Effects of Intranasal Administration of a Single Dose of Oxytocin Using a Novel Device in Healthy Adults

Study Overview
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Brief Summary
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Oxytocin (OT) is a small, naturally occurring peptide currently in clinical use to stimulate lactation in breastfeeding women. The intranasal administration of OT has recently attracted attention as a potential novel treatment in several psychiatric disorders including autism. However, given the anatomy of the nasal cavity, the current design of nasal sprays would be expected to provide an inadequate delivery of medication to the areas of the nasal cavity where direct transport into the brain via the olfactory nerve could potentially occur. OptiNose has developed an intranasal delivery device that provides improved reproducibility of nasal delivery, improved deposition to the upper posterior regions of the nasal cavity where the olfactory nerve innervates the nasal cavity. The primary objective of this study is to identify any differences between single dose 8 or 24 international units (IU) oxytocin delivered intranasally with the optimised OptiNose device and 1 IU oxytocin administered as slow intravenous infusion in healthy volunteers. This will be measured in terms of brain activity as measured with functional magnetic resonance imaging (fMRI), performance on cognitive tests, and physiological markers.

Official Title
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Intranasal (Optinose Bidirectional Nose-to-brain Device) Versus Intravenous Slow Infusion of Oxytocin - a Randomized, Placebo- Controlled Double-blind, Double-dummy 4-period Cross-over Study in Healthy Adult Volunteers Evaluating Brain Functional Magnetic Resonance Imaging Changes, Cognitive Response, Heart Rate Variability, Plasma Pharmacokinetics and Saliva Concentration After Single-dose Oxytocin 8 or 24 International Units (IU) Intranasally or 1 IU as Slow Intravenous Infusion

Conditions
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Healthy Male Adults

