Neuro Biomarkers of Smoking Behavior

• Sponsor: University of Illinois at Chicago (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03811951
• Collaborator: (none)
• Enrollment: 4
• Location: 1
• Arms: 2
• Actual Duration (Months): 12.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate cognition in smokers and nonsmokers. It involves administration of intranasal insulin (Novolin R), an investigational medication followed by a brief non-invasive cognitive test. All participants will receive both Novolin R and placebo in two separate testing sessions.

Condition or Disease	Intervention/Treatment	Phase
Smoking Cessation	Drug: Novolin R	Phase 2

Detailed Description

This program of research focuses on identifying neurologic biomarkers of smoking behavior in order to develop individualized smoking cessation aids. The intranasal insulin administered is an investigational drug and has been granted IND status by the FDA (IND#129432). During the times of drug effects, the investigators will evaluate a biomarker using computerized tasks. Non-smokers and smokers will participate in two testing sessions where the biomarker will be critically evaluated after administration of intranasal insulin and compared to the cognitive processes elicited by placebo administration.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: The University of Illinois Hospital and Health Sciences System Investigational Drug Service (IDS) randomizes treatment order to study subjects and prepares drug product and placebo. All other roles, including participant, investigator, and non-IDS study personnel are masked from treatment order.
• Primary Purpose: Diagnostic
• Official Title: Neurologic Biomarkers of Smoking Behavior
• Actual Study Start Date: Sep 12, 2018
• Actual Primary Completion Date: Sep 27, 2019
• Actual Study Completion Date: Sep 27, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Smokers All participants receive both Novolin R (experimental drug) and 14% NaCl (Sodium Chloride) solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.	Drug: Novolin R; Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.; Other Names: McKesson Corporation, Novo Nordisk
Experimental: Non-Smokers All participants receive both Novolin R (experimental drug) and 14% NaCl solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.	Drug: Novolin R; Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.; Other Names: McKesson Corporation, Novo Nordisk

Outcome Measures

Primary Outcome Measures

1. Go/No-Go Accuracy [From time of drug administration to 70 minutes following drug administration, up to 90 minutes]

   Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go). Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age between 21-40 years

• Smokers only: Begin smoking within 5 minutes of waking (verified by carbon monoxide concentrations greater than 10 ppm).

• Non-smokers only: No self-reported cigarette use in the past 1-year period.

• Non-smokers only: Carbon monoxide concentration < 6 ppm.

• Normal vitals (blood pressure < 120/80 mmHg; heart rate between 60 and 100 bpm, body temperature <37 °C)

• Point-of-care (POC) blood glucose between 80 and 140 mg/dL

• Body mass index between 18.5 and 30 kg/m2

Exclusion Criteria:

• Use of non-cigarette tobacco products, e-cigarettes, or smoking cessation treatment

• Positive urine drug screen test

• Current pregnancy (urine test-verified) or lactation, or a plan to become pregnant

• Breath Alcohol Concentration >0.00%

• Shipley IQ (Intelligence Quotient) test <80

• Hyposmic or anosmic individuals (identifying less than 10 of 12 smells correctly)

• Abnormal physical exam of the nares

• Lifetime DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-5) Axis 1 disorder (except anxiety and depression)

• Current DSM-5 Axis depression or anxiety disorder

• Prescription medications

• Over-the-counter psychotropic medications

• Use of any medications administered intranasally

• Allergies to any ingredients in intranasal insulin or placebo

• Braided hair that would cause noise in EEG recording

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois Department of Pharmacy Practice	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• University of Illinois at Chicago

Investigators

• Principal Investigator: Ajna Hamidovic, PharmD, MS, University of Illinois at Chicago

Study Documents (Full-Text)

• Informed Consent Form - Nov 8, 2018
• Study Protocol and Statistical Analysis Plan - Jan 15, 2019

More Information

Publications

• Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997 Jun;29(7):1422-31. Review.
• de la Monte SM. Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin Drug Deliv. 2013 Dec;10(12):1699-709. doi: 10.1517/17425247.2013.856877. Epub 2013 Nov 12. Review.
• Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology? Eur J Pharmacol. 2000 Sep 29;405(1-3):43-54. Review.
• Franken IH, van Strien JW, Kuijpers I. Evidence for a deficit in the salience attribution to errors in smokers. Drug Alcohol Depend. 2010 Jan 15;106(2-3):181-5. doi: 10.1016/j.drugalcdep.2009.08.014. Epub 2009 Sep 24.
• Hamidovic A, Khafaja M, Brandon V, Anderson J, Ray G, Allan AM, Burge MR. Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial. Mol Psychiatry. 2017 Oct;22(10):1413-1421. doi: 10.1038/mp.2016.234. Epub 2017 Feb 28.
• Kern W, Born J, Schreiber H, Fehm HL. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999 Mar;48(3):557-63.
• Luijten M, van Meel CS, Franken IH. Diminished error processing in smokers during smoking cue exposure. Pharmacol Biochem Behav. 2011 Jan;97(3):514-20. doi: 10.1016/j.pbb.2010.10.012. Epub 2010 Oct 31.
• Nedelcovych MT, Gadiano AJ, Wu Y, Manning AA, Thomas AG, Khuder SS, Yoo SW, Xu J, McArthur JC, Haughey NJ, Volsky DJ, Rais R, Slusher BS. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. ACS Chem Neurosci. 2018 Apr 18;9(4):809-816. doi: 10.1021/acschemneuro.7b00434. Epub 2018 Jan 4.
• Ott V, Benedict C, Schultes B, Born J, Hallschmid M. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab. 2012 Mar;14(3):214-21. doi: 10.1111/j.1463-1326.2011.01490.x. Epub 2011 Nov 16. Review.
• Rass O, Fridberg DJ, O'Donnell BF. Neural correlates of performance monitoring in daily and intermittent smokers. Clin Neurophysiol. 2014 Jul;125(7):1417-26. doi: 10.1016/j.clinph.2013.12.001. Epub 2013 Dec 11.
• Reger MA, Craft S. Intranasal insulin administration: a method for dissociating central and peripheral effects of insulin. Drugs Today (Barc). 2006 Nov;42(11):729-39. Review.
• Schmid V, Kullmann S, Gfrörer W, Hund V, Hallschmid M, Lipp HP, Häring HU, Preissl H, Fritsche A, Heni M. Safety of intranasal human insulin: A review. Diabetes Obes Metab. 2018 Jul;20(7):1563-1577. doi: 10.1111/dom.13279. Epub 2018 Apr 6.
• Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012 Feb;97(2):366-76. doi: 10.1210/jc.2011-1802. Epub 2011 Dec 7. Review.
• Strachan MW. Insulin and cognitive function in humans: experimental data and therapeutic considerations. Biochem Soc Trans. 2005 Nov;33(Pt 5):1037-40. Review.
• West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A. A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology (Berl). 2000 Apr;149(3):198-202.

