A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study of Elismetrep (K-304) in the Treatment of Migraine

Inclusion criteria

• Be a male or female, age 18 to 70 years, inclusive, at the time of signing informed consent.
• Patient has greater than a one-year history of migraine with or without aura as defined by International Conference on Harmonization (IHS) criteria 1.1 and 1.2 and his/her migraines typically last between 4 to 72 hours, if untreated as documented in the patient's medical records from his/her treating physician and confirmed by the investigator.
• Patient has had ≥2 and ≤10 moderate or severe migraine attacks per month in each of the two months prior to screening (Visit 1).
• Meet the following requirements:

• Is a male OR
• Is a female who is of non-childbearing potential defined by at least 1 of the following criteria:
• Postmenopausal (aged >45 years and with a minimum of 12 months of spontaneous amenorrhea with a Screening serum follicle-stimulating hormone (FSH) level in the menopausal range established for the central laboratory.
• Post hysterectomy, bilateral oophorectomy or bilateral salpingectomy, based on the subject's recall of their medical history.

OR

• Is a female of reproductive potential and:
• agrees to remain abstinent from heterosexual activity*

*Abstinence can be used as the sole method of contraception if it is in line with the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ethics committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.

• or agrees to use (or have their partner use) a birth control method that is acceptable from the first dose of study drug until the end of trial (EoT) visit. Acceptable methods of birth control are:

• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

• oral
• intravaginal
• transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation:

• oral
• injectable
• implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomised partner
• sexual abstinence
• progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
• male or female condom with or without spermicide
• cap, diaphragm or sponge with spermicide
• A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods)

This condition is waived if the subject is proven to have no child-bearing potential (eg, hysterectomy).

• Patient voluntarily agrees to participate in the study by giving written informed consent.
• Patient is able to read, understand and complete the study questionnaires and diary.
• Be willing and able to comply with the study schedule of visits, all trial procedures and restrictions.
• Be willing to use their own personal, qualified smartphone to download study specific eDiary applications for use during the study.

Exclusion criteria

• Is a female who is pregnant, breast-feeding or intends to become pregnant during the planned course of the study. Note: Participants must have a negative serum pregnancy test (β-human chorionic gonadotropin (β-hCG)) performed by the central laboratory prior to enrollment in the study and negative urine pregnancy result at the randomization visit.

Migraine history-related

• Patient has difficulty distinguishing his/her migraine attacks from tension-type headaches.
• Patient has a history of predominantly mild migraine attacks or migraines that usually resolve spontaneously in less than two hours.
• Patient has more than 15 headache-days per month or has taken medication for acute headache on more than 10 days per month in any of the three months prior to screening (Visit 1).
• Patient has brainstem (a.k.a. basilar-type) or hemiplegic migraine headache, or retinal migraine.
• Patient was >50 years old at age of first migraine onset.
• Patient is taking migraine prophylactic medication where the prescribed daily dose has changed during the 3 months prior to screening (Visit 1) or anticipates any change during the study. Any withdrawal of preventive medications for the treatment of migraine should be completed at least 30 days prior to screening.

Medical history related

• Patient has, in the opinion of the investigator, other confounding pain syndromes, psychiatric conditions such as uncontrolled major depression, history of psychosis, dementia or significant neurological disorders other than migraine. [Patients who are currently being treated with non-prohibited medication for depression and symptoms are well controlled, in the opinion of the investigator, are eligible to participate in this study].
• Patient is at imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicidality Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Patients must be excluded if they report suicidal ideation with intent, with or without a plan (i.e., Type 4 or 5 on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months.
• Has a recent history (within the past 3 years of the screening visit) or current diagnosis or evidence of endocrine, hematological, immunological, renal, respiratory, neurologic, gastrointestinal, biliary, or genitourinary abnormalities or diseases that, per the investigator's judgement, may jeopardize the subject's safety or compliance with the protocol, or otherwise interfere with interpretation of efficacy and/or safety results.
• Has a history of malignant neoplasms within the past 5 years prior to screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed if they have received treatment and follow-up consistent with local standard of care.
• Patient history with current evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and cerebral ischemia. Patients with Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), percutaneous Coronary Intervention (PCI), cardiac surgery, stroke or transient ischemic attack (TIA) during the 6 months prior to screening.
• Has a history of human immunodeficiency virus disease.
• Patient has a history of gastric or small intestinal surgery (including gastric bypass surgery or banding but not including cholecystectomy or appendectomy) or has a disease that causes malabsorption.

Laboratory, vital sign, and electrocardiogram (ECG) related

• Has a positive test result at Screening for hepatitis B surface antigen (Ag), hepatitis C virus antibody.
• Has a screening estimated Glomerular Filtration Rate (eGFR) estimated with the Modification of Diet in Renal Disease (MDRD) equation of <45 ml/min/1.73 m2.
• Has a screening result for alanine aminotransferase or aspartate aminotransferase (ALT or AST) of >2.0X upper limit of normal (ULN) or total bilirubin >1.5X ULN at the Screening visit. Note: An isolated bilirubin >1.5X ULN is acceptable if bilirubin is fractionated, and direct bilirubin is within the laboratory normal range.
• Has a corrected QT interval to Fridericia's formula (QTcF) >450 milliseconds (msec) for males and >470 msec for females at screening.
• Has a mean value for triplicate seated systolic blood pressure >160 mmHg and/or diastolic blood pressure (BP) >95 mmHg measured after at least 5 minutes at rest at the Screening Visit.

Note: If a subject's BP is exclusionary on the first triplicate assessment at the Screening visit, they may have 1 repeat triplicate BP assessment at that visit after another rest of at least 10 minutes.

Medication use and substance abuse related

• Has known history of or suspected abuse of alcohol or recreational drugs at Screening.
• Has use of soft drugs (such as marijuana or any substances containing tetrahydrocannabinol (THC) or cannabidiol (CBD)) within 3 months prior to Screening, or hard drugs (such as cocaine, illicit narcotics/opiates) within 6 months prior to Screening.
• Has a positive drug screen at Screening. Note: If benzodiazepines are detected on the drug screen, this is not exclusionary if they are prescribed a benzodiazepine for a therapeutic purpose (e.g. for insomnia) and confirmatory documentation is obtained from the prescribing physician.
• Is currently in violation of study requirements for prohibited and permissible concomitant medications (not already specified in other criteria) or is anticipated to violate these requirements during study participation.
• Has any use of prescription opiate medications within 14 days of screening or any anticipated/potential use of opiates during study participation.
• History of use of ergotamine medications on greater than/equal 10 days per month on a regular basis for greater than/equal 3 months prior to screening.
• History of non-narcotic analgesic intake on greater than/equal 15 days per month for greater than/equal 3 months prior to screening.

Other

• Has known or suspected hypersensitivity to trial product(s) or related products.
• Has a history of multiple significant and/or any severe allergies (e.g., food, drug, latex allergy) or has had an anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food.
• Has any surgery scheduled for the duration of the trial.
• Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the Screening Visit; has a screening hemoglobin <11.0 g/dL (males) or <10.0 g/dL (females), or has a known hemoglobinopathy (e.g. sickle cell anemia, hemolytic anemia).
• Has previous participation in this trial. Participation is defined as signed informed consent.
• Has participated in any clinical trial of an approved or non-approved investigational biological medicinal product (e.g. antibody therapy) within 90 days of Screening or has participated in any clinical trial of an approved or non-approved investigational small molecule medicinal product within 30 days or 5 half-lives (whichever is longer) of Screening.
• Has any other disorder, unwillingness or inability, not covered by any of the other exclusion criteria, which in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol, or otherwise interfere with interpretation of efficacy and/or safety results.
• Is an employee or immediate family member (e.g., spouse, parent, child, sibling) of the Sponsor or study site.