Intervention / Treatment
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* Drug: 8IU intranasal oxytocin
* Drug: 24 IU intranasal oxytocin
* Drug: 1 IU intravenous oxytocin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, male subjects aged 18 to 35 years inclusive. Subjects must be in good general health, as determined by the investigator. Subject's pre-study physical examination, vital signs and electrocardiogram (ECG) are normal or do not show any clinically significant abnormalities as determined by the investigator. Vital signs must not have any clinically significant deviations outside of the following ranges when measured sitting after 5 minutes rest: Heart rate: 40 to 90 beats per minute Systolic blood pressure (BP): 90 to 140 mmHg Diastolic BP: 50 to 90 mmHg Oral temperature: 36.0 to 37.5°C Respiratory rate: 12 - 18 breaths per minute Body Mass Index (BMI) of 18.5 - 29.9 kg/m2 (both inclusive) Subjects must be able to communicate well with the Investigator, to understand and comply with the requirements of the study, and understand and sign the written informed consent Provision of written informed consent. Exclusion Criteria: An ear, nose and throat (ENT) specialist will inspect the noses of all individuals who enter the study. In order to participate in the study subjects must not meet any of the following exclusion criteria; Individuals showing major septal deviation or a significantly altered nasal epithelium. Participants with evidence of previous nasal disease, surgery, and dependence on inhaled drugs. Individuals with current significant nasal congestion due to common colds. Subjects with a clinically relevant history of significant hepatic, renal, endocrine, cardiac, nervous, psychiatric, gastrointestinal, pulmonary, haematological or metabolic disorder. Subjects with current or history of, any clinically significant disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs. Subject is taking any regular prescribed or over-the-counter (OTC) medications including vitamin supplements and herbal remedies. There must be at least 14 days between stopping these products and the first dose of study medication). Systemic illness requiring treatment within 2 weeks prior to Study Day 1. History of significant drug or alcohol abuse (as per a self-report measure / instrument; World Health Organisation criteria/Alcohol use disorders identification test/Drug use disorders identification test). Subjects with a positive screen for alcohol or drugs of abuse at screening/admission will be excluded from participation in the study. Self-reported significant psychiatric conditions. Any abnormal laboratory values outside normal range, and which is clinically significant as deemed by investigator. Full scale intelligence quotient (IQ) < 75 (due to the prerequisite ability to complete self report measures). Known allergic reactions or hypersensitivity to any component of the study medication in the nasal spray, such as E216, E218 and chlorobutanol hemihydrate. Participation in any (other) clinical trial with an investigational medicinal product or medical device within 3 months prior to randomisation. Current evidence of any mental or physical disorder or collaboration attitude which, in the judgment of the investigator makes the subject unsuitable for enrolment, and/or may interfere with the study evaluations or affect subject's safety. Subjects with any metal implants. Subjects with claustrophobia. Other unspecified reasons that, in the opinion of the Investigator or the sponsor make the subject unsuitable for enrolment. Subjects with female partners of child-bearing potential must use an adequate form of contraception prior to entry into the study until three months following the post-study medical visit. Subjects must not have a partner who is either pregnant or breastfeeding for the duration of the study. Adequate contraception is defined as the usage by the female partner of any form of hormonal contraception or intra-uterine device (which should be established prior to the start of the study) plus usage by one of the partners of an additional spermicide- containing barrier method of contraception.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 international unit (IU) intravenous oxytocin<br>Using a double-dummy design participants will be administered 1 IU oxytocin (mixed in 200 ml 0.9% sodium chloride) slow infusion with varying infusion rate over 20 minutes and placebo delivered with the OptiNose Breath Powered Bi-Directional liquid device. Subject to pilot data this may be increased to 2 IU oxytocin (mixed in 200 ml 0.9% sodium chloride) and the infusion time/rate may change to best match the pharmacokinetic profile of intranasally administered oxytocin. | Drug: 1 IU intravenous oxytocin<br> <br> |
| Placebo Comparator: Placebo<br>Using a double-dummy design participants will be administered Placebo delivered with the OptiNose Breath Powered Bi-Directional liquid device and placebo delivered intravenously (0.9% sodium chloride 200 ml slow infusion for 20 minutes) | Drug: Placebo<br> <br> |
| Experimental: 8IU intranasal oxytocin<br>Using a double-dummy design participants will be administered 8IU oxytocin liquid delivered with the OptiNose Breath Powered Bi directional liquid device and IV placebo (0.9% sodium chloride, 200 ml slow infusion for 20 minutes) | Drug: 8IU intranasal oxytocin<br> <br> |
| Experimental: 24IU intranasal oxytocin<br>Using a double-dummy design participants will be administered 24IU oxytocin liquid delivered with the OptiNose Breath Powered Bi directional liquid device and IV placebo (0.9% sodium chloride, 200 ml slow infusion for 20 minutes) | Drug: 24 IU intranasal oxytocin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aim 1a: Brain activity | Scanning procedures for functional magnetic resonance imaging (fMRI) will include a functional scan during a social cognition task and structural connectivity during rest | 30 minutes after oxytocin/placebo administration | 
| Aim 1b: Performance on a social cognition test | Participants will complete a task evaluating emotional expressions (either happy expressions, fear expressions or neutral expressions). These stimuli are identical to those published previously by Leknes et al., (2012). | 45 mins after oxytocin/placebo administration | 
| Aim 1c: Heart rate variability | Electrocardiogram data will be collected to assess heart rate variability, a measure of cardiac autonomic function. | 20 minutes after oxytocin placebo administration | 
| Aim 1d: Eyetracking | An eyetracking device will measure eyegaze and pupillometry. | 20 minutes after oxytocin placebo administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of oxytocin | Blood will be collected to assess levels of oxytocin present in peripheral blood to measure PK profile of 8 and 24 international units (IU) oxytocin delivered with OptiNose device and of 1 IU oxytocin after slow intravenous (IV) infusion. | 5 minutes prior to oxytocin/placebo administration | 
| Plasma concentration of cortisol | Blood will be drawn at various intervals for the pharmacokinetic analysis of plasma cortisol. | 20 minutes before fMRI procedure | 
| Oxytocin levels in saliva | Saliva will be collected for pharmacokinetic analysis of oxytocin and cortisol in saliva. | 20 prior to fMRI procedure | 
| Cortisol levels in saliva | Saliva will be collected for pharmacokinetic analysis of oxytocin and cortisol in saliva. | 20 minutes prior to fMRI procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxytocin, fMRI, social cognition, heart rate variability, pupillometry, eye tracking