Double-Blind Comparison of the Efficacy and Safety of C213 to Placebo for the Acute Treatment of Cluster Headaches

Inclusion Criteria:

1. Able to provide written informed consent
2. Women or men 18 to 65 years of age
3. Greater than 1-year history of episodic or chronic cluster headache with onset priorto 50 years of age. Diagnosis must comply with ICHD-3 (International Headache Society (IHS) diagnostic criteria). Diagnostic criteria must include a history of at least 5attacks not attributed to any other disorder that include all of the followingcriteria:
4. Severe or very severe unilateral orbital, supraorbital and/or temporal painlasting 45-180 minutes (average, when untreated)
5. Either or both of the following:
6. At least one of the following symptoms or signs, ipsilateral to the pain:
7. Conjunctival injection and/or lacrimation
8. Nasal congestion and/or rhinorrhea
9. Eyelid edema
10. Forehead and facial sweating
11. Miosis and or/ptosis
12. A sense of restlessness or agitation
13. Attacks have a frequency between one every other day and eight per day for morethan half of the time when the disorder is active.
14. Not better accounted for by another International Classification of HeadacheDisorders (ICHD) diagnosis
15. Cluster history during the 12-month period prior to the screening visit must include:
16. At least 1 cluster period
17. Averaging 2-6 headaches per day
18. Lasting at least 7 days
19. Subject can distinguish cluster headaches from other headaches (i.e., migraine andtension-type headaches)
20. Women of child-bearing potential must not be pregnant, must agree to avoid pregnancyduring the trial, and must use one of the following or be surgically sterilized:intrauterine device, or a hormonal contraceptive
21. Able to understand the operation of the electronic diary and able to apply the demostudy drug patch correctly.

Exclusion Criteria:

1. Contraindications to triptans
2. Use of any prohibited concomitant medications within 30 days of screening
3. History of hemiplegic migraine or migraine with brainstem aura
4. Participation in another investigational trial within 30 days or 5 half-lives ofinvestigational product (whichever is longer).
5. Previous M207/C213 exposure in a clinical trial
6. Subject has other significant pain problems that might confound the study assessmentsin the opinion of the investigator
7. Diagnosis of any malignant disease (other than adequately treated or excisednon-metastatic basal cell carcinoma or squamous cell carcinoma of the skin) within the 5 years prior to screening
8. History of unstable psychiatric illness requiring medication or hospitalization in the 12 months prior to study initiation
9. Subjects who have a known allergy or sensitivity to zolmitriptan or its derivatives orformulations
10. Subjects who have a known allergy or sensitivity to adhesions
11. Subjects who have skin lesions or tattoos covering the entire potential area(s) ofC213 application
12. Woman who are pregnant, breast-feeding or plan a pregnancy during this study
13. Clinically significant liver disease [Alanine Aminotransferase (ALT) > 150 U/L;Aspartate Aminotransferase (AST) > 130 U/L or bilirubin > 2x ULN]
14. Clinically significant kidney disease (eGFR < 60 ml/min / 1.73 m² or to creatinine > 1.5 x ULN)
15. Subject has clinically significant ECG findings, defined by:
16. ischemic changes (defined as > 1mm of down-sloping ST segment depression in atleast two contiguous leads)
17. Q-waves in at least two contiguous leads
18. clinically significant intra-ventricular conduction abnormalities (left bundlebranch block or Wolf-Parkinson-White syndrome)
19. clinically significant arrhythmias (e.g., current atrial fibrillation)
20. History of coronary artery disease (CAD), coronary vasospasm (including Prinzmetal'sangina), aortic aneurysm, peripheral vascular disease or other ischemic diseases (e.g., ischemic bowel syndrome or Raynaud's syndrome)
21. Three or more of the following CAD risk factors:
22. Current tobacco use
23. Hypertension (systolic BP > 140 or diastolic BP > 90) or receivinganti-hypertensive medication for treatment of hypertension
24. Hyperlipidemia - LDL > 159 mg/dL and/or HDL < 40 mg/dL (or on prescribedanti-cholesterol treatment)
25. Family history of premature coronary artery disease (CAD) (< 55 years of age inmale first-degree relatives or < 65 years of age in female first degreerelatives)
26. Diabetes mellitus
27. History of cerebral vascular accident (CVA), transient ischemic attacks (TIA), orseizures
28. History of concurrent illness that requires hospitalization within 30 days prior tostudy initiation
29. Any other household member currently participating in a C213 study or relative of sitestaff member
30. Any reason to believe that compliance with the study requirements and completion ofevaluations required for this study will not be possible
31. Any language barrier that, in the opinion of the Investigator, would precludecommunication and compliance with the study requirements
32. History or current abuse of or dependence on alcohol or drugs that would interferewith the results or adherence to study requirements
33. Any positive drug screens for phencyclidine (PCP), 3,4-methylenedioxy-methamphetamine (MDMA) (ecstasy), cocaine, and/or meth/amphetamine(s)
34. Current or planned use of hallucinogens (e.g. psilocybin) during the trial
35. Any clinically relevant abnormal findings in the physical exam, vital signs orlaboratory tests that, in the opinion of the Investigator, may put the subject at risk