Clinical trial NCT05349318: 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
Overall status: RECRUITING
Phase: NA
Conditions: Prodromal Alzheimer's Disease
Cerebral Vascular Disorder
Mild Cognitive Impairment
Vascular Cognitive Impairment
Lead sponsor: Assaf-Harofeh Medical Center
Sponsor class: OTHER_GOV
First posted: 2022-04-27
Enrollment: 100
Sex: ALL
Minimum age (years): 60
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)
timeFrame: At baseline, 3 months
measure: Change from baseline of neurocognitive functions evaluation by Mindstreams cognitive battery test (Neurotrax)
timeFrame: 9 months
Secondary outcomes:
measure: Brain amyloid PET using Flumetamol (Vizamyl) tracer
timeFrame: At baseline, 3 months, 9 months
measure: Whole-brain quantitative perfusion imaging
timeFrame: At baseline, 3 months, 9 months
measure: Brain microstructure MRI evaluation
timeFrame: At baseline, 3 months, 9 months
measure: Brain volume MRI evaluation
timeFrame: At baseline, 3 months, 9 months
measure: Brain functional connectivity imaging
timeFrame: At baseline ,3 months, 9 months
Other outcomes:
measure: Quality of life SF-36 questionnaire
timeFrame: At baseline, 3 months, 9 months
measure: The Pittsburgh Sleep Quality Index (PSQI) questionnaire
timeFrame: At baseline, 3 months, 9 months
measure: The Depression, Anxiety and Stress Scale-21 (DASS-21)
timeFrame: At baseline, 3 months, 9 months
measure: Advanced Activities of Daily Function (a-ADL)
timeFrame: At baseline, 3 months, 9 months
measure: Clinical Dementia Rating (CDR) scale - sum of boxes
timeFrame: At baseline, 3 months, 9 months
measure: Montreal Cognitive Assessment (MOCA)
timeFrame: At baseline, 3 months, 9 months
measure: Mini Mental State Exam (MMSE)
timeFrame: At baseline, 3 months, 9 months
measure: Serum inflammatory markers
timeFrame: At baseline, 3 months, 9 months
measure: Alzheimer's disease (AD) biomarkers: Abeta 42/40
timeFrame: At baseline, 3 months, 9 months
measure: Alzheimer's disease (AD) biomarkers: P-tau181
timeFrame: At baseline, 3 months, 9 months
measure: Alzheimer's disease (AD) biomarkers: P-tau231
timeFrame: At baseline, 3 months, 9 months
measure: Alzheimer's disease (AD) biomarkers: neurofilament light (NfL)
timeFrame: At baseline, 3 months, 9 months
measure: Alzheimer's disease (AD) biomarkers: plasma glial fibrillary acidic protein (GFAP)
timeFrame: At baseline, 3 months, 9 months
measure: Vascular biomarker- Vascular endothelial growth factor (VEGF)
timeFrame: At baseline, 3 months, 9 months
measure: Passive behavioral monitoring using BHQ smartphone application
timeFrame: Through study completion, up to one year
measure: Cardiopulmonary exercise test (CPET)
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation - Static balance
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation- Timed Up and Go test
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation - 10 meter walk
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation - Sit to Stand test
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation - Hand held dynamometery
timeFrame: At baseline, 3 months, 9 months
measure: Neuro-physical evaluation - 6 minute walk
timeFrame: At baseline, 3 months, 9 months
measure: Event-related synchronization (ERS) change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Event-related desynchronization (ERD) change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Grand average P300 ERP change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Alpha band power change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Beta band power change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Gamma band power change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Delta band power change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: Theta to alpha bands power ratio change - EEG
timeFrame: At baseline, 3 months, 9 months
measure: N-back match/no match percentage change - EEG
timeFrame: At baseline, 3 months, 9 months
Locations:
city: Zerifin
country: Israel
facility: Shamir Medical Center (Assaf Harofeh)
Study officials:
affiliation: Senior Neurologist and director of the neuropsychology and physiology unit
name: Karin Elman Shina, MD
role: PRINCIPAL_INVESTIGATOR
References: