Inclusion Criteria:

• A diagnosis of episodic cluster headache according to the International Classification of Headache Disorders 3rd edition
• A history of at least 2 prior headache bouts
• Onset of cluster headache before age 50 years
• Cluster headache attacks last a minimum duration of 45 minutes (if untreated)
• Evidence of signed informed consent (ICF) as described in the protocol, indicating compliance with the requirements and restrictions listed in the ICF and this protocol

Exclusion Criteria:

General exclusions

• Pregnant or breastfeeding patients.
• Inability to follow training instructions for use of nasal device.
• Unable to speak or read English.
• Unable to access the internet (for the Questionnaires / Case Report Forms).
• Females of childbearing potential, without the ability to use 2 acceptable methods of contraception to avoid pregnancy for up to 48 hours after each study drug administration, followed by 1 acceptable method for 28 days after the last administration of study treatment.
• Body mass index ≥ 35 kg/m2
• Prisoners or subjects who are involuntarily incarcerated.
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Have participated in another clinical research study with biological investigational agents (or other relevant agents) in the last 90 days.
• Positive drug screen for drugs of abuse at the investigator's discretion (e.g., positive amphetamines may be allowed when prescribed for an approved indication such as ADHD)

Past medical history exclusions:

• Co-existing disease or other characteristics that precludes appropriate diagnosis of cluster headache. Other headache and facial pain disorders are allowed as long as their attacks are distinguishable from cluster headache attacks
• Currently uncontrolled, unstable, or recently diagnosed cardiovascular or neurovascular disease, Raynaud's disease, uncontrolled hypertension, a history of myocardial infarction , Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), cardiac surgery, stroke or Transient Ischemic Attack (TIA) in the prior 6 months
• A known history of severe hepatic impairment, or diagnosis of Gilbert's Syndrome or any other active hepatic or biliary disorder
• A history of Human Immunodeficiency Virus (HIV).
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
• Response of "yes" to Question 4 or 5 for suicidal ideation, or any suicidal behavioral question on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening (or up to 1 year prior to the screening, as assessed in the medical history), or any indication of serious risk of suicide in the opinion of the investigator
• Psychiatric disorders that, in the opinion of the site investigator, would interfere with adherence to study requirements. This includes participants who have confirmed but untreated psychiatric disorders, or have psychiatric disorders that, in the opinion of the site investigator, would make them unable to undergo an ECG, have laboratory testing, or administer the medication at the appropriate time. "Psychiatric disorders" refers specifically to the following Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) classes of disorders: Schizophrenia Spectrum and Other Psychotic Disorders, Bipolar and Related Disorders, Depressive Disorders, Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related disorders, Dissociative Disorders, Somatic Symptom and Related Disorders, Feeding and Eating Disorders, Disruptive, Impulse-Control and Conduct Disorders, Substance-Related and Addictive Disorders, or Neurocognitive Disorders
• Hematologic or solid malignancy diagnosis within 5 years prior to the screening visit. Subjects with a history of localized basal cell or squamous cell skin cancer are eligible for the study if they are cancer-free prior to the screening visit

Nasal issues

• History of nasal surgery in the 6 months preceding the screening visit
• Nose piercings that might interfere with positioning of the study medication
• Evidence at screening of significant nasal conditions that may affect the administration or absorption of the nasal product (e.g., severe septum deviation, nasal deformity or blockage, inflammation, perforation, mucosal erosion or ulceration, polyposis, nasal trauma) as evaluated by the Investigator or medically qualified delegate
• Prominent nasal congestion or rhinorrhea associated with cluster headache attacks that, in the opinion of the study team, will interfere with ipsilateral absorption of a nasal spray

Laboratory and ECG abnormalities within 3 months of screening including:

• ECG abnormalities including Corrected QT interval (QTc) > 470 msec, Left Bundle Branch Block (LBB), Right Bundle Branch Block (RBB) with QRS>150 msec, or Intraventricular Conduction Defect with a QRS duration ≥ 150 msec
• History of stage 4 renal disease (creatinine clearance<30 mL/min)
• Any unacceptable findings on laboratory studies or physical examination including bilirubin >1.5x upper limit of normal(ULN), Neutrophil count ≤ 1000/uL (or equivalent), Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) >1.5x ULN
• Uncontrolled diabetes, defined as HbA1c ≥ 7.5%

Zavegepant-specific exclusions

• History of hypersensitivity reaction to zavegepant or to any of the components of zavegepant
• Previous use of zavegepant, or previously intolerant of zavegepant (if tried for noncluster headache reasons)
• Concomitant use of potent inhibitors/inducers of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) or Sodium/Taurocholate Cotransporting Polypeptide (NTCP) transporters including atazanavir, clarithromycin, cyclosporine, estrone sulfate, lopinavir, gemfibrozil, rifampin, or ritonavir