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Trial registered on ANZCTR


Registration number
ACTRN12617001381370
Ethics application status
Approved
Date submitted
22/09/2017
Date registered
28/09/2017
Date last updated
12/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Comparative Bioavailability Study of Dihydroergotamine Mesylate (DHE) Administered by I123 Precision Olfactory Delivery (PODTM) Device Nasal Spray, DHE for Injection (Intravenous), and Migranal® Nasal Spray in Healthy Male and Female adult Subjects
Scientific title
A Phase I, Three-Period, Three-Way, Randomized, Open-Label, Single-Dose, Cross-Over, Comparative Bioavailability Study of Dihydroergotamine Mesylate (DHE) Administered by I123 Precision Olfactory Delivery (PODTM) Device Nasal Spray, DHE for Injection (Intravenous), and Migranal® Nasal Spray in Healthy Adult Subjects
Secondary ID [1] 292938 0
Sponsor Protocol no: INP104-101
Universal Trial Number (UTN)
U1111-1202-4581
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Migraine headache 304826 0
Condition category
Condition code
Neurological 304128 304128 0 0
Other neurological disorders
Anaesthesiology 304217 304217 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Single dose 1.45 mg Dihydroergotamine Mesylate (DHE), administered by I123 Precision Olfactory Delivery (POD TM) device nasal spray (INP104). The 'wash out' period between each treatment will be 7days.
Intervention code [1] 299172 0
Treatment: Drugs
Intervention code [2] 299230 0
Treatment: Devices
Comparator / control treatment
Arm 2: Single dose 1 mg Dihydroergotamine Mesylate (D.H.E. 45), for intravenous injection
Arm 3: Single dose 2 mg Migranal Nasal Spray (dihydroergotamine mesylate)
Control group
Active

Outcomes
Primary outcome [1] 303448 0
1. DHE pharmacokinetics (PK) after a single dose of INP104, D.H.E.45 for Injection (IV) and Migranal Nasal Spray including plasma Cmax, Tmax, AUC0-t, kel, T1/2, AUC0-inf, and CL/F (CL for IV administration).
Timepoint [1] 303448 0
0 - 48 hr post dose (pre-dose, 5, 10, 20, 30, 40, 50 min; 1, 1,25, 1.5, 1.75, 2, 3, 4, 8, 12, 24, 36, 48 hr)
Secondary outcome [1] 338950 0
1. Safety and tolerability, including the assessment of physical examinations, electrocardiograms (ECGs), vital signs, clinical laboratory results, and adverse events .
Timepoint [1] 338950 0
7 days following dosing
ECG: pre-dose, 1, 4, 24, 48 hr
Vital signs: pre-dose, 5, 10, 20, 30, 40, 50 min; 1, 1,25, 1.5, 1.75, 2, 3, 4, 8, 12, 24, 36, 48 hr
Clinical laboratory results: pre-dose, 4, 24, 48 hr
Adverse events: pre-dose, 5, 10, 20, 30, 40, 50 min; 1, 1,25, 1.5, 1.75, 2, 3, 4, 8, 12, 24, 36, 48 hr
Secondary outcome [2] 338951 0
2. 8’-OH-DHE pharmacokinetics after a single dose of INP104, D.H.E. 45 for Injection (IV) and Migranal Nasal Spray including plasma Cmax, Tmax, AUC0-t, kel, T1/2, AUC0-inf, and CL/F (CL for IV administration).
Timepoint [2] 338951 0
0-48hrs post dose (pre-dose, 5, 10, 20, 30, 40, 50 min; 1, 1,25, 1.5, 1.75, 2, 3, 4, 8, 12, 24, 36, 48 hr)
Secondary outcome [3] 339150 0
3. Comparison of the subject acceptability of INP104 to that of DHE for Injection (IV) and Migranal Nasal Spray by completion of a sponsor designed questionnaire specifically for this study by all subjects
Timepoint [3] 339150 0
1 hour following administration of all 3 treatments

