Calcitonin Gene-related Peptide Levels in Chronic Migraine

Study Overview
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Brief Summary
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Twenty patients will be enrolled in a 2-site, 7-month, double-blind study conducted to evaluate a reduction in headache days and attacks and calcitonin gene-related peptide (CGRP) levels in saliva following treatment with OnabotulinumtoxinA versus saline. Eligible patients will be randomized and receive injections of OnabotulinumtoxinA or Saline at Visit 1. Following 3 months plus a 1 month wash out, patients will receive cross-over injections at Visit 5. Patients will return for monthly visits and exit the study at Visit 8. Patients will collect saliva at monthly intervals and document in a daily headache diary throughout the study .

Detailed Description
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This double-blind study will evaluate reduction in number of headache days following treatment with OnabotulinumtoxinA versus Saline. Additionally, CGRP levels in saliva will be correlated with a reduction in headache attacks. At Visit 1, eligible subjects will be randomized 1:1 to receive injections of OnabotulinumtoxinA or Saline in an identical manner. Subjects will collect 3 saliva samples during each month of the 7 month study: 1 collection at Baseline headache level, 1 collection at onset of headache that is one degree worse than Baseline level that will be treated with acute therapy, and 1 collection at 2 hours following treatment. Subjects will document headache and headache symptoms in a daily diary and return to the clinic with diary and saliva samples at monthly visits. Following 4 months (including a 1 month washout after Visit 4), subjects will return at Visit 5 and receive cross-over injections. Subjects randomized to OnabotulinumtoxinA at Visit 1 will receive injections of Saline. Subjects randomized to saline at Visit 1 will receive injections of OnabotulinumtoxinA. Subjects will document headache and headache symptoms in a daily diary and return to the clinic with diary and saliva samples at monthly visits. At Visit 8, 3 months following re-injection at Visit 5, subjects will exit the study.

Official Title
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Calcitonin Gene-related Peptide (CGRP) Levels in the Pathogenesis of Chronic Migraine

