Safety, and Tolerability
Conditions
Keywords
Dihydroergotamine mesylate, Inhalation powder
Brief summary
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.
Detailed description
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.
Interventions
COMBINATION_PRODUCTDHE inhalation powder low dose administered via dry powder inhaler (DPI) device
The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder low dose formulation for oral inhalation
COMBINATION_PRODUCTDHE inhalation powder high dose administered via dry powder inhaler (DPI) device
The DHE inhalation powder is a pre-metered drug-device combination product containing DHE dry powder high dose formulation for oral inhalation
DRUGDHE injected intravenously (1 mg)
A single dose of DHE injection consists of 1 mg/mL ampoule of DHE solution for slow intravenous administration.
DRUGDHE 2 mg administered by nasal spray (Migranal®)
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.
Sponsors
Aspeya Switzerland SA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
None (open-label)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects must meet all the following criteria to be included in the study: 1. Male or female, ≥ 18 and ≤ 55 years of age, with body mass index (BMI) \>18.5 and \< 32.0 kg/m2 2. Healthy subjects 3. Female subjects of non-childbearing potential or childbearing potential willing to use protocol required methods of contraception 4. Current non-smoker 5. Able to understand the study procedures and provide signed informed consent to participate in the study.
Exclusion criteria
* Subjects to whom any of the following applies will be excluded from the study: 1. Positive pregnancy test or lactating female subjects at screening or on Day 1 of each treatment period 2. Clinically significant abnormal laboratory or serology test results 3. History or current diagnosis of uncontrolled or significant cardiac disease 4. Significant risk factors for cardiovascular disease 5. Subject with abnormal lung function at screening 6. History or current diagnosis of lung disease e.g. asthma, COPD 7. Known allergic reactions, hypersensitivity or contraindications to DHE, other ergot-derived products or to any excipient 8. History of drug or alcohol abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area under the curve (AUC 0-t) of DHE | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero until the last observed plasma concentration of DHE (AUC 0-t) |
| Pharmacokinetics: Area under the curve (AUC 0-inf) of DHE | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero to infinity (extrapolated) of plasma concentrations of DHE (AUC 0-inf) |
| Pharmacokinetics: Peak plasma concentration (C max) of DHE | For each of the 4 treatment periods on baseline and post-dose measurements from 2 minutes up to 48 hours | Maximal observed plasma concentration of DHE (C max) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Peak plasma concentration (C max) of 8'-OH-DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Maximal plasma observed concentration of 8'-OH-DHE (C max) |
| Pharmacokinetics: Time of peak maximal concentration (T max) of DHE and 8'-OH-DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Time when the maximal plasma concentration of DHE and 8'-OH-DHE are observed (T max) |
| Pharmacokinetics: Terminal elimination half-life (T 1/2 el) of DHE and 8'-OH-DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Terminal elimination half-life of plasma concentrations of DHE and 8'-OH-DHE (T 1/2 el) |
| Pharmacokinetics: Area under the curve (AUC 0-2 hours) of DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero to 2 hours of plasma concentrations of DHE (AUC 0-2 hours) |
| Pharmacokinetics: Apparent clearance of DHE (CL/F) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Apparent clearance of DHE (CL/F) for DHE inhalation powder and DHE nasal spray Migranal® |
| Pharmacokinetics: Clearance of DHE (CL) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Clearance of DHE for intravenous DHE (CL) |
| Pharmacokinetics: Apparent volume of distribution of DHE (Vz/F) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Apparent volume of distribution (Vz/F) during terminal phase of DHE for DHE inhalation powder and DHE nasal spray Migranal® |
| Pharmacokinetics: Volume of distribution of DHE (Vz) | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Volume of distribution (Vz) of DHE intravenous |
| Safety: Number of participants with adverse events | From the time of signing the informed consent until the last visit on Day 7 after the last treatment period | Adverse events will be recorded and evaluated for their seriousness, severity and relationship to the study drug |
| Safety: Blood pressure in mmHg | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods | The changes from baseline in systolic and diastolic blood pressure will be assessed |
| Safety: Heart rate in beats/min | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods | The changes from baseline in heart rate will be assessed |
| Safety: Respiratory rate in breaths/min | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods | The changes from baseline in respiratory rate will be assessed |
| Safety: Oral body temperature in degree Celsius | Baseline and post-dose measurements from 10 minutes up to 48 hours for each of the 4 treatment periods | The changes from baseline in oral body temperature will be assessed |
| ECG PR interval in msec | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods | The changes from baseline in 12-lead ECG PR interval will be assessed |
| ECG QRS complex in msec | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods | The changes from baseline in 12-lead ECG QRS complex will be assessed |
| ECG QT interval in msec | Baseline and post-dose measurements from 10 minutes up to 4 hours for each of the 4 treatment periods | The changes from baseline in 12-lead ECG QT interval and Fridericia's corrected QT interval will be assessed |
| Physical examination | At screening, and for each of the 4 treatment periods at baseline, and post-dose at day 2 and day 3 | Physical examination (including oral cavity, nasal cavity and injection site examination) will be performed |
| Lung function by spirometry : Forced Expiratory Volume in 1 sec in % of predicted normal (FEV1 ) | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours | 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. |
| Lung function by spirometry : Forced Vital Capacity (FVC) in liters | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours | Effect of DHE on lung function will be measured by collecting Forced Vital Capacity pre- and post-dose at specified timepoints |
| Lung function by spirometry : FEV1/FVC ratio | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours | Effect of DHE on lung function will be measured by collecting the FEV1/FVC ratio pre- and post-dose at specified timepoints |
| Lung function by spirometry : Forced Expiratory Flow 25-75 in % | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours | 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 |
| Pharmacokinetics: Area under the curve (AUC 0-30 min) of DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero to 30 min of plasma concentrations of DHE (AUC 0-30min) |
| Clinical laboratory tests blood and urine | At screening, and for each of the 4 treatment periods at pre-dose, and post-dose up to 48 hours | Change from baseline in clinical laboratory tests (including hematology, biochemistry, coagulation, and urinalysis) will be analyzed at different timepoints |
| Pharmacokinetics: Area under the curve (AUC 0-t) of 8'-OH-DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero until the last observed plasma concentration of 8'-OH-DHE (AUC 0-t) |
| Pharmacokinetics: Area under the curve (AUC 0-inf) of 8'-OH-DHE | For each of the 4 treatment periods on Baseline and post-dose measurements from 2 minutes up to 48 hours | Area under the concentration-time curve from time zero to infinity (extrapolated) of plasma concentrations of 8'-OH-DHE (AUC 0-inf) |
Countries
United States
Outcome results
None listed