Eligibility
Key inclusion criteria
1. Adult male and females, 18 to 55 years of age (inclusive) at the time of screening.
2. Subjects must be in good general health, with no significant medical history (including migraine), have no clinically significant abnormalities on physical examination at screening, and/or before administration of the initial dose of investigational product.
3. Subjects must have a Body Mass Index (BMI) between 18 and 32 kg/m2, inclusive.
4. Subjects must have clinical laboratory values within normal range as specified by the testing laboratory, or assessed as not clinically significant by the Principal Investigator.
5. Negative urine drug screen/alcohol breath test at screening.
6. Subjects who are willing to refrain from smoking for the duration of the study.
7. Female subjects of childbearing potential must agree to use 2 methods of adequate contraception during the study and for 30 days after the last dose of investigational product. A female of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable, or mechanical contraception; women who are single; women whose husbands have been vasectomized or whose husbands have received or are utilizing mechanical contraceptive devices.
8. Male subjects and their partners must agree to use two forms of effective methods of contraception during the study and for 90 days after study completion.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Subjects with a recent history of migraine and its variants including hemiplegic migraine and basilar migrane. A recent history of migraine is defined as (a) current or past history of migraine with at least 1 attack in last 6 months or (b) those receiving antimigraine prophylaxis.
2. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).
3. Subjects who have ingested caffeine within 48 hours before admission on Day -1. Subjects must also agree to refrain from consumption of caffeinated drinks for 48 hours before admission of Days 7 and 14 (i.e. prior to each subsequent dosing), and throughout confinement.
4. Subjects with ischemic heart disease or subjects who have clinical symptoms or findings consistent with coronary artery vasospasm including Prinzmetal’s variant angina.
5. Subjects with hypertension, known peripheral arterial disease, Raynaud’s phenomenon, sepsis, history of vascular surgery or severely impaired hepatic or renal function
6. Subjects who have previously shown hypersensitivity to ergot alkaloids.
7. Females who are pregnant or lactating.
8. Subjects with any underlying physical, psychological or medical condition that, in the opinion of the Investigator, would make it unlikely that they would comply with the study requirements.
9. Use of any relevant prescription, over-the-counter medication (with the exception of oral contraceptives), foods (e.g. grapefruit juice) or supplements (including herbal) within 14 days of randomization [especially those affecting the Cytochrome P450 3A4 (CYP3A4) metabolic pathway].
10. Abnormal, clinically significant laboratory tests.
11. History or presence of alcoholism or drug abuse within the 2 years prior to the first investigational product administration.
12. Blood donation or significant blood loss within 60 days prior to the first investigational product administration.
13. Plasma donation within 7 days prior to the first investigational product administration.
14. Administration of IP in another trial within 30 days or 5 half-lives (whichever is longer) prior to the first investigational product administration.
15. Surgery within the past three months prior to the first investigational product administration as determined by the PI to be clinically relevant.
16. Failure to satisfy the PI of fitness to participate for any other reason (including under the influence of alcohol or drugs of abuse).
17. Active infection and/or use of macrolide antibiotics within 14 days prior to enrolment.
18. History of recurrent infections.
19. Serious local infection or systemic infection within 3 months requiring antibiotic treatment.
20. Any acute illness within 30 days prior to Day 1, unless the subject has recovered from recent minor ailments.
21. Any nasal congestion or physical blockage in either nostril or deviated nasal septum as determined by nasal examination.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Thirty-six subjects will be randomized (approximately equal numbers of men and women desired) to ensure at least 30 subjects complete all treatments. Treatment assignment will be randomised in a three-treatment, three-period balanced crossover study of 6 sequences.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
The sample size for this study was estimated to meet each of the following criteria:
1. The upper bound of the 90% confidence interval of the geometric ratios for AUC0-t, AUC0-inf and Cmax of DHE between INP104 and the reference product, DHE for Intravenous Injection is less than or equal to 125%, and
2. The lower bound of the 90% confidence interval of the geometric mean ratios for AUC0-t, AUC0-inf and Cmax of DHE between INP104 and the reference product, Migranal Nasal Spray is greater than or equal to 80%.
Assuming a highest possible intra-subject variability of 60 % (CV), a geometric mean ratio of INP104 to DHE for Injection IV of 80% and a geometric mean ratio of INP104 to Migranal Nasal Spray of 120%, a sample size of 30 subjects is deemed sufficient to achieve a power greater than 80% for the aforementioned criteria. Final study sample size was set at 36 subjects to ensure at least 30 subjects complete all three treatments.

