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A partially randomized, open-label, 3-way crossover, single-center, systemic and CSF PK and bioavailability study in healthy volunteers.
An Open-Label Single-Dose Crossover Study Comparing the Plasma and Cerebrospinal Fluid Pharmacokinetics and Bioavailability of Fentanyl Delivered Intranasally Versus Sublingually Versus Intravenously in Healthy Volunteers
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nasal fentanyl | Active Comparator | nasal fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute. Will be administered on either study day 1 or 3 per protocol and randomization. |
|
| Sub-Lingual fentanyl | Active Comparator | sublingual fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue. Will be administered on either study day 1 or 3 per protocol and randomization. |
|
| IV fentanyl | Active Comparator | IV fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes. Will be administered on study day 5 per protocol. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fentanyl | Drug | Lazanda (nasal spray), Subsys (sub-lingual) and intravenous fentanyl |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | |
| Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | |
| Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) | |
| Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | Cmax (pg/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
| Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-tlast) of Fentanyl in Plasma (2 of 5) | AUC 0-tlast (pg*h/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
| Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | AUC 0-inf (pg*h/mL) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
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Inclusion Criteria:
No clinically meaningful findings in the physical examination, oral and nasal examination and 12-lead electrocardiogram.
Negative for drugs of abuse, alcohol, and nicotine. Negative for hepatitis A, B, and C and Human Immunodeficiency Virus (HIV). No clinical laboratory values outside of the acceptable range, unless, in the opinion of the Principal Investigator, they are deemed not clinically significant.
Exclusion Criteria:
Subject has a known history of allergic reaction, hypersensitivity, or clinically significant intolerance to opioids, fentanyl or components of the study drugs.
2. Subjects with a high potential for opioid addiction (personal or family history).
3. Subject is lactating or considered at risk of pregnancy. 4. Subject has impaired liver function (e.g., alanine aminotransferase [ALT] ≥ 3 times the upper limit of normal [ULN] or bilirubin ≥ 3 times ULN), known active hepatic disease (e.g., hepatitis), or evidence of clinically significant liver disease or other condition affecting the liver that may suggest the potential for an increased susceptibility to hepatic toxicity with oral diclofenac exposure.
5. Subject has any history of renal disease that, in the opinion of the investigator, would contraindicate study participation; or subject has significantly impaired renal function as evidenced by an estimated GFR of ≤60 ml/min/1.73m2.
6. Subject has a history or evidence of significant nasal pathology, including polyps or nasal obstructions.
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| Name | Affiliation | Role |
|---|---|---|
| Head of R&D | Depomed | Study Director |
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A total of 13 healthy subjects were randomly assigned to treatment in this crossover study: 6 in the "Nasal Fentanyl First, then Sublingual Fentanyl and IV Fentanyl" arm and 7 in the "Sublingual Fentanyl First, then Nasal Fentanyl and IV Fentanyl" arm.
