 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

60 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of Mild cognitive impairment (MCI) due to AD or mixed AD and vascular dementia pathology MMSE score of 20 and above Stable psychological and pharmacological treatment for more than three months prior to inclusion. Caregiver that is seeing the patient at least twice per week and is willing to participate and accompany the patient and fill questionnaires Subject willing and able to read, understand and sign an informed consent Exclusion Criteria: Inability to attend scheduled clinic visits and/or comply with the study protocol History of traumatic brain injury, brain tumors, brain surgery, chronic subdural haemorrhages, Epilepsy Active malignancy Substance use at baseline, except for prescribed cannabis if vaporized or taken PO as tincture History of other neurodegenerative diseases including Parkinson's disease (PD), Lewy body dementia (LBD), Frontotemporal dementia (FTD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Creutzfeld Jacob disease (CJD), Multisystem atrophy (MSA), Pseudobulbar palsy (PSP), Corticobasal degeneration (CBD), Wernicke Korsakoff syndrome Chronic use of medications that may compromise cognitive function and cannot be stopped: Anticonvulsants, Anticholinergics, antiparkinsonian, corticosteroids, Benzodiazepines Moderate to severe sleep apnea with no use of CPAP Diagnosis of a psychiatric disorder including: major depression, schizophrenia, bipolar disorder Serious suicidal ideation Renal or liver insufficiency, electrolyte imbalances Chronic heart failure with ejection fraction of 35 or less HBOT for any reason prior to study enrolment Chest pathology incompatible with pressure changes (including active asthma or COPD) Ear or Sinus pathology incompatible with pressure changes (above 3 otolaryngologist visits a year) An inability to perform an awake brain MRI or Amyloid PET An inability to perform computerized cognitive tests (Neurotrax) MMSE score below 20 No evidence of amyloid in the brain PET No evidence of vascular related lesions in the brain MRI Active smoking Participation in another study

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Karin Elman Shina, MD

Phone

0097289778061

karine@shamir.gov.il

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Karin Elman Shina, MD

Organizational Affiliation

Senior Neurologist and director of the neuropsychology and physiology unit

Official's Role

Principal Investigator

Facility Information:

Facility Name

Shamir Medical Center (Assaf Harofeh)

City

Zerifin

ZIP/Postal Code

70300

Country

Israel

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Karin Elman Shina, MD

karine@shamir.gov.il

12. IPD Sharing Statement

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Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease

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