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

• ClinicalTrials.gov Identifier: NCT05349318
• Recruitment Status: Recruiting
• First Posted: April 27, 2022
• Last Update Posted: February 6, 2024
• Sponsor: Assaf-Harofeh Medical Center
• Information provided by (Responsible Party): Assaf-Harofeh Medical Center

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.

Condition or disease	Intervention/treatment	Phase
Prodromal Alzheimer's Disease; Cerebral Vascular Disorder; Mild Cognitive Impairment; Vascular Cognitive Impairment	Device: Hyperbaric oxygen therapy; Device: Sham	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.

• Primary Purpose: Treatment
• Official Title: Hyperbaric Oxygen Therapy for Prodromal Alzheimer´s Disease With Cerebrovascular Disease: A Prospective, Randomized, Double Blind Study
• Actual Study Start Date: March 31, 2022
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: March 2025

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Hyperbaric Oxygen Therapy active arm; 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.	Device: Hyperbaric oxygen therapy; Each session will include exposure of 90 minutes to 100% at 2 ATA, with 5 minutes air breaks every 20 minutes
Sham Comparator: Sham active arm; 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.	Device: Sham; 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

Outcome Measures

Primary Outcome Measures :

1. Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax) [ Time Frame: At baseline, 3 months ]
   Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.
2. Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax) [ Time Frame: 9 months ]
   Memory, attention and information process will be evaluated using the NeuroTrax computerized cognitive evaluation battery.

Secondary Outcome Measures :

1. Brain amyloid PET using Flumetamol (Vizamyl) tracer [ Time Frame: At baseline, 3 months, 9 months ]
   Brain amyloid assessment using PET scan with Flumetamol (Vizamyl) tracer will be used to assess change in amyloid burden
2. Whole-brain quantitative perfusion imaging [ Time Frame: At baseline, 3 months, 9 months ]
   Whole-brain quantitative perfusion imaging will be performed using Dynamic susceptibility contrast (DSC)-MRI technique
3. Brain microstructure MRI evaluation [ Time Frame: At baseline, 3 months, 9 months ]
   Fractional anisotropy (FA) and Mean diffusivity (MD) will be evaluated using diffusion tensor imaging (DTI) MRI protocol
4. Brain volume MRI evaluation [ Time Frame: At baseline, 3 months, 9 months ]
   Gray matter and hippocampal volumetric measurement using high-resolution MP-RAGE 3D MRI
5. Brain functional connectivity imaging [ Time Frame: At baseline ,3 months, 9 months ]
   Resting state functional MRI

Other Outcome Measures:

