Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001201662
Ethics application status
Approved
Date submitted
2/10/2023
Date registered
21/11/2023
Date last updated
21/05/2024
Date data sharing statement initially provided
21/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate Single Doses of Dihydroergotamine Mesylate Inhalation Powder and Dihydroergotamine Mesylate Intravenous in Healthy Adult Subjects
Scientific title
A Phase 1, Single Center, Open-Label Study to Evaluate the Pharmacokinetics, Bioavailability, Dose Proportionality, Safety, and Tolerability of Single Ascending Doses of Dihydroergotamine Mesylate (Zephyr) Inhalation Powder, and Dihydroergotamine Mesylate Intravenous, in Healthy Adult Subjects.
Secondary ID [1] 310644 0
Zephyr_C101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Migraine 331528 0
Condition category
Condition code
Neurological 328268 328268 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention name:
Zephyr (DHE-Dihydroergotamine Mesylate) inhalation powder

Chemical name: ergotaman-3', 6', 18-trione, 9, 1 0-dihydro-12'-hydroxy-2'methyl-
5'-(phenylmethyl)-, (5'a)-, monomethanesulfonate

Study design and drug administration:

This is a Phase 1, open-label, single center study to evaluate the pharmacokinetics (PK), bioavailability (BA), dose proportionality, safety, and tolerability of single ascending doses of orally inhaled Zephyr inhalation powder, and DHE intravenous (IV), in healthy participants.

The study will consist of up to approximately 28 participants. The study will be enrolled in to four Cohorts (groups). Each Cohort will enroll 7 participants. The planned dosing Cohort details are outlined below:
1. Cohort 1 will receive a single low dose (1 mg) of Zephyr powder via DPI (Dry Powder Inhaler).
2. Cohort 2 (comparator arm) will receive a single dose (1 mg) of DHE via IV injection (supplied by vendor as 1mg/ml single dose ampules).
3. Cohort 3 will receive a single dose (2mg) of Zephyr powder via DPI
4. Cohort 4 will receive a single dose (3 mg) of Zephyr powder via DPI.
Each single dose treatment will be followed by up to 48 hours of serial post-dose PK, safety, and tolerability assessments.

To evaluate the comparative bioavailability, PK and dose proportionality, Cohort 2 will be administered DHE via an IV injection and this will be compared with Cohorts receiving Zephyr powder via DPI.

The cohorts will be enrolled in order, starting with Cohort 1. Following completion of each dose level, a Data Safety Monitoring Board (DSMB) will review the safety and tolerability data up to 48 hours for a minimum of 5 (out of 7) subjects in order to make recommendations whether to escalate to the next dose level, decrease the next dose level, repeat a dose level, or to not evaluate any additional dose.
Intervention code [1] 327051 0
Treatment: Drugs
Intervention code [2] 327052 0
Treatment: Devices
Comparator / control treatment
Study is active controlled.

This study will be using comparator – approved formulation of IV DHE to compare pharmacokinetics and bioavailability with new inhaled formulation. Each cohort where participants receive IP (Zephyr powder via DPI) will be compared to Cohort 2 where participants receive the established drug - DHE via an IV injection.
Control group
Active

Outcomes
Primary outcome [1] 336140 0
To investigate the PK (Pharmacokinetics) of single ascending doses of orally inhaled DHE powder (Zephyr inhalation powder doses: 1 mg, 2 mg, and 3 mg) and a single dose (1 mg) of DHE administered via IV injection in order to select the recommended dose.
Timepoint [1] 336140 0
Blood samples for the PK analysis will be collected at the below timepoints:
1. Day 1: Predose (within 60mins), 2 mins, 5 mins, 10 mins, 15 and 30 mins, 45 mins and 1 hour, 2,3 and 4 hours, 8 hours and 12 hours post-dose.
2. Day 2: 24 hours, 36 hours post-dose.
3. Day 3: 48 hours post-dose.
Primary outcome [2] 336395 0
To investigate the comparative BA (Bioavailability) (Cohort 1 vs Cohort 2 i.e., Zephyr 1mg VS 1 mg DHE via IV)
Timepoint [2] 336395 0
Blood samples for the analysis will be collected at the below timepoints:
1. Day 1: Predose (within 60mins), 2 mins, 5 mins, 10 mins, 15 and 30 mins, 45 mins and 1 hour, 2,3 and 4 hours, 8 hours and 12 hours post-dose.
2. Day 2: 24 hours, 36 hours post-dose.
3. Day 3: 48 hours post-dose.
Primary outcome [3] 336396 0
To investigate the dose proportionality of single ascending doses of orally inhaled DHE powder (Zephyr inhalation powder doses: 1 mg, 2 mg, and 3 mg)
Timepoint [3] 336396 0
Blood samples for the analysis will be collected at the below timepoints:
1. Day 1: Predose (within 60 mins), 2 mins, 5 mins, 10 mins, 15 and 30 mins, 45 mins and 1 hour, 2,3 and 4 hours, 8 hours and 12 hours post-dose.
2. Day 2: 24 hours, 36 hours post-dose.
3. Day 3: 48 hours post-dose.
Secondary outcome [1] 427030 0
To evaluate the safety and tolerability of single dose administrations of Zephyr inhalation powder in healthy adult subjects.
Timepoint [1] 427030 0
1. AEs will be assessed continuously as they are reported and observed. These will be reviewed from Predose (within 60 mins) through to Day 3 (End of the study/Early termination visit).