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| ID | Title | Description |
|---|---|---|
| FG000 | Nasal Fentanyl First, Then Sublingual Fentanyl and IV Fentanyl | Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 1 per protocol. Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 3 per protocol. IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. |
| FG001 | Sublingual Fentanyl First, Then Nasal Fentanyl and IV Fentanyl | Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 1 per protocol. Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 3 per protocol. IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Nasal Fentanyl First, Then Sublingual Fentanyl and IV Fentanyl | Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 1 per protocol. Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 3 per protocol. IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Cerebrospinal Fluid (CSF) (1 of 3) | The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions. | Posted | Median | Full Range | h | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) |
|
8 weeks
Adverse Events were reported from the signed informed consent to 30 days after the last dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Nasal Fentanyl | Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 1 or 3 per protocol. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Post Lumbar Puncture Syndrome | Injury, poisoning and procedural complications |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Operations | Depomed | 510-744-8000 | clinicaltrials@depomed.com |
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| ID | Term |
|---|---|
| D005283 | Fentanyl |
| ID | Term |
|---|---|
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | Tmax (h) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
| Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | t1/2 (h) | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
| BG001 | Sublingual Fentanyl First, Then Nasal Fentanyl and IV Fentanyl | Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 1 per protocol. Nasal Fentanyl, 200 μg, administered as one 100 μg spray (100 μL) to each nostril; both completed within one minute on Study Day 3 per protocol. IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
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| Primary | Maximum Observed Concentration (Cmax) of Fentanyl in Cerebrospinal Fluid (CSF) (2 of 3) | The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions. | Posted | Mean | Standard Deviation | pg/mL | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) |
|
|
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| Primary | Area Under the Concentration-Time Curve From Hour 0 to Hour 6 (AUC 0-6h) of Fentanyl in Cerebrospinal Fluid (CSF) (3 of 3) | The CSF PK population included all subjects who completed all study periods and Cmax was less than 5% pre-dose. The above CSF PK outcome compares nasal and sublingual fentanyl interventions. | Posted | Mean | Standard Deviation | pg*h/mL | 6 hrs (pre-dose, 5, 10, 20, 30, 45, & 60 min, and 2, 3, 4, & 6 hrs post-dose on Study Days 1 & 3) |
|
|
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| Primary | Maximum Observed Concentration (Cmax) of Fentanyl in Plasma (1 of 5) | Cmax (pg/mL) | The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
|
|
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| Primary | Area Under the Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUC 0-tlast) of Fentanyl in Plasma (2 of 5) | AUC 0-tlast (pg*h/mL) | The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
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| Primary | Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) of Fentanyl in Plasma (3 of 5) | AUC 0-inf (pg*h/mL) | The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. The AUC 0-inf values were excluded where %AUC extrap was greater than 20%. | Posted | Geometric Mean | Geometric Coefficient of Variation | pg*h/mL | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
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| Primary | Time to Reach Maximum Observed Concentration (Tmax) of Fentanyl in Plasma (4 of 5) | Tmax (h) | The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. | Posted | Median | Full Range | h | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
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| Primary | Terminal Elimination Half-Life (t1/2) of Fentanyl in Plasma (5 of 5) | t1/2 (h) | The Plasma PK population included all subjects who received at least 1 dose of study drug and had at least 1 evaluable PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h | 24 hrs (pre-dose, 5, 10, 15, 20, 30, 45, & 60 min, and 1.5, 2, 3, 4, 6, 8, 12, & 24 hrs on Study Days 1 & 3 for Nasal Fentanyl / Sublingual Fentanyl; pre-dose, 2, 5, 10, 20, 30, & 60 min, and 2, 4, 6, 8, 12, & 24 hrs on Study Day 5 for IV Fentanyl) |
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| 0 |
| 12 |
| 2 |
| 12 |
| EG001 | Sublingual Fentanyl | Sublingual Fentanyl, 200 μg, administered as a single spray (100 μL) under the tongue on Study Day 1 or 3 per protocol. | 1 | 13 | 6 | 13 |
| EG002 | IV Fentanyl | IV Fentanyl, 100 μg in 2 mL administered as an intravenous injection over 1-3 minutes on Study Day 5 per protocol. | 0 | 12 | 0 | 12 |
| Abdominal Distension | Gastrointestinal disorders |
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| Vomiting | Gastrointestinal disorders |
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| Headache | Nervous system disorders |
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| Radicular Pain | Nervous system disorders |
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| Catheter Site Pain | General disorders |
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| Back Pain | Musculoskeletal and connective tissue disorders |
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The PI agrees that sponsor shall have the right to the first publication of the study results which is intended to be a joint, multi-center publication. Following the first publication, the PI may publish study data or results, provided however PI submits the proposed publication to sponsor for review at least 60 days prior to the date of the proposed publication. Sponsor may remove any information that is considered confidential and / or proprietary other than study data.