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Trial registered on ANZCTR


Registration number
ACTRN12616000050459
Ethics application status
Approved
Date submitted
7/01/2016
Date registered
20/01/2016
Date last updated
16/07/2019
Date data sharing statement initially provided
16/07/2019
Date results information initially provided
16/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Crossover Comparison of the Tolerability and Pharmacokinetics of ZP-Zolmitriptan Intracutaneous Microneedle System with Oral Zolmitriptan and Subcutaneous (SC) Sumatriptan in Healthy Volunteers
Scientific title
Crossover Comparison of the Tolerability and Pharmacokinetics of ZP-Zolmitriptan Intracutaneous Microneedle System with Oral Zolmitriptan and SC Sumatriptan in Healthy Volunteers
Secondary ID [1] 288250 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Migraine 297181 0
Condition category
Condition code
Neurological 297399 297399 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In this study, ZP-Zolmitriptan will be compared to oral zolmitriptan and SC sumatriptan. ZP-Zolmitriptan is a microneedle patch system consisting of a disposable microneedle patch and a reusable applicator. The user applies the patch by pressing the applicator/patch ring assembly onto the skin site on the upper arm. The ZP applicator is designed to ensure that the same force is applied across different users.

Each of the 20 subjects will receive each of the treatments once (A-G) every 5 days i.e. 120 hours between dosing days.

In Part 1, each of the subjects will be randomly assigned to one of the five treatments (A-E) on the first dosing day. On the second dosing day, they will be randomly assigned to one of the remaining four treatments. On dosing days 3,4, and 5, they will be randomly assigned to one of the other remaining treatments until all five treatments (A-E) have been taken by each of the subjects. On any dosing day, for the 20 subjects, four will receive Treatment A, four will receive Treatment B, four will receive Treatment C, four will receive Treatment D, and four will receive Treatment E.

Treatment A: ZP-Zolmitriptan intracutaenous system MF 1663 0.48 mg
Treatment B: Two patches of ZP-Zolmitriptan intracutaenous system MF 1663 0.48 mg
Treatment C: ZP-Zolmitriptan intracutaenous system MF 1663 1.9 mg
Treatment D: Zolmitriptan 2.5 mg tablet
Treatment E: Sumitriptan Succinate 6.0 mg/0.5 mL for SC injection

In Part 2, all subjects will receive Treatment F (ZP-Zolmitriptan intracutaenous system MF 1663 1.9 mg x2).

Treatment F: Two patches of ZP-Zolmitriptan intracutaenous system MF 1663 1.9 mg

In Part 3, all subjects will receive Treatment G (ZP-Zolmitriptan 3.8 mg).

Treatment G: ZP-Zolmitriptan intracutaenous system MF 1790 3.8 mg

For each treatment, drug is administered once. Treatments B and F consist of two patches that should be applied on the same arm as quickly as possible. All drug administration and application is done by the site staff.

At the end of each dosing day, the safety data from the subjects will be evaluated. If tolerability is deemed to be acceptable by the Principal Investigator and sponsor representatives, a decision will be made to proceed to the next dosing day.

All ZP-Zolmitriptan Patch System components are to be used only in accordance with this protocol under the supervision of the Investigator. The Investigator will maintain detailed and verifiable records that document the receipt, storage, dispensing, and return of all ZP-Zolmitriptan Patch System components provided by Zosano Pharma. These records will include a listing of which study drug supplies were dispensed for particular subjects treated in the study, by whom, when, and the specific quantities dispensed and remaining at the completion of the subject’s investigational treatment. Reasons for departure from the expected dispensing and dosing regimen will also be documented. All leftover used and unused study patches should be retained for drug accountability auditing to be performed by Zosano Pharma or its representatives. At the conclusion of the study, the study drug accountability records must accurately reflect the receipt and final disposition of all study drug shipped to the site. Destruction or return of remaining used and unused drug supplies by the study site will occur only upon receipt of written authorization by Zosano Pharma or its representatives.
Intervention code [1] 293536 0
Treatment: Drugs
Comparator / control treatment
Zolmitriptan 2.5 mg oral
Sumatriptan 6.0 mg SC
Control group
Active