All randomized subjects who receive any amount of any investigational product (Safety Population) will be included in the safety analyses.

All randomized subjects who receive all scheduled doses of IP and who provide a sufficient number of blood samples for non-compartmental analysis will be included in the PK analysis for each dosing (PK Analysis Population). Data will be summarized by administration method.

Safety and Tolerability:
Continuous safety data will be summarized with descriptive statistics (arithmetic mean, standard deviation (SD), median, minimum, and maximum) by administration method. Categorical safety data will be summarized with frequency counts and percentages by administration method.
The number of subjects experiencing treatment emergent AEs (TEAEs) and number of individual TEAEs will be summarized by administration method, system organ class and preferred term. TEAEs will also be summarized by worst severity and by relationship to investigational product.

Laboratory evaluations, vital signs assessments and ECG parameters will be summarized by administration method and protocol-specified collection time point. A summary of change-from-baseline at each protocol-specified time point by administration method will also be presented.

Changes in physical examinations will be listed for each subject and described in the text of the final report.

Prior and concomitant medications will be listed by subject and coded using the most current World Health Organization (WHO) drug dictionary.

Medical history will be listed by subject.

Scores from the subject product acceptability questionnaire will be summarized as appropriate.

Pharmacokinetics:
Descriptive Statistics
Individual DHE and 8’-OH-DHE concentration data will be listed and summarized by administration method with descriptive statistics (sample size [N], arithmetic mean, standard deviation [SD], median, minimum, maximum and geometric mean). Individual and mean DHE and 8’-OH-DHE concentration-time profiles for each administration method will also be presented graphically.
Plasma DHE and 8’-OH-DHE non-compartmental analysis (NCA) PK parameters for time of the maximum plasma drug concentration (Tmax), maximum observed drug plasma concentration (Cmax), area under the curve (AUC) from time zero to the time of the last measurable concentration
(AUC0-t), terminal elimination rate constant (kel), AUC from time zero to infinity (AUC0-inf), elimination half-life (t1/2), total apparent body clearance (CL/F; CL for IV administration) and apparent volume of distribution at the terminal phase (Vz/F; Vz for IV administration) (where data are sufficient for parameter determination) will be estimated. All subjects who have completed at least one treatment and have sufficient PK samples collected to generate PK parameters will be included in the descriptive statistics analyses.
Pharmacokinetic parameters will be listed for each individual and summarized by administration method using descriptive statistics (N, arithmetic mean, SD, coefficient of variation [CV%], median, minimum, maximum and geometric mean). Geometric mean will be calculated for AUC0-t, AUC0-inf, and Cmax.

