A Study of M207 With Intranasal Zolmitriptan in Healthy Volunteers

This is a single-center, open-label, randomized, four-way crossover study to compare the pharmacokinetics, safety and tolerability of:

M207 3.8 mg administered to the upper arm to M207 3.8 mg administered to the thigh, particularly with respect to skin irritation (erythema, edema, bruising, bleeding):

M207 3.8 mg worn for 30 minutes on the upper arm to M207 3.8 mg worn for 1 hour on the upper arm; and M207 3.8 mg to intranasal zolmitriptan 2.5 mg.

Each subject will receive each of the four study treatments once, followed by in-clinic monitoring and extensive blood sample collection for pharmacokinetic analysis.

M207 application sites will be observed for erythema, edema, bruising, and bleeding at various timepoints throughout the study.

Dosing will occur approximately 48 hours apart, until completion of dosing in randomized order per the treatment sequence tables. Plasma samples from the dosing days will be sent to the analytical laboratory for analysis and tolerability for each of the dose levels will be summarized.

After completion of the four dosing days, subjects will be assessed one final time and dismissed from the study.

• A: M207 3.8mg, 30 min, upper arm (Drug), also known as A: Zolmitriptan patch, 3.8 mg, 30 min, upper arm: A: M207 3.8 mg administered as two 1.9 mg patches, 30 min wear time (upper arm application)
• B: M207 3.8 mg, 30 min, thigh (Drug), also known as B: Zolmitriptan patch 3.8 mg, 30 min, thigh: B: M207 3.8 mg administered as two 1.9 mg patches, 30 min wear time (thigh application)
• C: M207 3.8 mg, 1 hr, upper arm (Drug), also known as C: Zolmitriptan patch, 3.8 mg, 1 hour, upper arm: C: M207 3.8 mg administered as two 1.9 mg patches, 1 hour wear time (upper arm application)
• D:zolmitriptan nasal spray (Drug), also known as Zomig Nasal Spray: D: 2.5 mg/0.1 mL intranasal zolmitriptan

Primary outcomes

• Cmax [pre-dose, 2, 5, 10, 15, 20, 30, 45, 60, 90 minutes, 2, 4, 8, 12, 24 hours post-dose]: maximum observed plasma concentration

Secondary outcomes

• Adverse Events [24 hours]: number of subjects that experienced at least one adverse event
• t(1/2) [pre-dose, 2, 5, 10, 15, 20, 30, 45, 60, 90 minutes, 2, 4, 8, 12, 24 hours post-dose]: apparent half-life

Sex: All, ages: 18 Years to 50 Years, accepts healthy volunteers

Inclusion Criteria:

1. Women or men 18 to 50 years of age.
2. Good general health with no clinically significant abnormalities as determined by medical history, physical examination, complete blood count (CBC), blood chemistry, urinalysis, and ECG.
3. Negative urine drug and alcohol screens and negative serum pregnancy tests (for female subjects) at screening.
4. Consent of female subjects to use a medically effective method of contraception throughout the entire study period and for 30 days after the subject completes the study. Medically effective methods of contraception that may be used by the subject include abstinence, use of diaphragm and spermicide, intrauterine device (IUD), condom and vaginal spermicide, hormonal contraceptives (subjects must be stable on hormonal contraceptives for at least the prior 3 months), surgical sterilization, and post-menopausal (≥ 2 years of amenorrhea).
5. Ability to read, understand, and provide written informed consent that they understand the purpose of the study and procedures required for the study before enrolling in the study, and willingness to comply with all study procedures and restrictions.

Exclusion Criteria:

1. Evidence of significant history of hepatic, reproductive, gastrointestinal, renal, bleeding, or hematological disorders including coagulation, pulmonary, neurological, respiratory, endocrine, or cardiovascular system abnormalities (especially hypertension, peripheral vascular disease, coronary artery disease, transient ischemic attacks, 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. Any contraindication to zolmitriptan administration including:

   * History of coronary artery disease or coronary vasospasm
   * Symptomatic Wolf-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders
   * History of stroke, transient ischemic attack, or hemiplegic or basilar migraine
   * Peripheral Vascular Disease
   * Ischemic bowel disease
   * Uncontrolled hypertension
   * Any history of hepatic impairment
4. History of contact dermatitis or known dermatological disorders that would interfere with the study procedures or assessments
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 and over the counter medications other than the following:

   * Hormone Replacement Therapy (HRT)
   * Birth control pills, patches, injections, or implants (all hormonal contraceptives) are allowed provided the dose has been stable for at least one month prior to screening and may be continued throughout the study
   * Antihistamines
   * Intermittently used NSAIDS
   * Acetaminophen if medically necessary (not more than 2 g/day)
   * Exceptions may be allowed on a case by case basis
8. Subjects who have a known allergy or sensitivity to zolmitriptan or its derivatives or formulations
9. Known allergy or sensitivity to tapes, adhesives, or zolmitriptan
10. Regular or recent intake of prescription drugs, particularly drugs with an influence on blood pressure.
11. Use of any other investigational compound within one month of planned study drug dosing
12. On-going drug or alcohol abuse, or history of either deemed to be clinically significant by the investigator
13. Systolic BP (measured after remaining sitting for 5 minutes) greater than 140 mmHg and diastolic BP greater than 90 mmHg at screening
14. History of nasal pathology (e.g., polyps) or abnormal nasal exam
15. Body Mass Index (BMI) greater than 35 kg/m2
16. If, in the opinion of the investigator, the subject is not suitable for the study
17. Any positive urine drug screen result or alcohol breath test

Participant flow

Outcome results

• Cmax (Primary), Geometric mean, pg/mL: Treatment A 9180.9 +/- 4066.1; Treatment B 5925.9 +/- 2353.3; Treatment C 15224.3 +/- 12972.9; Treatment D 3758.3 +/- 1711.6
• Adverse Events (Secondary), Number, Participants: Treatment A 4; Treatment B 3; Treatment C 1; Treatment D 1
• t(1/2) (Secondary), Mean, hours: Treatment A 2.692 +/- 0.486; Treatment B 2.975 +/- 1.217; Treatment C 2.959 +/- 0.998; Treatment D 4.545 +/- 1.535

Adverse events

Time frame: 8 days

Other adverse events by term

• Study Protocol (PDF, 2018-09-12)
• Statistical Analysis Plan (PDF, 2019-01-05)

• Don Kellerman, Pharm.D., Study director, Zosano Pharma Corporation