COMMETS- Combination MCI Metabolic Syndrome

Official title

Combination of Intranasal Insulin With Oral Semaglutide to Improve Cognition and Cerebral Blood Flow: a Feasibility Study

Overview

The investigators propose a proof of concept RCT (randomized clinical trial), testing the efficacy of intranasal insulin (INI) with semaglutide, a combination therapy with strong biological plausibility to benefit impaired cognition through vascular mechanisms, in older adults with MetS (metabolic syndrome) and MCI (Mild Cognitive Impairment), who are enriched for cerebrovascular disease and at high dementia risk. The study will focus on cognitive and biological outcomes, allowing identification of relevant mechanisms.

Detailed description

The Specific Aims of the study are:

Aim 1. To examine the ease and precision of use of the intranasal device and once daily semaglutide pill.

Aim 2. To examine the adherence to the two types of treatment.

Aim 3. To examine the safety profile of the combination of intranasal insulin with semaglutide. The safety profile of each has been published broadly, but the safety of their combination has not been examined.

Aim 4. Although the primary goal of the pilot study is proof of concept essential to design a large combination therapy RCT, The investigators will compare the combination of intranasal insulin and semaglutide with the other three groups on a) cognition, b) cerebral blood flow (via ASL MRI), c) glucose uptake (via FDG PET), ADRD(Alzheimer's disease and related disorders)-related blood biomarkers (Aβ42/Aβ40 ratio, pTau181 and 231, NfL and GFAP), and expression of insulin signaling genes from brain derived exosomes.

Interventions

• Drug Semaglutide
  The medication is available in 3, 7, and 14-mg tablets for oral use. Participants will be instructed to start with an initiating dose of 3 mg once daily. If they do not experience adverse events (nausea, vomiting, and abdominal pain) then the dose will be titrated to 7 mg once daily after 30 days. Again, if the participant does not experience adverse events, the dose will be further titrated after 30 days to 14 mg once daily. This does will continue until the end of the study, at 12 months.
• Drug Intranasal insulin
  The study will use the ViaNase; Kurve Technology intranasal device to administer insulin intra-nasally. This device has been used in other studies of persons with AD and has shown insulin penetration into the brain via CSF studies. Through sniffing, the medication crosses the blood-brain barrier (BBB) at the top of the nasal cavity. Participants will be instructed to press a switch that will turn on the device, engaging a pump that releases a nebulized stream of insulin through a nose piece into
• Other Semaglutide placebo
  Rybelsus semaglutide - this medicine will simulate taking the pill Rybelsus /semaglutide once a day. A pill identical to the medicine pill will be given.
• Other Intranasal insulin placebo
  The placebo used in this study is saline. The investigators will administer saline, with exactly the same methods as the INI insulin (twice per day, 20 seconds each sniff, in each nostril.

Primary outcome measures

• Cognitive change - The effect of the combination of Semaglutide and intranasal insulin on cognitive functioning. [Time frame: 12 months]
• Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on cerebral blood flow (CBF). [Time frame: 6 months]
• Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on brain glucose intake. [Time frame: 6 months]

Secondary outcome measures (12)

• Change in specific cognitive domains - The effect of the combination of Semaglutide and intranasal insulin on executive functions and episodic memory. [Time frame: 12 months]
• Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on microstructural alterations indicative of tissue injury. [Time frame: 6 months]
• Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on gray matter and hippocampal volume. [Time frame: 6 months]
• Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on functional performance. [Time frame: 12 months]
• Functional outcome - The effect of the combination of Semaglutide with intranasal inulin on change in functional performance as measured by IADL (instrumental activities of daily living) questionnaires. [Time frame: 12 months]
• Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on physical capacity [Time frame: 6 months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Aβ. [Time frame: 6 Months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- P-tau181. [Time frame: 6 Months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers-P-tau231. [Time frame: 6 Months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- T-tau. [Time frame: 6 Months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- Neurofilament light (NfL). [Time frame: 6 Months]
• Neurobiological outcome - The effect of the combination of Semaglutide and intranasal insulin on ADRD-blood biomarkers- glial fibrillary acidic protein (GFAP). [Time frame: 6 Months]

Eligibility criteria

Inclusion criteria

• Diagnosis of MCI (based on a MOCA <27 and a clinical dementia rating scale \[CDR\] score of 0.5 representing questionable dementia).
• Diagnosis of MetS -requiring a) abdominal obesity (waist circumference >102cm for men and >88cm for women), and b) glucose intolerance (fasting glucose>110 mg/dL) and at least one of the following-c) dyslipidemia (high triglycerides \[>150 mg/dL\] and low HDL \[<40mg/dL for men and <50 mg/dL for women\]), or d) elevated blood pressure (>130/>85 mmHg).
• Fluent in Hebrew
• The study requires an active study partner

Exclusion criteria

• Diabetes (of any type)
• Taking medications that may affect glucose metabolism (including a GLP-1RA).
• Diagnosis of dementia and its subtypes, conditions that may directly affect cognition,
• short life expectancy or a medical condition that precludes consistent participation in the study,
• contraindications to either insulin or Semaglutide.
• Medications that may affect glucose metabolism such as corticosteroids.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Israel · 1 center

• Joseph Sagol Neuroscience center, Sheba Medical Center — Ramat Gan

Publications

• Love S, Miners JS. Cerebrovascular disease in ageing and Alzheimer's disease. Acta Neuropathol. 2016 May;131(5):645-58. doi: 10.1007/s00401-015-1522-0. Epub 2015 Dec 28. PMID 26711459
• Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res. 2017 Apr;95(4):943-972. doi: 10.1002/jnr.23777. Epub 2016 Jun 27. PMID 27350397
• Kim HW, Hong J, Jeon JC. Cerebral Small Vessel Disease and Alzheimer's Disease: A Review. Front Neurol. 2020 Aug 25;11:927. doi: 10.3389/fneur.2020.00927. eCollection 2020. PMID 32982937
• Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Ryden L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH PMID 31189511
• Gerstein HC, Hart R, Colhoun HM, Diaz R, Lakshmanan M, Botros FT, Probstfield J, Riddle MC, Ryden L, Atisso CM, Dyal L, Hall S, Avezum A, Basile J, Conget I, Cushman WC, Hancu N, Hanefeld M, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Munoz EGC, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T. The effect of dulaglutide on stroke: an exploratory analysis of the PMID 31924562
• Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, Garcia-Perez LE, Lakshmanan M, Bethel A, Xavier D, Probstfield J, Riddle MC, Ryden L, Atisso CM, Hall S, Rao-Melacini P, Basile J, Cushman WC, Franek E, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T. Effect of dulaglutide on cognitive impairment in type 2 diabetes PMID 32562683
• Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol. 2003 May;13(5):369-76. doi: 10.1016/s1047-2797(02)00464-7. PMID 12821276
• Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3907-12. doi: 10.1073/pnas.0807991106. Epub 2009 Feb 23. PMID 19237574

Identifiers

NCT: NCT06072963 · Pro2023001136

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