A Study to Evaluate Single Doses of Dihydroergotamine Mesylate Inhalation Powder and Dihydroergotamine Mesylate Intravenous in Healthy Adult Subjects

Exclusion Criteria47

• Positive pregnancy test or lactating female subjects at screening or prior to dosing.
• Significant history or clinical manifestation of any metabolic, allergic, dermatological,
• immunological, renal, hepatic, hematological, pulmonary, cardiovascular, gastrointestinal,
• neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator.
• History or current diagnosis of uncontrolled or significant cardiac disease indicating significant risk of safety for participation in the study at screening. This includes subjects with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or subjects who have clinical symptoms or findings consistent with coronary artery vasospasm, including Prinzmetal’s variant angina.
• Subject with abnormal lung function defined by spirometry testing such: FEV1 < 80% of
• predicted normal value OR FEV1/FVC ratio < 0.70 at screening.
• History or current diagnosis of COPD, asthma, including childhood asthma, or bronchospasm at screening.
• History of COVID-19 with unresolved respiratory symptoms and/or unresolved respiratory
• findings, or any previous hospitalization due to COVID-19.
• Presence of orthodontic braces or orthodontic retention wires, dentures, tongue piercing or any physical findings in the mouth or tongue that would be likely to interfere with completion of the dosing procedure in the opinion of the investigator.
• Known allergic reactions, hypersensitivity, or contraindications to DHE, other ergot derived products, or to any excipient in the formulation at screening.
• Blood pressure (BP) measured in a rested and relaxed condition, where systolic BP greater than or equal to 130 mmHg or diastolic BP greater than or equal to 80 mmHg at screening.
• Any of the following cardiac criteria at screening:
• a. Mean resting QT interval corrected by QTcF > 470 msec (females) or > 450 msec (males)
• obtained from 3 ECGs.
• b. Any clinically relevant abnormality in rhythm, conduction or morphology of resting ECG
• (e.g., complete left bundle branch block, third degree heart block, second degree heart
• block, PR interval >250 msec).
• c. Clinically relevant factor which in the opinion of the investigator may increase the risk of
• QTc prolongation or risk of arrhythmic events (e.g., heart failure, uncorrected hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval).
• History or presence of drug abuse within the 1 year prior to the first study drug administration or a positive result on the urine drug test at the Screening Visit.
• History of alcohol abuse within 1 year prior to screening or regular use of alcohol within
• months prior to screening that exceeds 10 units for women or 15 units for men of alcohol per week (1 unit = 375 mL of beer 3.5%, or 100 mL of wine 13.5%, or 30 mL of distilled alcohol
• %).
• Positive serology test results for hepatitis C virus (HCV) antibody, hepatitis B surface antigen (HbsAg) and/or human immunodeficiency virus (HIV) at screening. Subjects whose results are compatible with prior immunization for HbsAg or natural immunity may be included at the discretion of the investigator.
• Subjects with significant risk factors for coronary artery disease, or history of hypertension, diabetes, known peripheral arterial disease, cerebrovascular, ischemic bowel syndrome, Raynaud’s phenomenon, sepsis or vascular surgery (within 3 months prior to study start), or severely impaired hepatic or renal function.
• Positive urine cotinine test at screening or check-in.
• Use of any drugs or substances known or suspected to alter drug absorption, distribution, metabolism, or excretion:
• a. Inhibitors of any metabolic enzymes or drug transporters within 14 days or 5 half-lives,
• whichever is longer, prior to check-in.
• b. Inducers of any metabolic enzymes (including St. John’s wort) within 28 days or 5 half-lives, whichever is longer, prior to check-in.
• c. Use of any medication strongly or moderately affecting CYP3A4 Cytochrome P450
• metabolic pathway within 14 days or 5 half-lives, whichever is longer, prior to check-in.
• Use or intend to use any prescription medications/products within 14 days prior to check-in, or throughout the duration of the clinical study unless deemed acceptable by the investigator, medical monitor, and sponsor.
• Use or intent to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check-in or throughout the duration of the clinical study. Use of protein supplements may be allowed as determined by the investigator.
• Administration of an investigational drug (new chemical entity) in the past 30 days or 5 half-lives, whichever is longer, prior to check-in. Administration of a biological product in the
• context of a clinical research study within 90 days (or 5 half-lives, whichever is longer) prior
• to check-in, or concomitant participation in an investigational study.
• Depot injection or implant for 3 months prior to dosing.
• Any vaccine, including COVID-19 vaccine, within 14 days prior to dosing.
• For Cohorts 1, 3 and 4 only: Inability to demonstrate the correct inhalation
• manoeuvre as assessed via Clemente-Clarke In-Check Dial after training.
• Donation of plasma within 7 days prior to screening, or donation or loss of 500 mL or more of whole blood or platelets within 8 weeks prior to screening (including blood sampling volumes from previous study participation).
• Any reason which, in the opinion of the Investigator, would prevent the subject from
• participating in the study.
• Presence of a known, or suspected, impairment of the immune system including, but not limited to, autoimmune disorders, immunosuppressant therapy.