2. Vital Signs will be assessed at Assessed at Screening, Day -1, Day 1 (Predose-within 60 mins, 15 mins, 30 mins, 1 hour, 4 hours post dose), Day 2 (24 hours post dose) and Day 3 (48 hours post dose)

3. ECG will be assessed at Day 1(Predose-within 60 mins, 10 mins, 4 hours post dose) and Day 3 (48 hours post dose).

4. Physical examination will be assessed at Screening, Day -1, Day 1 (Predose-within 60 mins), Day 2 (24 hours post dose).

5. Clinical lab results will be assessed at Screening, Day -1, Day 2 (24 hours post dose) and Day 3 (48 hours post dose)
Secondary outcome [2] 427032 0
To characterize the PK of the major metabolite 8’-OH-DHE after administration of DHE
via inhalation and IV in healthy adult subjects.
Timepoint [2] 427032 0
Blood samples for the PK analysis will be collected at the below timepoints:
1. Day 1: Predose (within 60 mins), 2 mins, 5 mins, 10 mins, 15 and 30 mins, 45 mins and 1 hour, 2,3 and 4 hours, 8 hours and 12 hours post-dose.
2. Day 2: 24 hours, 36 hours post-dose.
3. Day 3: 48 hours post-dose.

Eligibility
Key inclusion criteria
1. Male or female, greater than or equal to 18 and less than or equal to 65 years of age, with BMI >18.5 and <32.0 kg/m2 at screening.

2. Healthy as defined by:
a. the absence of clinically significant illness and surgery within 4 weeks prior to dosing.
b. the absence of clinically significant history of neurological, endocrine, cardiovascular,
pulmonary, hematological (e.g., thrombocytopenia, neutropenia, bleeding disorders),
immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.

3. Female subjects of non-childbearing potential must be at screening:
a. Post-menopausal defined as aged more than 50 years and amenorrhea for at least 12 months prior to dosing following cessation of all exogenous hormonal treatments.
b. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and having luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the
post-menopausal range for the institution.
c. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

4. Female subjects of childbearing potential must be willing to use an acceptable contraceptive method throughout the study. If local regulations deviate from the listed contraception methods and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the Informed Consent Form (ICF). Use of hormone replacement therapy and oral, implantable, transdermal, injectable, or intrauterine hormonal contraceptives is not allowed.

5. Female subjects of childbearing potential must not donate ova during the study and for at least 30 days after the last dose of study drug.

6. Male subjects who are not vasectomized for at least 3 months prior to dosing, and who are sexually active with a female partner of childbearing potential must be willing to use one of the following acceptable contraceptive methods from the first dose and for 90 days after the last dose.

7. Male subjects (including men who have had a vasectomy) with a pregnant partner must agree to use a condom from the first dose and for 90 days after the last dose.

8. Male subjects must be willing not to donate sperm from the first dose and for 90 days after the last dose.

9. Current non-smoker: no use of tobacco or nicotine products, including any smoking cessation nicotine-containing products (i.e., nicotine replacement therapy [patch, spray, inhaler, gum, lozenge, bupropion SR, clonidine and nortriptyline], e-cigarettes, etc.) for at least 3 months prior to screening and no prior heavy smokers will be allowed (heavy smoking defined as the equivalent of 25 or more cigarettes per day).

10. Able to understand the study procedures and provide signed informed consent to participate in the study.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive pregnancy test or lactating female subjects at screening or prior to dosing.

2. 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.

3. 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.

4. Subject with abnormal lung function defined by spirometry testing such: FEV1 < 80% of
predicted normal value OR FEV1/FVC ratio < 0.70 at screening.

5. History or current diagnosis of COPD, asthma, including childhood asthma, or bronchospasm at screening.

6. History of COVID-19 with unresolved respiratory symptoms and/or unresolved respiratory
findings, or any previous hospitalization due to COVID-19.

