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

Inclusion Criteria

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

Exclusion Criteria

• Contraindications to triptans
• Use of any prohibited concomitant medications within 30 days of screening
• History of hemiplegic migraine or migraine with brainstem aura
• Participation in another investigational trial within 30 days or 5 half-lives of investigational product (whichever is longer).
• Previous M207/C213 exposure in a clinical trial
• Subject has other significant pain problems that might confound the study assessments in the opinion of the investigator
• Diagnosis of any malignant disease (other than adequately treated or excised non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin) within the 5 years prior to screening
• History of unstable psychiatric illness requiring medication or hospitalization in the 12 months prior to study initiation
• Subjects who have a known allergy or sensitivity to zolmitriptan or its derivatives or formulations
• Subjects who have a known allergy or sensitivity to adhesions
• Subjects who have skin lesions or tattoos covering the entire potential area(s) of C213 application
• Woman who are pregnant, breast-feeding or plan a pregnancy during this study
• Clinically significant liver disease [Alanine Aminotransferase (ALT) > 150 U/L; Aspartate Aminotransferase (AST) > 130 U/L or bilirubin > 2x ULN]
• Clinically significant kidney disease (eGFR 1.5 x ULN)
• Subject has clinically significant ECG findings, defined by:
• ischemic changes (defined as > 1mm of down-sloping ST segment depression in at least two contiguous leads)
• Q-waves in at least two contiguous leads
• clinically significant intra-ventricular conduction abnormalities (left bundle branch block or Wolf-Parkinson-White syndrome)
• clinically significant arrhythmias (e.g., current atrial fibrillation)
• History of coronary artery disease (CAD), coronary vasospasm (including Prinzmetal's angina), aortic aneurysm, peripheral vascular disease or other ischemic diseases (e.g., ischemic bowel syndrome or Raynaud's syndrome)
• Three or more of the following CAD risk factors:
• Current tobacco use
• Hypertension (systolic BP > 140 or diastolic BP > 90) or receiving anti-hypertensive medication for treatment of hypertension
• Hy