Intranasal Insulin and Olanzapine Study in Healthy Volunteers

NCT03741478 | Unknown Phase 1

• 1 other identifier: 075/2017
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief Summary

Antipsychotic (AP) medications are considered to be the gold standard treatment for psychotic disorders including schizophrenia. However, APs have also been commonly associated with serious metabolic adverse effects including weight gain and Type 2 Diabetes, with younger populations disproportionately affected. In addition, young individuals treated with these agents have also been found to be at high risk for glucose dysregulation, including higher rates of prediabetes, with significant associations found between AP use and insulin resistance. Due to the concerning prevalence of these AP metabolic effects, it becomes important to further elucidate the mechanisms underlying AP effects on glucose metabolism, which are still poorly understood. One potential underlying mechanism is insulin which has been found to regulate hepatic (liver) glucose production through insulin receptors in the brain. These insulin receptors also play a role in neuronal growth and memory, or more broadly, cognition. Preliminary data in rat models has demonstrated that the AP olanzapine (OLA) inhibits the ability of a central insulin stimulus (acting at the level of the brain) to decrease endogenous glucose production (EGP), making this mechanism a prime target to translate from rodent models to human research. Furthermore, intranasal insulin (INI) administration (an analogous central insulin stimulus) has been repeatedly associated with improved cognitive performance for verbal memory and visuospatial functions in humans. Given these findings and with the goal of translational research, the present study will investigate OLA's effects in healthy human volunteers including: (a) the ability of INI to reduce EGP during a pancreatic euglycemic clamp (PEC; a glucose metabolism and insulin procedure); and (b) the ability of INI to improve cognitive performance. More specifically, the present study hypothesizes that:

1. 1.INI will be associated with a decrease in EGP relative to intranasal placebo (INP) as measured by the PEC. This effect will be inhibited if OLA is co-administered.
2. 2.OLA administration will be associated with decrements in cognitive measures (i.e., visuospatial, and verbal memory) as compared to placebo (PL). Additionally, OLA co-administration will block the beneficial effects of INI on cognition previously supported by other studies.
3. 3.INI will result in adaptive changes in neurochemical and neurohemodynamic measures as studied using MRI imaging techniques.

Conditions

Healthy Controls

Outcome Measures

Primary Outcomes (1)

• Endogenous Glucose Production: Pancreatic Euglycemic Clamp Experiments

  Participants in the metabolic arm will complete four pancreatic euglycemic clamp (PEC) procedures. The PEC will measure changes in the ability of INI to reduce endogenous glucose production (EGP; the primary outcome measure) relative to INP and the presence of OLA (or PL). EGP will be reflected in dextrose infusion rates (InFR) measured during the PEC across treatment conditions.

  Visits 1-3 (12-16 weeks) for the metabolic arm

Secondary Outcomes (2)

• Changes in Cognitive Functioning: MRI scans across the 4 visit conditions

  Visits 1-4 (9-18 weeks) for the cognitive arm

• Oral Glucose Tolerance Test

  Screening Visit 2 (1-2 weeks) for both arms

Study Arms (2)

Metabolic Arm

EXPERIMENTAL

This arm includes a screening visit 1 and screening visit 2 to assess eligibility. This arm then includes the pancreatic euglycemic clamp procedure at visits 1 to 3. Visits 1 to 3 each consist of 3 days (day 0, day 1, and day 2). Olanzapine 2.5mg (or placebo) will be administered in doses of 5mg on day 0, 7.5mg on day 1, and 10mg on day 2. Day 2 consists of the final dose of olanzapine (or placebo) and the pancreatic euglycemic clamp procedure and other assessment procedures. On day 2, the participant is also randomized to and administered either intranasal insulin/Insulin Lispro 100 UNT/ML (or saline placebo) during the pancreatic euglycemic clamp procedure.

Drug: OLANZapine 2.5 MG; Drug: Placebo; Drug: Insulin Lispro 100 UNT/ML; Other: Saline

Cognitive and MRI Arm

EXPERIMENTAL

This arm includes a screening visit 1 and screening visit 2 to assess eligibility. This arm includes an MRI scan and cognitive testing at visits 1 to 4. Visits 1 to 4 each consist of 3 days (day 0, day 1, and day 2). Olanzapine 2.5mg (or placebo) will be administered in doses of 5mg on day 0, and 10mg on day 1. Cognitive testing and MRI scanning then occur on day 2. On day 2, the participant is also randomized to and administered either intranasal insulin/Insulin Lispro 100 UNT/ML (or saline placebo) prior to conducting the MRI imaging and cognitive testing.