7. 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.

8. Known allergic reactions, hypersensitivity, or contraindications to DHE, other ergot derived products, or to any excipient in the formulation at screening.

9. 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.

10. 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).

11. 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.

12. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within
6 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
40%).

13. 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.

14. 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.

15. Positive urine cotinine test at screening or check-in.

16. 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.

17. 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.

18. 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.

19. 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.

20. Depot injection or implant for 3 months prior to dosing.

21. Any vaccine, including COVID-19 vaccine, within 14 days prior to dosing.

22. For Cohorts 1, 3 and 4 only: Inability to demonstrate the correct inhalation
manoeuvre as assessed via Clemente-Clarke In-Check Dial after training.

23. 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).

24. Any reason which, in the opinion of the Investigator, would prevent the subject from
participating in the study.

25. Presence of a known, or suspected, impairment of the immune system including, but not limited to, autoimmune disorders, immunosuppressant therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Dose-ranging
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
It is planned to enroll up to approximately 28 healthy adult males and females (7 per cohort) for participation in this study (considering a drop-out rate of about 10%), to achieve a minimum of 24 subjects (6 per cohort) with evaluable PK, safety, and tolerability data.
The proposed number of subjects is in line with the sample sizes commonly used in clinical studies of this nature and is considered sufficient to achieve the study objectives. No formal sample size calculation was performed for this Phase 1 study.


Statistical Methods used:

1. Individual PK parameters for DHE and 8’-OH-DHE will be calculated using non-compartmental methods and summarized using graphical displays and descriptive statistics for the PK population.

2. PK parameters may include, but not be limited to: Cmax, Tmax, AUC0-t, AUC0-inf, T½ el,
Kel, Cl/F, Vz/F, and residual area.

3. Relative BA with associated summary statistics will be provided for AUC0-inf, AUC0-t and Cmax.

4. Additional non-compartmental PK parameters may be calculated, and complementary analyses, such as compartmental modeling, may be performed if deemed necessary. PK parameters will be compared between Zephyr inhalation powder (1 mg, 2 mg, and 3 mg) and DHE IV using graphics, descriptive statistics, and if appropriate, formal statistical tests.

5. The power model approach will be performed on AUC0-t, AUC0-inf, and Cmax data to
assess the dose-proportionality. Suitable nonparametric techniques will be used for the statistical analyses of Tmax, T½ el and Kel.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
7/01/2024
Actual
8/01/2024
Date of last participant enrolment
Anticipated
4/03/2024
Actual
4/04/2024
Date of last data collection
Anticipated
11/03/2024
Actual
19/04/2024
Sample size
Target
28
Accrual to date
Final
28
Recruitment outside Australia
Country [1] 25780 0
New Zealand
State/province [1] 25780 0
Christchurch

Funding & Sponsors
Funding source category [1] 314860 0
Commercial sector/Industry
Name [1] 314860 0
Vectura Inc.
Country [1] 314860 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Syneos Health New Zealand Ltd
Address
TMF Group, Level 11, 41 Shortland Street, Auckland 1010
Country
New Zealand
Secondary sponsor category [1] 316854 0
None
Name [1] 316854 0
Address [1] 316854 0
Country [1] 316854 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313859 0
Health and Disability Ethics Committees (HDEC)
Ethics committee address [1] 313859 0
Ethics committee country [1] 313859 0
New Zealand
Date submitted for ethics approval [1] 313859 0
13/09/2023
Approval date [1] 313859 0
13/10/2023
Ethics approval number [1] 313859 0
2023 FULL 18562

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129586 0
Dr Alexandra Cole
Address 129586 0
New Zealand Clinical Research (NZCR), 264 Antigua Street, Central City, Christchurch, 8011
Country 129586 0
New Zealand
Phone 129586 0
+64033729477
Fax 129586 0
Email 129586 0
[email protected]
Contact person for public queries
Name 129587 0
Alexandra Cole
Address 129587 0
New Zealand Clinical Research (NZCR), 264 Antigua Street, Central City, Christchurch, 8011
Country 129587 0
New Zealand
Phone 129587 0
+64 03 3729477
Fax 129587 0
Email 129587 0
[email protected]
Contact person for scientific queries
Name 129588 0
Megan van den Akker
Address 129588 0
Syneos Health New Zealand Ltd, TMF Group, Level 11, 41 Shortland Street, Auckland 1010, New Zealand
Country 129588 0
New Zealand
Phone 129588 0
+61488073980
Fax 129588 0
Email 129588 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.