Antagonism of Opioid-Induced Respiratory Depression by CX1739 With Preservation of Opioid Analgesia

Study Overview
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Brief Summary
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The study is an investigation to assess the capacity of ascending doses of CX1739 to antagonize the respiratory depressive effect of remifentanil. The study will also investigate whether ascending doses of CX1739 reduce the analgesic effect of remifentanil or alter the BIS measure of sedation and will evaluate the safety of CX1739 when used in conjunction with remifentanil.

Official Title
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Antagonism of Opioid-Induced Respiratory Depression by CX1739 With Preservation of Opioid Analgesia

Conditions
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Opiate Induced Respiratory Depression

Intervention / Treatment
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* Drug: CX1739 - 300 mg
* Drug: CX1739 - 600 mg
* Drug: CX1739 - 900 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for this trial, subjects must meet all of the following criteria: Males 18 to 50 years of age, inclusive Body mass index of 18.0 to 30.0 kg/m2, inclusive, using the formula: weight (kg)/height (m)2 Healthy, as determined by medical history, physical examination including vital signs, and clinical laboratory test results American Society of Anesthesiologists Physical Status Classification 1 Willing and able to provide voluntary, written informed consent Exclusion Criteria: If a subject meets any of the following criteria, he cannot be enrolled in the study: History of any chronic illness or evidence of clinically significant organic or psychiatric disease on medical history or physical examination which, in the opinion of the principal investigator (PI), would confound the study results or present a risk to the subject Acute illness within 2 weeks before dosing History of any clinically significant pulmonary condition (eg, asthma) within the last 2 years requiring admission to the hospital Previous diagnosis of obstructive sleep apnea based on polysomnography Currently using any prescription medication or use within the last 30 days Laboratory values (clinical chemistry, hematology, urinalysis) outside the laboratory reference range considered clinically significant (NOTE: in the event of any parameter lying outside of the normal range, the sample may be repeated once; this value will be accepted if it lies within the normal range) Presence of QT interval corrected > 440 msec on ECG Resting HR while awake < 45 or > 90 beats/minute History of daily use of tobacco or other nicotine-containing products within 1 year of study entry or positive cotinine test at screening and subsequent study visits History of allergic hypersensitivity to ampakines (CX717, CX1739), remifentanil, naloxone, or any component of these formulations; history of multiple drug allergies History or current evidence of abuse of any drug substance, licit or illicit, including alcohol; positive urine drug screen (UDS) for drugs of abuse at screening Inability to understand the protocol requirements; instructions; study-related restrictions; or nature, scope, and possible consequences of the study Unlikely to complete the study, eg, because of inability to return for follow-up visits Participation in another study with any investigational drug in the 3 months preceding this study Blood or plasma donation of more than 500 mL during the month before randomization and more than 50 mL in the 2 weeks before randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CX1739 - 300 mg<br>Study Drug - low dose | Drug: CX1739 - 300 mg<br>* Ampakine CX1739 - 300 mg<br>* Other names: Low dose;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo to 300 mg CX1739<br>* Other names: Placebo to 300 mg CX1739;|
| Experimental: CX1739 - 600 mg<br>Study drug - mid Dose | Drug: CX1739 - 600 mg<br>* CX1739 - 600 mg<br>* Other names: mid dose;|
| Experimental: CX1739 - 900 mg<br>Study drug - high dose | Drug: CX1739 - 900 mg<br>* CX1739 - 900 mg<br>* Other names: high dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory depression | Respiratory rate, tidal volume, minute volume as determined by plethysmography | Sequence #1 - 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain tolerance threshold | Analgesia assessed by pain tolerance threshold to 5, 250, and 2000 Hertz sine-wave electrical stimulation using the quantitative sensory testing device - Neurometer | Sequence #2 - 20 minutes | 
| Maintenance of sedation | Bispectral index (BIS) measure of sedation | Sequence #1 - 30 minutes | 
| The number of patients that experience an adverse drug reaction upon ingestion of CX1739 when used alone or in conjunction with remifentanil | Vital signs, including noninvasive blood pressure, heart rate, RR, end-tidal carbon dioxide, pulse oximetry saturation, and temperature Electrocardiograms Focused physical examinations Adverse events | up to 5 weeks | 
| Change in pupil size | Pupil size will be assessed intermittently with a noninvasive pupillometer incorporated into a pair of glasses placed on the subject's head | Sequence #2 - 20 minutes |