Outcomes
Primary outcome [1] 296948 0
Tolerability of ZP-Zolmitriptan Intracutaneous Microneedle systems. Tolerability will assessed through visual assessments of the application sites for erythema, edema, patch-related superficial punctuate bruising and bleeding. Adverse events are also recorded. The safety data, including AEs, laboratory data, vital signs, ECGs, concomitant medications, and reasons for withdrawal from study, will be listed and/or descriptively summarized by treatment dose and patch application subgroup.
Timepoint [1] 296948 0
At the end of each dosing day, the safety data from the subjects will be evaluated. If tolerability is deemed to be acceptable by the Principal Investigator and sponsor representatives, a decision will be made to proceed to the next dosing day.
Primary outcome [2] 296949 0
Pharmacokinetics of ZP-Zolmitriptan Intracutaneous Microneedle systems. Plasma zolmitriptan concentrations as a function of time following ZP-Zolmitriptan patch administration will be plotted and cross-compared among treatments. The following pharmacokinetic parameters will be calculated for each treatment - AUC0-t, AUC0-inf, AUC30min, Cmax, Tmax and t1/2.
Timepoint [2] 296949 0
Blood sample for pharmacokinetic analysis is collected prior to administering study drug, 2 min, 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 8 hr, 12 hr, 24 hours post dose administration.
Primary outcome [3] 296950 0
Determine the bioavailability of Zolmitriptan-ZP intracutaenous systems relative to a conventional release 2.5 mg Zolmitriptan tablet. Blood samples and analysed to calculate both mean and median values for each treatment.
Timepoint [3] 296950 0
Baseline, 2 min, 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 8 hr, 12 hr, 24 hours post dose administration.
Secondary outcome [1] 319754 0
Compare the pharmacokinetic profiles of Zolmitriptan-ZP Intracutaneous Microneedle systems (particularly Cmax) with oral zolmitriptan and SC sumatriptan. The following pharmacokinetic parameters will be calculated for each treatment - AUC0-t, AUC0-inf, AUC30min, Cmax, Tmax and t1/2.
Timepoint [1] 319754 0
Blood sample for pharmacokinetic analysis is collected prior to administering study drug, 2 min, 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 8 hr, 12 hr, 24 hours post dose administration.

Eligibility
Key inclusion criteria
1) Women or men 18 to 60 years of age
2) Absence of significant health issues
3) Systolic BP (measured after remaining supine for 5 minutes) inclusive of 90 and 160 mmHg and diastolic BP inclusive of 50 and 95 mmHg.
4) Body mass index (BMI) of less than or equal to 32 kg/m2
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) Evidence or significant history of hepatic, reproductive, gastrointestinal, renal, bleeding, or hematological disorders including coagulation, pulmonary, neurological, respiratory, endocrine, or cardiovascular system abnormalities (especially hypertension, coronary artery disease or cardiac rhythm abnormalities), psychiatric disorders, acute infection, or other conditions that would interfere with study participation or with the absorption, distribution, metabolism, or excretion of drugs.
2) Presence of two or more risk factors for cardiovascular disease (family history of premature heart disease, hyperlipidemia, or hypertension)
3) History of contact dermatitis or known dermatological disorders that would interfere with the study procedures or assessments
4) Known allergy or sensitivity to tapes, adhesives, or zolmitriptan
5) Planned participation in activities which cause inflammation, irritation, sunburn, lesions, or tattoos at the intended application sites from 2 weeks prior to screening through their last day of study participation
6) Use of warfarin within 1 month prior to the first dose or heparin within 1 week prior to study drug administration
7) Use of prescription medications other than the following:
a. Hormone Replacement Therapy (HRT)
b. Proton Pump Inhibitors (PPIs)
c. Antihistamines
d. Intermittently used NSAIDs
e. Exceptions may be allowed on a case by case basis by the sponsor.
8) History of epilepsy or other seizure disorder
9) History of tobacco usage within the past year or greater than 10 pack-years lifetime (1 pack-year = 1 pack every day for a year)
10) Female patients must not be pregnant. Women in child-bearing age must use an effective means of contraception.
11) Body weight less than 55 kg
12) Use of any other investigational compound within one month of planned study drug dosing
13) On-going drug or alcohol abuse, or history of either deemed to be clinically significant by the investigator
14) Subjects who, in the opinion of the investigator, should not participate in the study, or may not be capable of following the study schedule for any reason

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)
Allocation not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In Part 1, each of the subjects are randomly assigned one of the five treatments (A-E) on the first dosing day. On dosing days 2, 3, 4 and 5, participants are randomly assigned to one of the other remaining treatments until all five treatments (A-E) have been taken by each of the participant. On any dosing day, for the 20 subjects, four will receive Treatment A, four will receive Treatment B, four will receive Treatment C, four will receive Treatment D, and four will receive Treatment E. The randomised treatment assignment is presented in a computer-generated table in the protocol.

In Part 2, all subjects receive Treatment F.

In Part 3, ll subjects receive Treatment G.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
This is the first study Zosano is conducting with the ZP-Zolmitriptan product, therefore no specific planning information is available. In previous studies of Zosano intracutaenous products in healthy volunteers, a sample size of 20 was sufficient to provide directional information on tolerability, as well as clear-cut information on pharmacokinetics and pharmacodynamics.

