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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
44
The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder low dose formulation for oral inhalation
The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder high dose formulation for oral inhalation
A single dose of DHE injection consists of 1 mg/mL ampoule of DHE solution for slow intravenous administration.
Alliance for Multispecialty research (AMR)
Knoxville, Tennessee, United States
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)
Time frame: 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)
Time frame: 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)
Time frame: 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-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)
Time frame: 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
Area under the concentration-time curve from time zero to infinity (extrapolated) of plasma concentrations of 8'-OH-DHE (AUC 0-inf)
Time frame: 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)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
A single vial of DHE nasal spray (Migranal®) contains 1 mL of 4 mg/mL DHE solution.
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.
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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®
Time frame: 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)
Time frame: 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®
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours