A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with Episodic Cluster Headache

1. Male and female outpatients 18 to 65 years of age inclusive prior to signing informed consent.
2. At Visit 1, patients must have a history of episodic cluster headache and distinguished from chronic cluster headache as defined by IHS ICHD-3 beta (ICHD-3 2013).
3. At Visit 1, have a prior history of a cluster period lasting 6 weeks or greater.
4. At Visit 1, for patients currently in an active cluster period:
a. In opinion of investigator, would be expected to continue in the current period for at least another 6 weeks based on previous cluster period history.
b. They are not taking any excluded medications that require washout (see Criteria #9)
Note: patients not meeting criteria a and b must be a screen fail, but they may be
considered for re-screening
5. Not to be shared with potential patients: During SP II, have a baseline weekly cluster headache attack frequency (based on ePRO vendor eligibility report) preceding Visit 3 of:
a. minimum of 1 cluster headache attack every other day and at least 4 total attacks
b. maximum of 8 cluster headache attacks per day.
Note: a patient with 2 or more consecutive days without an attack during the baseline
assessment will be excluded. If a patient fails eligibility due to the occurrence of >8 cluster headache attacks per day, the patient may be considered for rescreen during their current cluster headache period, if, in the opinion of the investigator, the patient would be expected to continue in the current period for at least another 6 weeks based on previous cluster period history. If the patient is not expected to continue in the current period for another 6 weeks, the patient may be considered for rescreen during their next cluster headache period.
6. At Visit 1, are able to distinguish cluster headache attacks from other headaches (i.e. tension-type headaches, migraine).
7. Investigator judges the patient as reliable to follow all study procedures, keep all study visits, and be compliant with study requirements.
8. Women of child-bearing potential may participate in the study.
a. Women of child-bearing potential must test negative for pregnancy (based on a serum pregnancy test) at the time of enrollment and must agree to use a reliable method of birth control during the study and for 5 months following the last dose of investigational product.
b. Male patients agree to use a reliable method of birth control during the study and for 5 months following last dose of investigational product.
c. Women not of child-bearing potential are those who are infertile due to surgical sterilization (at least 6 weeks after surgical bilateral oophorectomy with or without hysterectomy or at least 6 weeks after tubal ligation) confirmed by medical history, or menopause.
9. Have not taken any of the following excluded medications or other treatments for cluster headache within the time frame noted:
a. use within 14 days prior to SP II of any of the following: dihydroergotamine or ergot derivatives; gabapentin; lithium; melatonin; methergine; topiramate; valproate; verapamil, opioids
b. use within 30 days prior to SP II of any of the following: systemic or injected corticosteroids; occipital nerve block; any ot her cranial or extracranial nerve block; any neurostimulation treatment.
Note: Patients are allowed to use only the following for acute/abortive treatment for their cluster headache attacks: high-flow oxygen; oral triptans, sumatriptan subcutaneous injection; sumatriptan nasal spray; zolmitriptan nasal spray; acetaminophen and NSAIDs.
10. Throughout the study (Informed Consent through Visit 9), agree to refrain from the use of drugs of abuse per United States Federal Guidelines (Schedule I) such as, but not limited to, cannabinoids, cannabis, psilocybin (mushrooms), LSD and 2-bromo-LSD.
11. Agree not to post any personal medical data related to the study or information related to the study on any website or social media site (for example, Facebook, Twitter, LinkedIn, Google+, etc.) until the entire trial has completed.
12. Have given written informed consent.
The planned patient population includes adult outpatients (18 to 65 years of age inclusive) who meet the International Headache Society*s International Classification of Headache Disorders, Third Edition, beta version (IHS ICHD-3-beta), diagnostic criteria for Episodic Cluster Headache. Please refer to Clinical Protocol page 27 for ICHD-3 beta diagnostic criteria for Cluster Headache.

13. Current enrollment in, or discontinuation within the last 30 days prior to Visit 1 from, a clinical trial involving any investigational drug or device, or concurrent enrollment in any other type of medical research judged not to be scientifically or medically compatible with this study.
14. Current use or any prior exposure to any CGRP antibody (including LY2951742), any antibody to the CGRP receptor, or antibody to nerve growth factor (NGF) including past participation in a clinical trial investigating CGRP, CGRP receptor, or NGF antibodies.
15. Patients who are taking other therapeutic antibodies or are expected to take during the course of the study (for example, adalimumab, infliximab, trastuzumab, bevacizumab, etc.). Prior use of other therapeutic antibodies is allowed if an adequate wash-out has occurred (>=5 half-lives) prior to SP II.