1. Quality of life SF-36 questionnaire [ Time Frame: At baseline, 3 months, 9 months ]
   Self reported SF-36 quality of life questionnaire
2. The Pittsburgh Sleep Quality Index (PSQI) questionnaire [ Time Frame: At baseline, 3 months, 9 months ]
   Self reported quality of sleep questionnaire
3. The Depression, Anxiety and Stress Scale-21 (DASS-21) [ Time Frame: At baseline, 3 months, 9 months ]
   Self reported questionnaire of depression, anxiety and stress
4. Advanced Activities of Daily Function (a-ADL) [ Time Frame: At baseline, 3 months, 9 months ]
   Questionnaire of activities of daily living for the patient and the informant
5. Clinical Dementia Rating (CDR) scale - sum of boxes [ Time Frame: At baseline, 3 months, 9 months ]
   Cognitive assessment of 6 cognitive and functional domains, based on an interview of the patient and a reliable informant
6. Montreal Cognitive Assessment (MOCA) [ Time Frame: At baseline, 3 months, 9 months ]
   Neurocognitive assessment
7. Mini Mental State Exam (MMSE) [ Time Frame: At baseline, 3 months, 9 months ]
   Neurocognitive assessment
8. Serum inflammatory markers [ Time Frame: At baseline, 3 months, 9 months ]
   Serum inflammatory markers include: IL-1, IL-6, tumor necrosis factor-alpha, hsCRP
9. Alzheimer's disease (AD) biomarkers: Abeta 42/40 [ Time Frame: At baseline, 3 months, 9 months ]
   Plasma will be tested for Abeta 42/40
10. Alzheimer's disease (AD) biomarkers: P-tau181 [ Time Frame: At baseline, 3 months, 9 months ]
    Plasma will be tested for P-tau181
11. Alzheimer's disease (AD) biomarkers: P-tau231 [ Time Frame: At baseline, 3 months, 9 months ]
    Plasma will be tested for P-tau 231
12. Alzheimer's disease (AD) biomarkers: neurofilament light (NfL) [ Time Frame: At baseline, 3 months, 9 months ]
    Plasma will be tested for neurofilament light (NfL)
13. Alzheimer's disease (AD) biomarkers: plasma glial fibrillary acidic protein (GFAP) [ Time Frame: At baseline, 3 months, 9 months ]
    Plasma will be tested for plasma glial fibrillary acidic protein (GFAP)
14. Vascular biomarker- Vascular endothelial growth factor (VEGF) [ Time Frame: At baseline, 3 months, 9 months ]
    Serum will be tested for VEGF
15. Passive behavioral monitoring using BHQ smartphone application [ Time Frame: Through study completion, up to one year ]
    An application will be installed on the participants' smartphones for continuous passive monitoring of human behavior
16. Cardiopulmonary exercise test (CPET) [ Time Frame: At baseline, 3 months, 9 months ]
    CPET determines the anaerobic threshold that is expected to change through the intervention
17. Neuro-physical evaluation - Static balance [ Time Frame: At baseline, 3 months, 9 months ]
    Static balance will be assessed by the Balance Error Scoring System (BESS)
18. Neuro-physical evaluation- Timed Up and Go test [ Time Frame: At baseline, 3 months, 9 months ]
    Dynamic balance and risk of falling will be assessed by the Timed Up and Go test (TUG)
19. Neuro-physical evaluation - 10 meter walk [ Time Frame: At baseline, 3 months, 9 months ]
    Dynamic balance and risk of falling will be assessed by 10-meter walk (10MW).
20. Neuro-physical evaluation - Sit to Stand test [ Time Frame: At baseline, 3 months, 9 months ]
    Muscle function will be assessed by the sit to stand (STS) test for the leg strength and endurance
21. Neuro-physical evaluation - Hand held dynamometery [ Time Frame: At baseline, 3 months, 9 months ]
    Muscle function will be assessed by the hand-held dynamometry (HHD) for the isometric grip strength.
22. Neuro-physical evaluation - 6 minute walk [ Time Frame: At baseline, 3 months, 9 months ]
    The sub-maximal aerobic capacity and endurance will be assessed by the 6-minute walk test (6MWT).
23. Event-related synchronization (ERS) change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
24. Event-related desynchronization (ERD) change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
25. Grand average P300 ERP change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
26. Alpha band power change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
27. Beta band power change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
28. Gamma band power change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
29. Delta band power change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
30. Theta to alpha bands power ratio change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task
31. N-back match/no match percentage change - EEG [ Time Frame: At baseline, 3 months, 9 months ]
    The EEG will include a three-level visual N-back task, and go-no-go task

Eligibility Criteria

• Ages Eligible for Study: 60 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

1. Inability to attend scheduled clinic visits and/or comply with the study protocol
2. History of traumatic brain injury, brain tumors, brain surgery, chronic subdural haemorrhages, Epilepsy
3. Active malignancy
4. Substance use at baseline, except for prescribed cannabis if vaporized or taken PO as tincture
5. 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
6. Chronic use of medications that may compromise cognitive function and cannot be stopped: Anticonvulsants, Anticholinergics, antiparkinsonian, corticosteroids, Benzodiazepines
7. Moderate to severe sleep apnea with no use of CPAP
8. Diagnosis of a psychiatric disorder including: major depression, schizophrenia, bipolar disorder
9. Serious suicidal ideation
10. Renal or liver insufficiency, electrolyte imbalances
11. Chronic heart failure with ejection fraction of 35 or less
12. HBOT for any reason prior to study enrolment
13. Chest pathology incompatible with pressure changes (including active asthma or COPD)
14. Ear or Sinus pathology incompatible with pressure changes (above 3 otolaryngologist visits a year)
15. An inability to perform an awake brain MRI or Amyloid PET
16. An inability to perform computerized cognitive tests (Neurotrax)
17. MMSE score below 20
18. No evidence of amyloid in the brain PET
19. No evidence of vascular related lesions in the brain MRI
20. Active smoking
21. Participation in another study

Contacts and Locations

Contacts

Contact: Karin Elman Shina, MD; 0097289778061; karine@shamir.gov.il

Locations

Israel

Shamir Medical Center (Assaf Harofeh); Recruiting

Zerifin, Israel, 70300

Contact: Karin Elman Shina, MD karine@shamir.gov.il

Sponsors and Collaborators

Assaf-Harofeh Medical Center

Investigators

• Principal Investigator: Karin Elman Shina, MD; Senior Neurologist and director of the neuropsychology and physiology unit

More Information

• Responsible Party: Assaf-Harofeh Medical Center
• ClinicalTrials.gov Identifier: NCT05349318
• Other Study ID Numbers: 254-21-ASF
• First Posted: April 27, 2022
• Last Update Posted: February 6, 2024
• Last Verified: February 2024

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Alzheimer Disease; Cerebrovascular Disorders; Vascular Diseases; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Cardiovascular Diseases