Drug: OLANZapine 2.5 MG; Drug: Placebo; Drug: Insulin Lispro 100 UNT/ML; Other: Saline

Interventions

OLANZapine 2.5 MG DRUG

Olanzapine capsules (2.5mg) will be administered with the following dosing schedules for each arm: 1. Metabolic arm - 5mg on Day 0, 7.5mg on Day 1, and 10mg on Day 2 2. Cognitive arm - 5mg on Day 0, 10mg on Day 1

Also known as: Mylan-Olanzapine

Cognitive and MRI Arm; Metabolic Arm

Placebo DRUG

Placebo capsules visually identical to those containing olanzapine will be administered according to the same dosing schedule for each arm.

Also known as: Olanzapine Placebo

Cognitive and MRI Arm; Metabolic Arm

Insulin Lispro 100 UNT/ML DRUG

Intranasal insulin spray (or placebo) will be administered on day 2 for each arm. For the metabolic arm: 40 IU of intranasal insulin lispro will be administered at timepoint 0 during the pancreatic euglycemic clamp procedure. For the cognitive arm: 160 IU of intranasal insulin lispro will be administered at about 11 am on day 2 prior to the MRI imaging and cognitive testing procedures.

Also known as: Intranasal Insulin

Cognitive and MRI Arm; Metabolic Arm

Saline OTHER

Placebo saline spray visually identical to the intranasal insulin spray will be administered on day 2 for each arm according the same dosing schedules.

Cognitive and MRI Arm; Metabolic Arm

Eligibility Criteria

• Age: 17 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Healthy non-obese volunteers
• Age: 17 to 45 (Cognitive Arm) OR Ages 17-65 (Metabolic Arm)

You may not qualify if:

• Left-handedness (only for the cognitive and MRI arm)
• Pre-diabetes or diabetes (fasting glucose ≥6.0mmol/L or use of anti-diabetic drug);
• Evidence of impaired glucose tolerance on screening OGTT
• Family history of diabetes
• Use of weight reducing agents or other medications based on the discretion of the PI
• History of liver disease or AST\> 2 times upper limit of normal
• History of kidney disease
• Major medical or surgical event within the last 6 months
• Any condition that interferes with safe acquisition of MRI data such as metal implants, pacemakers, cochlear implants, claustrophobia, etc. (only for the cognitive and MRI component)
• Pregnancy and/or breastfeeding

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead
• University Health Network, Toronto: collaborator

Study Sites (2)

University Health Network - Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

ACTIVE NOT RECRUITING

Center for Addiction and Mental Health

Toronto, Ontario, M5T 1R8, Canada

RECRUITING

Related Publications (1)

• Stogios N, Hamel L, Smith E, Sanches M, Remington G, Voineskos A, Dash S, Graff-Guerrero A, Hahn M, Agarwal SM. Investigating the effects of antipsychotics on brain insulin action: Study protocol for a multi-modality magnetic resonance imaging (MRI) study in healthy controls. PLoS One. 2022 Nov 28;17(11):e0277211. doi: 10.1371/journal.pone.0277211. eCollection 2022.

  PMID: 36441736 DERIVED

MeSH Terms

Interventions

Olanzapine; Sodium Chloride

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Margaret K Hahn, PhD, MD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

• Satya Dash, MD, PhD

  University Health Network, Toronto General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Margaret K Hahn, PhD, MD

CONTACT

416-535-8501; margaret.hahn@camh.ca

Mahavir Agarwal, MBBS, MD

CONTACT

416-535-8501; mahavir.agarwal@camh.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Participants will be masked to: 1. Knowing whether they were assigned to the olanzapine or placebo conditions 2. Knowing whether they were assigned to the intranasal insulin or intranasal placebo conditions. Investigators will only be masked to the randomization of placebo or olanzapine for the participants, but will know whether the participant receives intranasal insulin or intranasal placebo. In the Cognitive Arm, a separate staff member who is unaware of drug condition will administer cognitive assessments.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinician Scientist

Model Details: This study will follow a single-blind, crossover design wherein each participant will participate in all of the possible treatment combinations including: Cognitive Arm: 1. Intranasal placebo and placebo 2. Intranasal placebo and olanzapine 3. Intranasal insulin and placebo 4. Intranasal insulin and olanzapine Metabolic Arm: 1. Intranasal placebo and placebo 2. Intranasal insulin and placebo 3. Intranasal insulin and olanzapine

Study Record Dates

• First Submitted: November 3, 2018
• First Posted: November 15, 2018
• Study Start: October 22, 2019
• Primary Completion: July 30, 2024
• Study Completion: July 30, 2024
• Last Updated: July 17, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)