COMMETS- Combination MCI Metabolic Syndrome

NCT06072963 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: Pro2023001136
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Alzheimer Disease; Mild Cognitive Impairment; Metabolic Syndrome

Keywords

Alzheimer disease; Mild Cognitive Impairment; Metabolic syndrome; Dementia; Semaglutide; Intranasal insulin

Outcome Measures

Primary Outcomes (3)

• Cognitive change - The effect of the combination of Semaglutide and intranasal insulin on cognitive functioning.

  The cognitive outcome is a balanced composite sum of z-scores of four executive function tests (Trails B, Digit-Symbol, and Category Fluency (animals, fruits and vegetables), four episodic memory tests (immediate and delayed recall of the word list from the ADAS-Cog, and immediate and delayed recall of Logical Memory Story I from the Wechsler Memory Test). Z-scores are reversed if necessary so that a positive value refers to good cognition. Cognitive functioning will be measured at baseline, 6 months, and 12 months follow-ups.

  12 months

• Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on cerebral blood flow (CBF).

  Change in CBF will be measured using Arterial Spin Labeling (ASL) brain magnetic resonance imaging (MRI) scans. The unit of cerebral blood flow from ASL is ml/100g/min, which means the amount of blood flow into 100g of tissue in one minute. Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in blood flow between the time points.

  6 months

• Neuroimaging outcome -- The effect of the combination of Semaglutide and intranasal insulin on brain glucose intake.

  Brain Glucose intake will be measured by \[F18\]FDG-PET: Voxel-wise standardized uptake value ratio (SUVR) images will be created in native MRI space with the pons as reference region. \[F18\]FDG values will be extracted from ADRD-vulnerable regions of interest (dorsolateral prefrontal cortex, medial and lateral temporal lobe, and medial and lateral parietal cortex). Scans will be taken at baseline and 6 months follow-up. Baseline and 6 months scans will be compared and analyzed to assess change in glucose intake between the time points.

  6 months

Secondary Outcomes (12)

• Change in specific cognitive domains - The effect of the combination of Semaglutide and intranasal insulin on executive functions and episodic memory.

  12 months

• Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on microstructural alterations indicative of tissue injury.

  6 months

• Neuroimaging outcomes- The effect of the combination of Semaglutide and intranasal insulin on gray matter and hippocampal volume.

  6 months

• Functional outcome - The effect of the combination of Semaglutide and intranasal insulin on functional performance.

  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.

  12 months

Study Arms (4)

Group 1

EXPERIMENTAL

Will receive intranasal insulin therapy as well as Oral Semaglutide.

Drug: Semaglutide; Drug: Intranasal insulin

Group 2

SHAM COMPARATOR

Will receive active intranasal insulin therapy and placebo Oral Semaglutide.

Drug: Intranasal insulin; Other: Semaglutide placebo

Group 3

SHAM COMPARATOR

Will receive intranasal insulin placebo and active Oral Semaglutide .

Drug: Semaglutide; Other: Intranasal insulin placebo

Group 4

PLACEBO COMPARATOR

Will receive intranasal insulin placebo and Oral Semaglutide placebo.

Other: Semaglutide placebo; Other: Intranasal insulin placebo

Interventions

Semaglutide DRUG

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.

Also known as: Rybelsus

Group 1; Group 3

Intranasal insulin DRUG

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 a nostril for 20 seconds (the device includes an electronic timer), after which the device switches off. The process is then repeated in the other nostril. The investigators decided on administration of 20IU of INI twice per day as the literature suggests this as the optimal dosage.

Also known as: Actrapid

Group 1; Group 2

Semaglutide placebo OTHER

Rybelsus semaglutide - this medicine will simulate taking the pill Rybelsus /semaglutide once a day. A pill identical to the medicine pill will be given.

Group 2; Group 4

Intranasal insulin placebo OTHER

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.

Group 3; Group 4

Eligibility Criteria

• Age: 60 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rutgers, The State University of New Jersey: lead
• Alzheimer's Association: collaborator

Study Sites (1)

Joseph Sagol Neuroscience center, Sheba Medical Center

Ramat Gan, 5265601, Israel

RECRUITING

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MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Metabolic Syndrome; Dementia

Interventions

semaglutide; Insulin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Tal Davidy

  Sheba Medical Center

  STUDY DIRECTOR

• Michal Schnaider beeri

  Rutgers, The State University of New Jersey

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Iscka Yore

CONTACT

+972-35307262; Iscka.Yore@sheba.health.gov.il

Tal Niv

CONTACT

+972-35305406; Tal.Niv@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Alzheimer's Research Center.

Model Details: Eligible participants will be randomized with equal probability to each of the four study groups. Following the baseline assessment, participants will be assigned to one of the four intervention groups, as determined by an automated randomization algorithm

Study Record Dates

• First Submitted: November 3, 2022
• First Posted: October 10, 2023
• Study Start: January 30, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: March 22, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)