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A Phase 1 clinical trial to evaluate the pharmacokinetics, relative bioavailability, safety and tolerability of DHE inhalation powder delivered by dry powder inhaler, DHE IV, and DHE nasal spray.
This is an open-label, randomized, 4-treatment, 4-period crossover study to evaluate the PK, relative BA, safety, and tolerability of single doses of study medication in healthy adult subjects.
Following screening, eligible subjects will be enrolled and randomized to one of the 4 treatment sequences. Subjects will receive single doses of DHE inhalation powder (low dose and high dose), DHE IV (1 mg) and DHE nasal spray (2 mg).
Subjects will be administered one treatment in each period according to their assigned sequence. Each subject will receive all 4 treatments in the study.
During each treatment period subjects will remain in the clinical research unit for 3 days, until completion of the 48-hour post-dose assessments.
Subjects will return for their next treatment period after at least 7 days washout after the administration of their previous treatment until all periods have been completed in their sequence.
A follow-up will be conducted on Day 7 after the last dose in the study to assess safety.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A: inhaled DHE low dose | Experimental | Low dose of DHE inhalation powder |
|
| Treatment B: inhaled DHE high dose | Experimental | High dose of DHE inhalation powder |
|
| Treatment C: intravenous DHE | Active Comparator | 1 mg DHE injected intravenously |
|
| Treatment D: intranasal DHE | Active Comparator | 2 mg DHE nasal spray (Migranal®) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| DHE inhalation powder low dose administered via dry powder inhaler (DPI) device | Combination Product | The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder low dose formulation for oral inhalation |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics: Area under the curve (AUC 0-t) of DHE | Area under the concentration-time curve from time zero until the last observed plasma concentration of DHE (AUC 0-t) | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Area under the curve (AUC 0-inf) of DHE | Area under the concentration-time curve from time zero to infinity (extrapolated) of plasma concentrations of DHE (AUC 0-inf) | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Peak plasma concentration (C max) of DHE | Maximal observed plasma concentration of DHE (C max) | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics: Area under the curve (AUC 0-t) of 8'-OH-DHE | Area under the concentration-time curve from time zero until the last observed plasma concentration of 8'-OH-DHE (AUC 0-t) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Area under the curve (AUC 0-inf) of 8'-OH-DHE |
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Inclusion Criteria:
Subjects must meet all the following criteria to be included in the study:
Exclusion Criteria:
Subjects to whom any of the following applies will be excluded from the study:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Alliance for Multispecialty research (AMR) | Knoxville | Tennessee | 37920 | United States |
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Eligible subjects will be enrolled and randomized on Day 1 to one of the 4 treatment sequences composed of 4 periods of the crossover design.
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None (open-label)
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| DHE inhalation powder high dose administered via dry powder inhaler (DPI) device | Combination Product | The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder high dose formulation for oral inhalation |
|
| DHE injected intravenously (1 mg) | Drug | A single dose of DHE injection consists of 1 mg/mL ampoule of DHE solution for slow intravenous administration. |
|
| DHE 2 mg administered by nasal spray (Migranal®) | Drug | A single vial of DHE nasal spray (Migranal®) contains 1 mL of 4 mg/mL DHE solution. |
|
| Metoclopramide 10mg | Drug | To prevent nausea caused by IV administration of DHE, participants will receive antiemetic pre-medication with metoclopramide 10 mg administered by slow intravenous push over 1-2 min, given 5 to 10 minutes prior to IV DHE dosing. |
|
Area under the concentration-time curve from time zero to infinity (extrapolated) of plasma concentrations of 8'-OH-DHE (AUC 0-inf) |