Statistical Analysis
Analysis of variance (ANOVA) with effects for sequence, subject nested within sequence, period, and treatment will be performed on the ln-transformed DHE and 8’-OH-DHE AUC0-t, AUC0-inf and Cmax. Each ANOVA will include calculation of least squares mean (LSM), the difference between treatment LSM, and the standard error associated with the difference. Only subjects who have sufficient PK sample collection to generate the key PK parameters (AUC0-t, AUC0-inf and Cmax) for each administration method will be included in the ANOVA analysis.
Ratios of geometric means will be calculated using the exponentiation of the difference between treatment LSM from the analyses on the ln-transformed AUC0-t, AUC0-inf and Cmax. These ratios will be expressed as a percentage relative to the reference treatment (INP104 [test]/ DHE for IV injection (either D.H.E. 45 [reference] or Perrigo Pharmaceuticals [reference]) and INP104 [test]/ Migranal Nasal Spray [reference]). Consistent with the two one-sided tests for bioequivalence, 90% confidence intervals will be obtained for the ratio of geometric means for AUC0-t, AUC0-inf and Cmax.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/10/2017
Actual
27/10/2017
Date of last participant enrolment
Anticipated
6/11/2017
Actual
14/11/2017
Date of last data collection
Anticipated
27/11/2017
Actual
6/12/2017
Sample size
Target
36
Accrual to date
Final
38
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9079 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 17572 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297565 0
Commercial sector/Industry
Name [1] 297565 0
Impel NeuroPharma Inc
Country [1] 297565 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd
Address
Level 4, 88 Jephson St,
Toowong QLD 4066
Country
Australia
Secondary sponsor category [1] 296576 0
Commercial sector/Industry
Name [1] 296576 0
Impel NeuroPharma Inc
Address [1] 296576 0
915 East Pine Street
Suite 401-404
Seattle, Washington 98122
Country [1] 296576 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298660 0
Alfred Hospital Ethics Commitee
Ethics committee address [1] 298660 0
89 Commercial Road
Melbourne
VIC 3004
Ethics committee country [1] 298660 0
Australia
Date submitted for ethics approval [1] 298660 0
30/08/2017
Approval date [1] 298660 0
16/10/2017
Ethics approval number [1] 298660 0

Summary
Brief summary
This Phase I clinical trial will compare the bioavailability of dihydroergotamine mesylate (DHE) following a single dose administration of INP104 (DHE administered by I123 Precision Olfactory Delivery (POD TM) Device nasal spray to that of D.H.E. 45 for Injection (intravenous [IV]) and Migranal nasal spray in healthy adult subjects.
It is hypothesized that INP104 will address the current variability in nasal administration and give more reproducible dose delivery compared to Migranal nasal spray.
Blood concentrations of all three investigational products will be compared for 48 hours following dosing. The safety and tolerability of INP104 will be monitored throughout the study.
INP104 has been developed for the treatment of acute migraine headache. The device in which the drug will be delivered has been designed to deliver the medication to the upper nasal cavity with minimal variation in dose absorption, eg loss via dripping out of the nose or the dose being swallowed.
Approximately 36 participants in general good health (equal ratio of males and females desired) will be enrolled and will be allocated to receive 3 treatments in a randomised sequence. They will receive a single dose of INP104 via the POD device, a single dose of DHE via intravenous injection, and a single dose of Migranal Nasal Spray. There will be a wash out period where no treatment will be administered for at least 7 days in between each treatment. Participants are required to attend 3 inpatient periods and 1 final outpatient visit. Each participant will be in the study for up to 43 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77802 0
Dr Jason Lickliter
Address 77802 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct,
89 Commercial Road,
Melbourne
VIC 3004
Country 77802 0
Australia
Phone 77802 0
+61 3 9076 8960
Fax 77802 0
+61 3 9076 8911
Email 77802 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 77803 0
Dr Maria Jeleva
Address 77803 0
Impel NeuroPharma Inc
915 East Pine Street Suite 401-404
Seattle WA 98122
Country 77803 0
United States of America
Phone 77803 0
+1 206 568 1466
Fax 77803 0
Email 77803 0
jeleva@impelneuropharma.com
Contact person for scientific queries
Name 77804 0
Dr Maria Jeleva
Address 77804 0
Impel NeuroPharma Inc
915 East Pine Street Suite 401-404
Seattle WA 98122
Country 77804 0
United States of America
Phone 77804 0
+1 206 568 1466
Fax 77804 0
Email 77804 0
jeleva@impelneuropharma.com

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