• Responsible Party: Ajna Hamidovic, PharmD, MS, Assistant Professor, University of Illinois at Chicago
• ClinicalTrials.gov Identifier: NCT03811951
• Other Study ID Numbers: 2017-1288
• First Posted: Jan 22, 2019
• Last Update Posted: Mar 2, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ajna Hamidovic, PharmD, MS, Assistant Professor, University of Illinois at Chicago: Tobacco; Cigarettes; Nicotine; Insulin
• Additional relevant MeSH terms: Insulin

Study Results

Participant Flow

Arm/Group Title	Novolin R First, Then Placebo	Placebo First, Then Novolin R
Arm/Group Description	Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 1. Then, participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 2.	Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 1. Then, participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 2.
Period Title: First Intervention (1 Day)
STARTED	2	2
COMPLETED	2	2
NOT COMPLETED	0	0
Period Title: First Intervention (1 Day)
STARTED	2	2
COMPLETED	2	2
NOT COMPLETED	0	0
Period Title: First Intervention (1 Day)
STARTED	2	2
COMPLETED	2	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Novolin R First, Then Placebo	Placebo First, Then Novolin R	Total
Arm/Group Description	Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 1. Then, participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 2.	Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 1. Then, participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 2.	Total of all reporting groups
Overall Participants	2	2	4
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	24	24.5	24.25
Sex: Female, Male (Count of Participants)
Female	2 100%	2 100%	4 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	1 50%	1 50%	2 50%
Black or African American	0 0%	0 0%	0 0%
American Indian/Alaska Native	0 0%	0 0%	0 0%
Asian	1 50%	1 50%	2 50%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown/do not want to specify	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%	2 100%	4 100%

Outcome Measures

1. Primary Outcome

Title	Go/No-Go Accuracy
Description	Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go). Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.
Time Frame	From time of drug administration to 70 minutes following drug administration, up to 90 minutes

Outcome Measure Data

Analysis Population Description

All the participants were non-smokers

Arm/Group Title	Smokers	Non-Smokers
Arm/Group Description	All participants receive both Novolin R (experimental drug) and 14% NaCl (Sodium Chloride) solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose. Novolin R: Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.	All participants receive both Novolin R (experimental drug) and 14% NaCl solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose. Novolin R: Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.
Measure Participants	0	4
Run 1 (Insulin)	70.771 (25.82)
Run 2 (Placebo)	67.693 (27.95)

Adverse Events

Time Frame	2 sessions, up to 2 days
Adverse Event Reporting Description	All-Cause Mortality and Serious Adverse Events were monitored/assessed, but none observed
Arm/Group Title	Novolin R (First Intervention)		Placebo (First Intervention)		Placebo (Second Intervention)		Novolin R (Second Intervention)
Arm/Group Description	Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in first session.		Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in first session.		Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in second session.		Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in second session.
All Cause Mortality
	Novolin R (First Intervention)		Placebo (First Intervention)		Placebo (Second Intervention)		Novolin R (Second Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Novolin R (First Intervention)		Placebo (First Intervention)		Placebo (Second Intervention)		Novolin R (Second Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Novolin R (First Intervention)		Placebo (First Intervention)		Placebo (Second Intervention)		Novolin R (Second Intervention)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		2/2 (100%)		2/2 (100%)		2/2 (100%)
General disorders
Nasal Irritation	2/2 (100%)		1/2 (50%)		1/2 (50%)		1/2 (50%)
Sweating	0/2 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)
Sneezing	0/2 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)
Decreased sense of smell, but not total loss	0/2 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)
Partial anosmia (blunted)	1/2 (50%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Stinginess	0/2 (0%)		0/2 (0%)		0/2 (0%)		1/2 (50%)
Hunger	0/2 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)
Dizziness	0/2 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)
Sinus Pain	0/2 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)
Pain	2/2 (100%)		2/2 (100%)		2/2 (100%)		2/2 (100%)
Burning	2/2 (100%)		2/2 (100%)		2/2 (100%)		2/2 (100%)
Taste	2/2 (100%)		2/2 (100%)		2/2 (100%)		2/2 (100%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.