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Intranasal Insulin and Olanzapine Study in Healthy Volunteers (INI/OLA)

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ClinicalTrials.gov Identifier: NCT03741478
Recruitment Status : Not yet recruiting
First Posted : November 15, 2018
Last Update Posted : May 29, 2019
Sponsor:
Collaborator:
University Health Network, Toronto
Information provided by (Responsible Party):
Margaret Hahn, Centre for Addiction and Mental Health

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. 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. 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. INI will result in adaptive changes in neurochemical and neurohemodynamic measures as studied using MRI imaging techniques.

Condition or disease Intervention/treatment Phase
Healthy Controls Drug: OLANZapine 2.5 MG Drug: Placebo Drug: Insulin Lispro 100 UNT/ML Other: Saline Phase 1

Detailed Description:

The primary objective of the study is to examine whether a single dose of OLA given to young healthy volunteers during PECs can inhibit the activity of a central insulin stimulus (i.e, INI) to reduce endogenous glucose production. Secondarily, in an exploratory arm, this study seeks to examine whether a single dose of OLA can inhibit improvements associated with INI administration on specific cognitive domains (visuospatial, and verbal memory). Further, the study will also explore the effects of insulin and OLA on neurochemical and neurohemodynamic measures obtained through MRI imaging techniques.

To accomplish these objectives, this study will have two separate and parallel arms - a metabolic PEC arm to study the primary hypothesis, and an MRI imaging and cognitive testing arm to study the two secondary hypotheses.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

This study will follow a single-blind, crossover design wherein each participant will participate in all of the 4 possible treatment combinations (intranasal insulin or intranasal placebo, olanzapine or placebo) including:

  1. Intranasal placebo and placebo
  2. Intranasal placebo and olanzapine
  3. Intranasal insulin and placebo
  4. Intranasal insulin and olanzapine
Masking: Double (Participant, Investigator)
Masking Description:

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.

Primary Purpose: Basic Science
Official Title: Effect of Antipsychotics on Central Insulin Action in Relation to Glucose Metabolism and Cognition in Healthy Volunteers
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metabolic Arm

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 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, 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

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
Other Name: Mylan-Olanzapine

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

Drug: Insulin Lispro 100 UNT/ML

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.

Other Name: Intranasal Insulin

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

Experimental: Cognitive and MRI Arm

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

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
Other Name: Mylan-Olanzapine

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

Drug: Insulin Lispro 100 UNT/ML

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.

Other Name: Intranasal Insulin

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




Primary Outcome Measures :
  1. Endogenous Glucose Production: Pancreatic Euglycemic Clamp Experiments [ Time Frame: Visits 1-4 (16-24 weeks) for the metabolic arm ]
    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.


Secondary Outcome Measures :
  1. Changes in Cognitive Functioning: MRI scans across the 4 visit conditions [ Time Frame: Visits 1-4 (9-18 weeks) for the cognitive arm ]
    Participants in the cognitive arm will complete 4 MRI scans that will include intra-scanner testing to assess changes in cognitive functioning across randomization conditions.

  2. Oral Glucose Tolerance Test [ Time Frame: Screening Visit 2 (1-2 weeks) for both arms ]
    Following collection of baseline samples, a standard glucose drink (75mg) is given orally, and a blood sample of insulin and glucose is obtained 2 hours after the glucose drink is administered. Serums which will be collected during this procedure include fasting glucose and fasting insulin related to weight gain and glucose metabolism.



Information from the National Library of Medicine

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Ages Eligible for Study:   17 Years to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy non-obese volunteers
  • Age: 17 to 45

Exclusion Criteria:

  • History of current or past psychiatric illness (according to the Mini International Neuropsychiatric Interview [MINI])
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03741478


Contacts
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Contact: Margaret K Hahn, PhD, MD 416-535-8501 ext 34368 margaret.hahn@camh.ca
Contact: Mahavir Agarwal, MBBS, MD 416-535-8501 ext 30546 mahavir.agarwal@camh.ca

Locations
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Canada, Ontario
University Health Network - Toronto General Hospital Not yet recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: Satya Dash, MD, PhD    416-340-4800 ext 8094    satya.dash@uhn.ca   
Principal Investigator: Satya Dash, MD, PhD         
Center for Addiction and Mental Health Not yet recruiting
Toronto, Ontario, Canada, M5T 1R8
Contact: Margaret Hahn, MD, PhD    416-535-8501 ext 34368    margaret.hahn@camh.ca   
Contact: Mahavir Agarwal, MD, MBBS    416-535-8501 ext 30546    mahavir.agarwal@camh.ca   
Principal Investigator: Margaret Hahn, MD, PhD         
Sub-Investigator: Mahavir Agarwal, MD, MBBS         
Sponsors and Collaborators
Centre for Addiction and Mental Health
University Health Network, Toronto
Investigators
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Principal Investigator: Margaret K Hahn, PhD, MD Centre for Addiction and Mental Health
Principal Investigator: Satya Dash, MD, PhD University Health Network, Toronto General Hospital

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Responsible Party: Margaret Hahn, Clinician Scientist, Centre for Addiction and Mental Health
ClinicalTrials.gov Identifier: NCT03741478     History of Changes
Other Study ID Numbers: 075/2017
First Posted: November 15, 2018    Key Record Dates
Last Update Posted: May 29, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Insulin
Insulin, Globin Zinc
Insulin Lispro
Olanzapine
Hypoglycemic Agents
Physiological Effects of Drugs
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents