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

Randomized, Double-Blind, Multi-Center, Parallel-Group Comparison of the Efficacy and Safety of the C213 (Zolmitriptan Microneedle System) to Placebo for the Acute Treatment of Cluster Headaches

This is a double-blind, placebo-controlled study. Subjects who meet the entry criteria will be randomized o receive one of three blinded treatments [C213 1.9 mg patch and placebo patch; C213 3.8 mg (1.9 mg x 2 patches), two placebo patches] on Day 1 and will have up to 48 weeks to confirm and treat a cluster headache. Subjects will self-administer the patches and respond to questions in the electronic diary (eDiary) until 1-hour post treatment administration.

This is a randomized, double-blinded, placebo-controlled study. Approximately 120 subjects who meet the entry criteria will be randomized 1:1:1 to receive one of three blinded treatments [C213 1.9 mg patch and placebo patch; C213 3.8 mg (1.9 mg x 2 patches), two placebo patches].

Qualified subjects will randomize to the double-blind treatment period at Day 1 and will have up to 48 weeks to confirm and treat a cluster headache. Using the eDiary to confirm they are experiencing a cluster headache, subjects will self-administer the patches and continue to respond to questions in the eDiary until 1-hour post treatment administration.

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 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:

   1. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 45-180 minutes (average, when untreated)

   2. Either or both of the following:

      1. At least one of the following symptoms or signs, ipsilateral to the pain:

         1. Conjunctival injection and/or lacrimation
         2. Nasal congestion and/or rhinorrhea
         3. Eyelid edema
         4. Forehead and facial sweating
         5. Miosis and or/ptosis

      2. A sense of restlessness or agitation

   3. 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.

   4. Not better accounted for by another International Classification of Headache Disorders (ICHD) diagnosis

4. Cluster history during the 12-month period prior to the screening visit must include:

   1. At least 1 cluster period
   2. Averaging 2-6 headaches per day
   3. Lasting at least 7 days

5. Subject can distinguish cluster headaches from other headaches (i.e., migraine and tension-type headaches)

6. 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

7. Able to understand the operation of the electronic diary and able to apply the demo study 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 of investigational 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 assessments in the opinion of the investigator

7. 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

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 or formulations

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) of C213 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:

    1. ischemic changes (defined as > 1mm of down-sloping ST segment depression in at least two contiguous leads)
    2. Q-waves in at least two contiguous leads
    3. clinically significant intra-ventricular conduction abnormalities (left bundle branch block or Wolf-Parkinson-White syndrome)
    4. clinically significant arrhythmias (e.g., current atrial fibrillation)

16. 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)

17. Three or more of the following CAD risk factors:

    1. Current tobacco use
    2. Hypertension (systolic BP > 140 or diastolic BP > 90) or receiving anti-hypertensive medication for treatment of hypertension
    3. Hyperlipidemia - LDL > 159 mg/dL and/or HDL < 40 mg/dL (or on prescribed anti-cholesterol treatment)
    4. Family history of premature coronary artery disease (CAD) (< 55 years of age in male first-degree relatives or < 65 years of age in female first degree relatives)
    5. Diabetes mellitus

18. History of cerebral vascular accident (CVA), transient ischemic attacks (TIA), or seizures

19. History of concurrent illness that requires hospitalization within 30 days prior to study initiation

20. Any other household member currently participating in a C213 study or relative of site staff member

21. Any reason to believe that compliance with the study requirements and completion of evaluations required for this study will not be possible

22. Any language barrier that, in the opinion of the Investigator, would preclude communication and compliance with the study requirements

23. History or current abuse of or dependence on alcohol or drugs that would interfere with the results or adherence to study requirements

24. Any positive drug screens for phencyclidine (PCP), 3,4-methylenedioxy-methamphetamine (MDMA) (ecstasy), cocaine, and/or meth/amphetamine(s)

25. Current or planned use of hallucinogens (e.g. psilocybin) during the trial

26. Any clinically relevant abnormal findings in the physical exam, vital signs or laboratory tests that, in the opinion of the Investigator, may put the subject at risk