16. Any of the following headache-related or pain-related conditions are exclusionary*
a. Current diagnosis of Medication Overuse Headache as defined by ICHD-3 beta within 3 months prior to Visit 3. Note: daily triptan use for daily cluster headache attacks is allowed provided it is not resulting in an MOH of some other headache type.
b. Lifetime history of migraine variants that could implicate or could be confused with ischemia; specifically, hemiplegic (sporadic or familial) migraine, ophthalmoplegic migraine, and basilar-type migraine defined by ICHD-3 beta.
c. Are taking indomethacin and/or are suspected of having another distinct trigeminal autonomic cephalalgia such as hemicrania continua, paroxysmal hemicrania, or shortlasting unilateral neuralgiform headache attacks (SUNCT or SUNA).
d. Have other significant pain problem that might confound the study assessments in the opinion of the investigator.
17. Patients who have taken botulinum toxin type A or B, that was administered in the head or neck area, within 4 months of SP II for treatment of cluster headache or other disorders, or for cosmetic use.
18. Any (lifetime) history of deep brain stimulation.
19. Evidence of significant active or unstable psychiatric disease by medical history, such as bipolar disorder, schizophrenia, personality disorders, or other serious mood or anxiety disorders.
Note: Patients with major depressive disorder or generalized anxiety disorder, whose
disease state is considered stable and expected to remain stable throughout the course of
the study, in the opinion of the investigator, may be considered for inclusion if they are
not on excluded medication(s).
20. Are considered by the investigator to be at significant risk for suicide.
21. Women who are pregnant or nursing.
22. Any of the following cardiovascular-related conditions are exclusionary:
a. Prior to Visit 3 (randomization), have ECGs showing acute abnormalities of:
i. evidence of delayed ventricular repolarization including but not limited to a corrected QT (Bazett*s QT interval [QTcB]) interval >470 msec for women an >450 for men, and/or
ii. ii. evidence of atrioventricular (AV) depolarization of PR>220, or conduction delay of QRS>120, and/or
iii. iii. evidence of ischemia or any of the qualitative findings indicative of ST or J-point elevation, excluding those findings consistent with early repolarization (nonischemic).
b. History of myocardial infarction (MI), unstable angina (UA), percutaneous coronary intervention, coronary artery bypass graft, or deep vein thrombosis/pulmonary embolism within 6 months of screening, or have planned cardiovascular surgery or percutaneous coronary angioplasty.
c. Any lifetime history of vasospastic angina or stroke, or recent history (6 months) of emergency room visit for chest pain in which an ischemic or cardiac event was not ruled out.
d. Clinical evidence of peripheral vascular disease (e.g., Buerger*s Disease) or a diagnosis of Raynaud*s Phenomenon.
e. Have any history of intracranial or carotid aneurysm, intracranial hemorrhage, or stroke.
f. Have uncontrolled high blood pressure, characterized by systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg on 2 or more blood pressure assessments prior to Visit 3.
23. Any of the following medical conditions are exclusionary:
a. Have a lifetime history of seizures (except for childhood febrile seizures).
b. Have a history or presence of any other medical illness including but not limited to any cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or neurological disease, or any clinically significant laboratory abnormality, that in the judgment of the investigator, indicates a medical problem that would preclude study participation.
c. Prior to Visit 3, patients with an elevation of >=2X the upper limit of normal (ULN) for alanine aminotransferase (ALT), or >=1.5X ULN for total bilirubin (TBL) or alkaline phosphatase (ALP), may be retested.
d. Patients with a history of an intracranial tumor or head trauma must be discussed and judged not to indicate a medical problem that would preclude study participation by Lilly Medical prior to enrollment.
24. Any of the following drug- or alcohol- related conditions are exclusionary:
a. Patients who do not agree to abstain from alcohol consumption during SP II and SP III of the study. However, patients are encouraged to abstain from alcohol consumption throughout the entire study.
b. History of drug, alcohol, opioid, or barbiturate abuse/dependence within 1 year prior to SP II (excessive or habitual use as judged by the Investigator), or currently using drugs of abuse (including, but not limited to opioids, barbiturates and cannabis), or any prescribed or over-the-counter medication in a manner that the Investigator considers indicative of abuse/dependence. This exclusion criterion does not apply to tobacco and caffeine.
c. History of use of psilocybin (mushrooms), LSD, or 2-bromo-LSD within 2 months prior to SP II.
d. Have a positive urine drug screen (UDS) for any substances of abuse prior to randomization. Note: One retest may be performed if the UDS is positive for any prescribed substance or if, in the judgment of the investigator, there is an acceptable explanation for the positive result. The results of the retest must be negative at or prior to Visit 3. If a patient fails eligibility due to a positive UDS, the patient may be considered for rescreen during their current cluster headache period, if, in the opinion of the investigator, the patient would be expected to continue in the current period for at least another 6 weeks based on previous cluster period history. If the patient is not expected to continue in the current period for another 6 weeks, the patient may be considered for rescreen during their next cluster headache period.
25. Completion of less than 5 of 7 days of the daily ePRO diary entries during the baseline assessment (defined in Statistical Methods, Section 12) as evidence of inadequate compliance.
26. Employees of Lilly or investigational site personnel directly affiliated with this study and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
27. Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic proteins, or to LY2951742 or to any of the inactive ingredients.
28. Patients with a body mass index (BMI) >=40 kg/m2.