| For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Peak plasma concentration (C max) of 8'-OH-DHE | Maximal plasma observed concentration of 8'-OH-DHE (C max) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Time of peak maximal concentration (T max) of DHE and 8'-OH-DHE | Time when the maximal plasma concentration of DHE and 8'-OH-DHE are observed (T max) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Terminal elimination half-life (T 1/2 el) of DHE and 8'-OH-DHE | Terminal elimination half-life of plasma concentrations of DHE and 8'-OH-DHE (T 1/2 el) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Area under the curve (AUC 0-30 min) of DHE | Area under the concentration-time curve from time zero to 30 min of plasma concentrations of DHE (AUC 0-30min) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Area under the curve (AUC 0-2 hours) of DHE | Area under the concentration-time curve from time zero to 2 hours of plasma concentrations of DHE (AUC 0-2 hours) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Apparent clearance of DHE (CL/F) | Apparent clearance of DHE (CL/F) for DHE inhalation powder and DHE nasal spray Migranal® | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Clearance of DHE (CL) | Clearance of DHE for intravenous DHE (CL) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Apparent volume of distribution of DHE (Vz/F) | Apparent volume of distribution (Vz/F) during terminal phase of DHE for DHE inhalation powder and DHE nasal spray Migranal® | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Pharmacokinetics: Volume of distribution of DHE (Vz) | Volume of distribution (Vz) of DHE intravenous | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours |
| Safety: Number of participants with adverse events | Adverse events will be recorded and evaluated for their seriousness, severity and relationship to the study drug | From the time of signing the informed consent until the last visit on Day 7 after the last treatment period |
| Safety: Blood pressure in mmHg | The changes from baseline in systolic and diastolic blood pressure will be assessed | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods |
| Safety: Heart rate in beats/min | The changes from baseline in heart rate will be assessed | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods |
| Safety: Respiratory rate in breaths/min | The changes from baseline in respiratory rate will be assessed | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods |
| Safety: Oral body temperature in degree Celsius | The changes from baseline in oral body temperature will be assessed | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods |
| ECG PR interval in msec | The changes from baseline in 12-lead ECG PR interval will be assessed | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods |
| ECG QRS complex in msec | The changes from baseline in 12-lead ECG QRS complex will be assessed | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods |
| ECG QT interval in msec | The changes from baseline in 12-lead ECG QT interval and Fridericia's corrected QT interval will be assessed | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods |
| Physical examination | Physical examination (including oral cavity, nasal cavity and injection site examination) will be performed | At screening, and for each of the 4 treatment periods at baseline, and post-dose at day 2 and day 3 |
| Lung function by spirometry : Forced Expiratory Volume in 1 sec in % of predicted normal (FEV1 ) | Effect of DHE on lung function will be measured by collecting FEV 1 pre- and post-dose at specified timepoints and will be analyzed by FEV1 < 70 % of predicted normal and/or comparison of pre- and post-dose > 20 % decline in FEV1. | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours |
| Lung function by spirometry : Forced Vital Capacity (FVC) in liters | Effect of DHE on lung function will be measured by collecting Forced Vital Capacity pre- and post-dose at specified timepoints | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours |
| Lung function by spirometry : FEV1/FVC ratio | Effect of DHE on lung function will be measured by collecting the FEV1/FVC ratio pre- and post-dose at specified timepoints | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours |
| Lung function by spirometry : Forced Expiratory Flow 25-75 in % | Effect of DHE on lung function will be measured by collecting the mean Forced expiratory Flow between 25% and 75% of the forced vital capacity pre- and post-dose at specified timepoints | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours |
| Clinical laboratory tests blood and urine | Change from baseline in clinical laboratory tests (including hematology, biochemistry, coagulation, and urinalysis) will be analyzed at different timepoints | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours |
| ID | Term |
|---|---|
| D004087 | Dihydroergotamine |
| D008787 | Metoclopramide |
| ID | Term |
|---|---|
| D004879 | Ergotamines |
| D004876 | Ergot Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D001549 | Benzamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D062366 | para-Aminobenzoates |
| D062365 | Aminobenzoates |
| D001565 | Benzoates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D002723 | Chlorobenzoates |
| D062425 | Hydroxybenzoate Ethers |
| D062385 | Hydroxybenzoates |
| D006880 | Hydroxy Acids |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D010647 | Phenyl Ethers |
| D010636 | Phenols |
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