Fentanyl Sublingual Spray in Opioid Naive Participants

Study Overview
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Brief Summary
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The primary objective of this trial is to determine the pharmacokinetic and pharmacodynamic relationship of multiple dose administration of fentanyl sublingual spray in opioid naive participants. The secondary objective is to determine the safety and tolerability of multiple dose administration of fentanyl sublingual spray in opioid naive subjects.

Detailed Description
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For all cycles, blood will be drawn according to the following schedule: The 0 time (pre-dose) blood sample will be collected within 60 minutes prior to first study drug administration. Cohort l: 0 (pre-dose), 5, 15 and 30 minutes after the first dose and at 1, 2, 4 (prior to second-dose), 4.083, 4.25, 4.5, 5, 6, 8 (prior to third-dose), 8.083, 8.25, 8.5, 9, 10, 12, 16 and 24 hours after the first dose. Cohort 2: 0 (pre-dose), 5, 15 and 30 minutes after the first dose and at 1, 2 (prior to second-dose), 2.083, 2.25, 2.5, 3, 4 (prior to third-dose), 4.083, 4.25, 4.5, 5, 6, 8, 10, 12, 16 and 24 hours after the first dose. Cohort 3: 0 (pre-dose), 5, 15, 30 and 45 minutes after the first dose and at 1 (prior to second-dose), 1.083, 1.25, l.5, 1.75, 2 (prior to third-dose), 2.083, 2.25, 2.5, 2.75, 3, 4, 8, 12, 16 and 24 hours after the first dose. Cohort 4: 0 (pre-dose), 5, 15, 30 (prior to the second-dose), 35, and 45 minutes after the first dose and at I (prior to the third-dose), 1.083, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 4, 8, 12, 16 and 24 hours after the first dose.

Official Title
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A Phase 1, Multiple Ascending Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Fentanyl Sublingual Spray in Opioid Naive Subjects

Conditions
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Pharmacology

Intervention / Treatment
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* Drug: Fentanyl Sublingual Spray
* Drug: Fentanyl Citrate IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets protocol-specified criteria for qualification and contraception Willing and able to remain confined in the study unit for the entire duration of each treatment period and comply with restrictions related food, drink and medications Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures Exclusion Criteria: History or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters Signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: the safety or well-being of the participant or study staff the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding) the analysis of results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cycle 1, Cohort 1<br>Fentanyl Sublingual Spray (FSS) low dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every four hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 1, Cohort 2<br>FSS low dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every two hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 1, Cohort 3<br>FSS low dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every hour for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 1, Cohort 4<br>FSS low dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every 30 minutes for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 2, Cohort 1<br>FSS medium dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every four hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 2, Cohort 2<br>FSS medium dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every two hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 2, Cohort 3<br>FSS medium dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every hour for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 2, Cohort 4<br>FSS medium dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every 30 minutes for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 3, Cohort 1<br>FSS high dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every four hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 3, Cohort 2<br>FSS high dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every two hours for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 3, Cohort 3<br>FSS high dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every hour for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|
| Experimental: Cycle 3, Cohort 4<br>FSS high dose (n=6) or Fentanyl Citrate IV 50 mcg (n=2) will be administered once every 30 minutes for a maximum of three doses. | Drug: Fentanyl Sublingual Spray<br>* Fentanyl delivered at low, medium and high doses by sublingual spray (FSS)<br>* Other names: SUBSYS®;Drug: Fentanyl Citrate IV<br>* Fentanyl Citrate 50 mcg, delivered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) |  | within 24 hours (see detailed description) | 
| Time to reach peak or maximum concentration following drug administration (Tmax) |  | within 24 hours (see detailed description) | 
| Area under the concentration-time curve | Categories: during a dosing interval (AUCtau ), from the time of dosing to infinity (AUC0-inf), from the time of dosing to the last quantifiable time point (AUC0-t) | within 24 hours (see detailed description) | 
| Apparent elimination rate constant in the terminal phase by non-compartmental analysis |  | within 24 hours (see detailed description) | 
| Corresponding half-life (t1/2) |  | within 24 hours (see detailed description) | 
| Trough concentration during multiple dosing prior to next dose (Ctrough) |  | within 24 hours (see detailed description) | 
| Accumulation ratios | Categories: of Cmax (ARcmax), based on trough concentration (ARctrough), of AUCtau (ARauctau) | within 24 hours (see detailed description) | 
| Dose normalized Cmax |  | within 24 hours (see detailed description) | 
| Dose normalized AUC | Categories: AUC0-1, AUC0-inf, AUCtau | within 24 hours (see detailed description) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants with respiratory depression requiring the use of naloxone |  | within 24 hours | 
| Participants with hypoxia requiring oxygen administration |  | within 24 hours | 
| Participants needing noninvasive respiratory maneuvers (e.g., jaw thrust, bag-valve mask) to improve respiratory status at any point during the study |  | within 24 hours | 
| Participants with hypotension requiring intervention |  | within 24 hours |