Calcitonin Gene-related Peptide Levels in Chronic Migraine - Full Text View

Sponsor:	Cady, Roger, M.D.
Collaborator:	Allergan
Information provided by (Responsible Party):	Cady, Roger, M.D.
ClinicalTrials.gov Identifier:	NCT01071096

Purpose

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 Botox versus placebo.

Eligible patients will be randomized and receive injections of Botox or placebo 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 .

Condition	Intervention	Phase
Chronic Migraine	Drug: Botox Drug: Placebo	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Calcitonin Gene-related Peptide (CGRP) Levels in the Pathogenesis of Chronic Migraine

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: Botox Headache Migraine

Drug Information available for: Calcitonin Onaclostox Salmon calcitonin

U.S. FDA Resources

Further study details as provided by Cady, Roger, M.D.:

Primary Outcome Measures:

Change in Number of Headache Days Per Month From Baseline (BL) to Months 1 Through 7. [ Time Frame: Baseline (collected historically at screening) versus (vs.) Month (Mo) 1, Mo 2, Mo 3, Mo 4, Mo 5, Mo 6, and Mo 7 ] [ Designated as safety issue: No ]
Baseline number of headache days per month collected historically at screening. Post-treatment number of headache days collected per month via diary.
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). [ Time Frame: 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 ] [ Designated as safety issue: No ]
Baseline number of headache days per month collected historically at screening. Post-treatment number of headache days collected per month via diary.

Secondary Outcome Measures:

Inter-ictal (Baseline) Levels of Saliva CGRP [ Time Frame: Baseline levels collected for BOTOX and Placebo treatment during Months 1 through 7 ] [ Designated as safety issue: No ]
CGRP Level collected each month when subject did not have a headache or was at lowest pain level of headache that month.
Saliva CGRP Levels for Responders (Reduction of Headache Days Greater Than 30%) vs. Non-responders to Botox and Placebo [ Time Frame: For BOTOX and Placebo treatment months 1, 2 and 3 ] [ Designated as safety issue: No ]
Due to the crossover nature of the study and an extended Botox effect, responders includes both Botox and Placebo. 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.
Changes Between Inter-ictal (Baseline) Levels and Attack Levels of Cytokine in Saliva Following Botox vs. Placebo Treatment Months 1, 3 and 7. [ Time Frame: For BOTOX and Placebo 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 ] [ Designated as safety issue: No ]
Cytokine levels >0.5 fluorescence units (FU). Values normalized to positive control array spots after background subtraction: Angiogenin, Brain-Derived Neurotrophic Factor(BDNF), Epidermal Growth Factor(EGF), Epithelial Neutrophil-Activating Protein(ENA)-78, Growth Regulated Oncogene(GRO), GRO-alpha, Interleukin(IL)-1alpha, 1beta, 2, 3, 6-8, & 10, Leukocyte Inhibitory Factor(LIF), Monocyte Chemoattractant Protein(MCP)-1 & 4, Neutrophil-Activating Protein(NAP)-2, Oncostatin M, Transforming Growth Factor(TGF)-beta3, Tissue Inhibitor of Metalloproteinases(TIMP)-1, Tumor Necrosis Factor(TNF)-alpha

Enrollment:	20
Study Start Date:	June 2010
Study Completion Date:	June 2011
Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Botox Minimum dose of 155 U Botulinum Toxin Type A Purified Neurotoxin Complex administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas.	Drug: Botox Minimum dose of 155 U Botulinum Toxin Type A 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 Botulinum Toxin Type A Purified Neurotoxin Complex may be administered unilaterally or bilaterally, using follow-the-pain paradigm. Other Name: Botulinum Toxin Type A Purified Neurotoxin Complex
Placebo Comparator: Placebo 0U Placebo administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas.	Drug: Placebo 0U Placebo 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 0 U Placebo may be administered unilaterally or bilaterally, using follow-the-pain paradigm.

Arms

Assigned Interventions

Active Comparator: Botox

Minimum dose of 155 U Botulinum Toxin Type A Purified Neurotoxin Complex administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas.

Drug: Botox

Minimum dose of 155 U Botulinum Toxin Type A 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 Botulinum Toxin Type A Purified Neurotoxin Complex may be administered unilaterally or bilaterally, using follow-the-pain paradigm.

Other Name: Botulinum Toxin Type A Purified Neurotoxin Complex

Placebo Comparator: Placebo

0U Placebo administered at 31 fixed-site, fixed-dose injections across seven specific head/neck muscle areas.

Drug: Placebo

0U Placebo 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 0 U Placebo may be administered unilaterally or bilaterally, using follow-the-pain paradigm.

Detailed Description:

This double-blind study will evaluate reduction in number of headache days following treatment with Botox versus placebo. 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 BOTOX or placebo 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 Botox at Visit 1 will receive injections of placebo. Subjects randomized to placebo at Visit 1 will receive injections of Botox. 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.

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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 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 ot BTX 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01071096

Locations

United States, Missouri
Clinvest
Springfield, Missouri, United States, 65807
United States, New York
Island Neurological Associates, P.C.
Plainview, New York, United States, 11803

Sponsors and Collaborators

Cady, Roger, M.D.

Allergan

Investigators

Principal Investigator:

Roger K Cady, MD

Clinvest

More Information

Publications:

Bellamy JL, Cady RK, Durham PL. Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache. 2006 Jan;46(1):24-33.

Cady RK, Vause CV, Ho TW, Bigal ME, Durham PL. Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. Headache. 2009 Oct;49(9):1258-66.

Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004 Jan;44(1):35-42; discussion 42-3.

Bruno PP, Carpino F, Carpino G, Zicari A. An overview on immune system and migraine. Eur Rev Med Pharmacol Sci. 2007 Jul-Aug;11(4):245-8. Review.

Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V. Plasma cytokine levels in migraineurs and controls. Headache. 2005 Jul-Aug;45(7):926-31.

Sarchielli P, Alberti A, Vaianella L, Pierguidi L, Floridi A, Mazzotta G, Floridi A, Gallai V. Chemokine levels in the jugular venous blood of migraine without aura patients during attacks. Headache. 2004 Nov-Dec;44(10):961-8.

Munno I, Marinaro M, Bassi A, Cassiano MA, Causarano V, Centonze V. Immunological aspects in migraine: increase of IL-10 plasma levels during attack. Headache. 2001 Sep;41(8):764-7.

Responsible Party:	Cady, Roger, M.D.
ClinicalTrials.gov Identifier:	NCT01071096 History of Changes
Other Study ID Numbers:	10-001AL
Study First Received:	February 17, 2010
Results First Received:	January 16, 2012
Last Updated:	May 3, 2012
Health Authority:	United States: Institutional Review Board

Keywords provided by Cady, Roger, M.D.:

Botox
Botulinum Toxin Type A
Chronic Migraine
Calcitonin Gene-Related Peptide
Saliva

Additional relevant MeSH terms:

Migraine Disorders
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Calcitonin Gene-Related Peptide
Salmon calcitonin
Calcitonin
Botulinum Toxins, Type A
Botulinum Toxins

Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Bone Density Conservation Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents
Anti-Dyskinesia Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on May 23, 2012