Conditions
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Chronic Migraine

Intervention / Treatment
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* Drug: OnabotulinumtoxinA
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: must be outpatient, male or female, of any race, between 18 and 65 years of age. if female of childbearing potential must have negative pregnancy test result at Screening Visit and practice reliable method of contraception. A female is considered of childbearing potential unless she is post menopausal for at least 12 months prior to administration of study drug, without a uterus and/or both ovaries or has been surgically sterilized for at least 6 months prior to study drug administration. Reliable methods of contraception are: Complete abstinence from intercourse from 2 weeks prior to administration of the investigational product, throughout the study, and for a time interval (5 days) after completion or premature discontinuation from the study; or, History of bilateral tubal ligation; or, Sterilization of male partner; or, Implants of levonorgestrel; or, Injectable progestogen; or, Oral contraceptive (combination therapy with ethinyl estradiol plus a progestin) with a placebo week every 1-3 months; or, Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (not all IUD's meet this criterion) in use at least 30 days prior to study drug administration; or, Spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm); or, Any other barrier methods (only is used in combination with any of the above acceptable methods) in use at least 14 days prior to study drug administration; or, Any other methods with published data showing that the highest expected failure rate for that methods is less than 1% per year. must have history of chronic migraine (with or without aura) according to the criteria proposed by the Headache Classification Committee of the International Headache Society (IHS) for at least 3 months prior to enrollment. must be able to understand the requirements of the study including maintaining a headache Diary, and signing informed consent. must be in good general health as determined by investigator. if taking migraine preventive, must be on a stable dose of preventive medication for at least 3 months prior to screening. Exclusion Criteria: if female, is pregnant, planning to become pregnant during the study period, is breast feeding, or is of childbearing potential and not practicing a reliable form of birth control. has headache disorders outside IHS-defined chronic migraine definition. has evidence of underlying pathology contributing to their headaches. has any pathology of the salivary glands such as sialadenitis (e.g. Sjogren's syndrome, viral or bacterial sialadenitis) or condition or symptom that would alter the content of saliva. has any medical condition that may increase their risk with exposure to OnabotulinumtoxinA including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other significant disease that might interfere with neuromuscular function. has profound atrophy or weakness of muscles in the target areas of injection. has skin conditions or infections at any of the injection sites. has allergy or sensitivities to any component of the test medication. who in the opinion of the investigator, has active major psychiatric or depressive disorders including alcohol/drug abuse. meets International Headache Society criteria for Medication Overuse with opioid or butalbital containing products. is planning or requiring surgery during the study. has a history of poor compliance with medical treatment. is currently participating in an investigational drug study or has participated in an investigational drug study within the previous 30 days of the screening visit.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OnabotulinumtoxinA<br>Minimum dose of 155 international units (U) OnabotulinumtoxinA Purified Neurotoxin Complex administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas. | Drug: OnabotulinumtoxinA<br>* Minimum dose of 155 U OnabotulinumtoxinA Purified Neurotoxin Complex administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas. Subjects will continue to monitor headache symptoms with a headache diary and collect saliva samples as instructed. At investigator's discretion, additional 40 U OnabotulinumtoxinA Purified Neurotoxin Complex may be administered unilaterally or bilaterally, using follow-the-pain paradigm.<br>* Other names: Botox;|
| Placebo Comparator: Saline<br>155 U Saline administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas. | Drug: Saline<br>* 155 U Saline administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas. Subjects will continue to monitor headache using a headache diary and collect saliva samples as instructed. At investigator's discretion, additional Saline may be administered unilaterally or bilaterally, using follow-the-pain paradigm.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Headache Days Per Month From Baseline (BL) to Months 1 Through 7. | Baseline number of headache days per month collected historically at screening. Post-treatment number of headache days collected per month via diary. | Baseline (collected historically at screening) versus (vs.) Month (Mo) 1, Mo 2, Mo 3, Mo 4, Mo 5, Mo 6, and Mo 7 | 
| Change in Number of Headache Days Per Month From Baseline to Month 1 (M1), Month 1 to Month 2 (M2), and Month 2 to Month 3 (M3). | Baseline number of headache days per month collected historically at screening. Post-treatment number of headache days collected per month via diary. | Baseline (collected historically at screening) vs. Mo 1, Mo 1 vs. Mo 2, Mo 2 vs. Mo 3, Mo 3 vs. Mo 4, Mo 4 vs. Mo 5, Mo 5 vs. Mo 6, and Mo 6 vs. Mo 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inter-ictal (Baseline) Levels of Saliva Calcitonin Gene-related Peptide (CGRP) | CGRP Level collected each month when subject did not have a headache or was at lowest pain level of headache that month. | Baseline levels collected for OnabotulinumtoxinA and Saline treatment during Months 1 through 7 | 
| Saliva CGRP Levels for OnabotulinumtoxinA Responders (Reduction of Headache Days Greater Than 30%) vs. Non-responders and Saline | Saliva samples collected at Baseline (at no headache or lowest level of headache), at headache attack directly before taking rescue medication and 2 hours after treating with rescue medication. | For OnabotulinumtoxinA and Saline treatment months 1, 2 and 3 | 
| Changes Between Inter-ictal (Baseline) Levels Between Responders and Non-responders | Only cytokines with a mean densimetric value 1.65 times the background grey value in a minimum of 3 patients were considered detectable. These are reported below. Values normalized to positive control array spots after background subtraction: C5/C5a, CD40 Ligand, Granulocyte Colony Stimulating Factor (G-CSF), Growth Regulated Oncogene(GRO)-alpha, Soluble Intercellular Adhesion Molecule (sICAM)-1, Interferon gamma (IFN-y), Interleukin(IL)-1alpha, 1beta, 1ra, 8, 16, 17E, & 23, Interferon Gamma-Induced Protein 10 (IP-10), Interferon-inducible T cell alpha chemoattractant (I-TAC), Macrophage Migration Inhibitory Factor (MIF), Serpin E1, and Regulated Upon Activation Normal T-cell Expressed (RANTES) | For OnabotulinumtoxinA and Saline treatment months 1, 2 and 3 at Baseline level (inter-ictal) and at onset of headache that is one degree worse than Baseline level and that will be treated with acute therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Botox, OnabotulinumtoxinA, Chronic Migraine, Calcitonin Gene-Related Peptide, Saliva