All subjects who have been dosed will be included in the summaries of the descriptive statistics. Means will be shown for all subjects and for the group that completes all treatments. Drop-outs within a 24-hour period are not anticipated; however should they occur prior to 2 hours after patch application then additional eligible subjects will be enrolled.

Plasma zolmitriptan concentrations as a function of time following ZP-Zolmitriptan patch administration will be plotted and cross-compared among treatments. For each zolmitriptan patch treatment, the bioavailability relative to the comparator treatment (tablet) will be calculated. Both mean and median values for each treatment will be calculated.

All subjects who receive study drug and have at least one safety assessment will be included in the safety analyses. Verbatim AEs will be mapped to preferred term and body-organ system using MedDRA. The number and percentage of subjects reporting AEs will be summarized by AE preferred term and AE body-organ system. Scores of the visual assessments of the application sites will be presented by treatment group, including both mean values and cumulative fractions for each score.

Analyses may be performed to quantify the amount of drug remaining on the ZP-Zolmitriptan patch system and the amount of drug recovered from the skin of the subject following removal of each of the patches. In that case, a description of the disposition of the remaining drug will be presented. The results from analysis of residual zolmitriptan on the skin and the residual zolmitriptan on the used patches will provide a basis for the calculation of the total amount of drug delivered from each treatment.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 12492 0
3001 - Melbourne

Funding & Sponsors
Funding source category [1] 292628 0
Commercial sector/Industry
Name [1] 292628 0
Zosano Pharma, Inc.
Address [1] 292628 0
34790 Ardentech Court
Fremont, California 94555
Country [1] 292628 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Pharmaceutical Solutions Ltd
Address
Level 9 Avaya House, 123 Epping Road, North Ryde, NSW 2113
Country
Australia
Secondary sponsor category [1] 291346 0
None
Name [1] 291346 0
Address [1] 291346 0
Country [1] 291346 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294111 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 294111 0
The Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004
Ethics committee country [1] 294111 0
Australia
Date submitted for ethics approval [1] 294111 0
01/07/2015
Approval date [1] 294111 0
05/08/2015
Ethics approval number [1] 294111 0

Summary
Brief summary
Zolmitriptan is a 5HT1 agonist widely used for the treatment of migraine. Like other compounds in the triptan class, it has been shown to be effective and well-tolerated in placebo-controlled clinical trials. Zolmitriptan is available as a conventional release tablet (2.5 mg and 5.0 mg), a “fast melt” orally disintegrating tablet (2.5 mg and 5.0 mg) and a nasal spray (5.0 mg). The last two formulations were developed to potentially provide a more rapid onset of effect than the conventional release tablet, as speed of onset is an attribute that patients often cite as important in migraine relief products.

The bioavailability of zolmitriptan conventional release tablets has been found to be between 41 and 48% mainly due to first-pass metabolism. Therefore, a product which which avoided first-pass metabolism, the potential for food interaction and lesser absorption during a migraine could have advantages over existing zolmitriptan formulations. Additionally, an important consideration for a non-oral formulation of zolmitriptan is the high incidence of nausea that occurs during a migraine attack. In 60-70% of migraine attacks, nausea is a significant symptom that patients experience. Hence, a product that can be administered without using the gastrointestinal system (and not being susceptible to being vomited up) could be advantageous for the subject experiencing a migraine.

The aim of this study is to compare the pharmacokinetics of the parent compound and the metabolites, and tolerability of various doses of intracutaenous zolmitriptan doses to a standard oral dose (2.5 mg) of zolmitriptan. The study will provide preliminary information on the potential advantages of the ZP-Zolmitriptan system use for the treatment of migraine.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62510 0
Dr Jason Lickliter
Address 62510 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct, 89 Commercial Rd, Melbourne VIC 3001, Australia
Country 62510 0
Australia
Phone 62510 0
+61 3 9076 8960
Fax 62510 0
Email 62510 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 62511 0
Mrs Elaine Gent
Address 62511 0
Pharmaceutical Solutions
Level 1, The Levy Building, 20 Customs Street East, Auckland 1010
Country 62511 0
New Zealand
Phone 62511 0
+64 3 453 6563
Fax 62511 0
+64 9 379 8244
Email 62511 0
elaineg@pharmasols.com
Contact person for scientific queries
Name 62512 0
Dr Jason Lickliter
Address 62512 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct, 89 Commercial Rd, Melbourne VIC 3001, Australia
Country 62512 0
Australia
Phone 62512 0
+61 3 9076 8960
Fax 62512 0
Email 62512 0
j.lickliter@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary