CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Menstrual Migraine Before and After Treximet

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Cady, Roger, M.D.
ClinicalTrials.gov Identifier:
NCT01329562
First received: March 17, 2011
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

The purpose of this study is to (1) evaluate pain-free efficacy of Treximet™ following treatment of menstrual migraine, (2) investigate levels of Calcitonin gene-related peptide (CGRP), estrogen, cortisol, vasoactive intestinal peptide (VIP), alpha (a)-amylase, Prostaglandin E2 (PGE2), Prostaglandin I2 (PGI2) and beta (ß)-endorphin in saliva before and after Treximet™, (3) evaluate efficacy of Treximet™ to return to baseline levels following treatment, and (4) correlate estrogen in saliva vs. urinary estradiol at mid-luteal, onset of menstrually-related migraine, and after successful treatment with Treximet™.


Condition Intervention Phase
Menstrual Migraine
Drug: Treximet
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Evaluation of CGRP, Estrogen, Cortisol, VIP, α-Amylase, PGE2, PGI2 and ß-Endorphin Levels in Saliva of Menstrual Migraine Patients Before and After Treatment With Treximet™

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Migraine Recurrence [ Time Frame: From onset of a single menstrual migraine episode to 24 hours post menstrual migraine treatment. ] [ Designated as safety issue: No ]

    Number of subjects either pain free or mild at 2 hours then pain level increases within 24 hours following treatment with Treximet versus (vs.) Placebo for 1 menstrual migraine.

    0-3 pain scale with 0=No Pain, 1=Mild, 2=Moderate,and 3=Severe.


  • Time to Pain Free [ Time Frame: From onset of 1 menstrual migraine headache until pain free. ] [ Designated as safety issue: No ]

    Duration of 1 menstrual migraine from time of treatment at menstrual migraine headache onset until pain free in Treximet vs. Placebo arms.

    0-3 pain scale with 0=No Pain, 1=Mild, 2=Moderate, and 3=Severe.


  • Biomarkers Measured at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment [ Time Frame: From Baseline until 2 hours post treatment of 1 menstrual migraine headache ] [ Designated as safety issue: No ]

    Vasoactive Intestinal Peptide (VIP), Prostaglandin E2 (PGE2), Cortisol, Prostaglandin I2 (PGI2), Estradiol, and β-endorphin** levels collected at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Treximet vs. Placebo arms for 1 menstrual migraine headache * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure. Calcitonin Gene-Related Peptide (CGRP) and α-amylase both have their own outcome measure reported individually.

    **β-endorphin levels were not assayed due to limitations on saliva sample volumes.


  • CGRP Measured at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment [ Time Frame: From Baseline until 2 hours post treatment for 1 menstrual migraine headache ] [ Designated as safety issue: No ]

    CGRP levels collected at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Treximet vs. Placebo arms for 1 menstrual migraine headache

    * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.


  • α-Amylase Measured at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment [ Time Frame: From Baseline until 2 hours post treatment for 1 menstrual migraine headache ] [ Designated as safety issue: No ]

    α-Amylase levels collected at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Treximet vs. Placebo arm for 1 menstrual migraine headache

    * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.


  • Biomarkers Measured at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free. [ Time Frame: From baseline to 24 hours post headache gone for 1 menstrual migraine headache. ] [ Designated as safety issue: No ]

    VIP, PGE2, Cortisol, PGI2, Estradiol, and β-endorphin** levels collected at Menstrual Migraine Headache Onset, Migraine Headache Free and 24 Hours Migraine Headache Free in Treximet vs. Placebo arm for 1 menstrual migraine headache.

    * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure. CGRP and α-amylase both have their own outcome measure reported individually.

    **β-endorphin levels were not assayed due to limitations on saliva sample volumes.


  • CGRP Measured at Menstrual Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free. [ Time Frame: From baseline to 24 hours post headache gone for 1 menstrual migraine headache ] [ Designated as safety issue: No ]

    CGRP levels collected at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Treximet vs. Placebo arm for 1 menstrual migraine headache.

    * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.


  • α-Amylase Measured at Menstrual Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free. [ Time Frame: From baseline to 24 hours post headache gone for 1 menstrual migraine headache ] [ Designated as safety issue: No ]

    α-Amylase levels collected at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Treximet vs. Placebo arm for 1 menstrual migraine headache

    * This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.


  • Correlation of Mean Estrogen Levels in Saliva and Urine Estradiol at Mid Luteal and at Menstrual Migraine Headache Free. [ Time Frame: From mid luteal phase and for the duration of 1 menstrual migraine headache and until headache free ] [ Designated as safety issue: No ]

    Correlation of mean estrogen levels in saliva and urine estradiol at mid luteal, menstrual migraine headache onset*, and at migraine headache free following treatment with Treximet vs. Placebo for 1 menstrual migraine headache

    *Urine estradiol levels were not collected at migraine onset, therefore; correlations could not be completed for that time point.



Secondary Outcome Measures:
  • Migraine Recurrence Responders vs Non-Responders [ Time Frame: From the onset of 1 menstrual migraine until 24 hours post treatment. ] [ Designated as safety issue: No ]

    Number of subjects either pain-free or mild at 2 hours then pain level increases within 24 hours following treatment in Treximet vs. Placebo arm for 1 menstrual migraine headache with Treximet vs. Placebo in responders* vs. non-responders.

    0-3 Pain Scale with 0=No Pain, 1=Mild, 2=Moderate, and 3=Severe

    *A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • Time to Pain-Free in Responders vs Non-Responders [ Time Frame: From the onset of 1 menstrual migraine headache until pain-free. ] [ Designated as safety issue: No ]

    Duration of time from treatment at menstrual migraine headache onset until pain-free in Treximet vs. Placebo arms in responders* vs. non-responders for 1 menstrual migraine.

    0-3 Pain Scale, with 0=No Pain, 1=Mild, 2=Moderate, and 3=Severe.

    *A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • Biomarkers Measured at Baseline, Menstrual Migraine Onset, and 2 Hours Post Treatment in Responders vs Non-Responders [ Time Frame: From Baseline until 2 Hours post menstrual migraine treatment for 1 menstrual migraine headache. ] [ Designated as safety issue: No ]

    VIP, PGE2, Cortisol, PGI2, Estradiol, and β-endorphin** levels collected for 1 menstrual migraine headache at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Treximet vs. Placebo arms in responders vs. non-responders***.

    *This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same unit of measure. CGRP and α-amylase both have their own outcome measure reported individually.

    **β-endorphin levels were not assayed due to limitations on saliva sample volumes.

    ***A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • CGRP Measured at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post-Treatment in Responders vs Non-Responders [ Time Frame: From Baseline until 2 Hours post menstrual migraine treatment for 1 menstrual migraine headache. ] [ Designated as safety issue: No ]

    CGRP levels collected for 1 menstrual migraine headache at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post-Treatment in Responders vs Non-Responders**.

    *This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.

    **A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • α-Amylase Measured at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Responders vs Non-Responders [ Time Frame: From Baseline until 2 hours post treatment of 1 menstrual migraine headache. ] [ Designated as safety issue: No ]

    α-Amylase levels collected at Baseline, Menstrual Migraine Headache Onset, and 2 Hours Post Treatment in Responders vs Non-Responders*.

    *A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • Biomarkers Measured at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders [ Time Frame: From Baseline for the duration of 1 menstrual migraine headache, an estimated 7 days ] [ Designated as safety issue: No ]

    VIP, PGE2, Cortisol, PGI2, Estradiol, and β-endorphin** levels collected for 1 menstrual migraine headache at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders***.

    *This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure. CGRP and α-amylase both have their own outcome measure reported individually.

    **β-endorphin levels were not assayed due to limitations on saliva sample volumes.

    ***A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment. A non-responder is one that fails to meet the responder criteria.


  • CGRP Measured at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders [ Time Frame: From Baseline to 24 hours post headache gone for 1 menstrual migraine. ] [ Designated as safety issue: No ]

    CGRP levels collected for 1 menstrual migraine headache at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders**.

    *This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.

    **A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • α-Amylase Measured at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders [ Time Frame: From Baseline from 24 hours post migraine gone for 1 menstrual migraine. ] [ Designated as safety issue: No ]

    α-Amylase levels collected for 1 menstrual migraine at Menstrual Migraine Headache Onset, Migraine Headache Free, and 24 Hours Migraine Headache Free in Responders vs Non-Responders**.

    *This endpoint was separated into 3 outcome measures as all biomarkers were not reported in the same units of measure.

    **A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.


  • Correlation of Mean Estrogen Levels in Saliva and Urine Estradiol at Mid-Luteal and at Menstrual Migraine Headache Free in Responders vs Non-Responders [ Time Frame: From mid luteal phase and for the duration of 1 menstrual migraine until headache free. ] [ Designated as safety issue: No ]

    Correlation of mean estrogen levels in saliva and urine estradiol at mid-luteal, menstrual migraine headache onset* and at migraine headache free following treatment in responders vs. non-responders**.

    *Urine estradiol levels were not collected at migraine onset, therefore; correlations could not be completed for that time point.

    ***A responder is defined as those who at the time of two hours post treatment reported mild or no pain. Additionally, these subjects could not have taken a rescue medication or have a pain level increase within 24 hours post treatment.

    A non-responder is one that fails to meet the responder criteria.



Enrollment: 41
Study Start Date: May 2011
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Treximet

Subjects randomized to Group A will be provided with 1 tablet of Treximet to be taken at onset of menstrual migraine headache pain.

All subjects will be provided with 1 tablet of Treximet for treatment of persistent or recurring headache between 2 and 24 hours following treatment with study medication at headache onset.

Drug: Treximet
Tablet for oral administration contains sumatriptan 85mg / naproxen sodium 500mg.
Other Name: Sumatriptan/Naproxen Sodium
Placebo Comparator: Placebo

Subjects randomized to Group B will be provided with 1 tablet of placebo to be taken at onset of menstrual migraine headache pain.

All subjects will be provided with 1 tablet of Treximet for treatment of persistent or recurring headache between 2 and 24 hours following treatment with study medication at headache onset.

Drug: Placebo
A placebo tablet matching Treximet for oral administration.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subject

  1. is female between the ages of 18-45 and, if of child-bearing potential, has a negative pregnancy test (urine or serum) at screen, and agrees to one of the following:

    • 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,
    • History of bilateral tubal ligation
    • 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 IUDs meet this criterion); or,
    • Spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm); or,
    • Any other barrier methods (only if used in combination with any of the above acceptable methods); or,
    • Any other methods with published data showing that the highest expected failure rate for that method is less than 1% per year.
  2. is formally diagnosed with International Classification of Headache Disorders (ICHD) menstrual migraine
  3. has regular and predictable monthly menstrual cycles within a range of 22-32 days for the past 3 cycles.
  4. has fewer than 15 headache days per month in past 3 months
  5. has headache that, if left untreated, would have at least 1 symptom of migraine (nausea, vomiting, photophobia, or phonophobia) or respond to a triptan or ergotamine-containing medication with at least 50% of headaches
  6. has a history of reliably predicting menstrual migraine headache onset at least 70% of the time
  7. is medically stable as determined by the Investigator
  8. if taking any concomitant medications, is on a stabilized dosage at the discretion of the investigator
  9. is able to understand and communicate intelligibly with the study observer
  10. is able to take oral medication, adhere to the medication regimens and perform study procedures
  11. is able to read and comprehend written instructions and be willing to complete all procedures and assessments required by this protocol
  12. is able to demonstrate the willingness to participate by signing and understanding an informed consent after full explanation of the study

Exclusion Criteria:

Subject

  1. has a history of serotonin syndrome.
  2. has any medical condition that, in the opinion of the investigator, could alter the response to study medication or confound the results of the study (ie. pathology of the salivary glands such as viral or bacterial sialadenitis or obstructive sialadenitis or Sjögren's Syndrome)
  3. is of childbearing potential and not using adequate contraceptive measures
  4. has history of retinal, basilar or hemiplegic migraine, cluster headache, or secondary headaches (such as due to trauma, infection, alterations of homeostasis, ear, nose and throat (ENT) or psychiatric disorders, cranial or cervical disorders or neuralgias)
  5. in the investigator's opinion, is likely to have unrecognized cardiovascular or cerebrovascular disease (based on history or the presence of risk factors including but not limited to, hypertension, hypercholesterolemia, smoker, obesity, diabetes, or family history of coronary artery disease)
  6. has blood pressure equal to or greater than 160/90 millimeters of mercury (mmHg) in 2 out of 3 blood pressure (BP) measurements at screening or is taking any angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
  7. has a history of significant congenital heart disease, cardiac arrhythmias requiring medication, or a history of a clinically significant electrocardiogram abnormality that, in the investigator's opinion, contraindicates participation in this study
  8. has evidence or history of any ischemic vascular diseases including: ischemic heart disease, ischemic abdominal syndromes, peripheral vascular disease or Raynaud's Syndrome, or signs/symptoms consistent with any of the above
  9. has evidence or history of central nervous system pathology including stroke and/or transient ischemic attacks (TIAs), epilepsy or structural brain lesions which lower the convulsive threshold; or has been treated with an antiepileptic drug for seizure control within 5 years prior to screening
  10. has a history of impaired hepatic or renal function that, in the investigator's opinion, contraindicates participation in this study
  11. has hypersensitivity, intolerance, or contraindication to the use of any triptan, non-steroidal anti-inflammatory drug (NSAID) or aspirin (including all sumatriptan and naproxen preparations) or has nasal polyps and asthma
  12. is currently taking, or has taken in the previous three months, a migraine prophylactic medication containing methysergide; or is taking a migraine or menstrual migraine prophylactic medication that is not stabilized (eg. Perimenstrual use of triptans and estradiol patches)
  13. has a recent history of regular use of opioids or barbiturates for treatment of their migraine headache and/or other non-migraine pain or any medication overuse that in the opinion of the investigator has exacerbated or contributed to the current headache pattern of the subject. Overuse is defined as an average of 10 days per month over the last 6 months.
  14. has taken, or plans to take, a monoamine oxidase inhibitor (MAOI), including herbal preparations containing St. John's Wort (Hypericum perforatum), anytime within the 2 weeks prior to screening through 2 weeks post final study treatment.
  15. is currently taking and plans to continue an oral steroid any time from screening through onset of menses that will be treated with study medication (at the discretion of the investigator)
  16. has history of any bleeding disorder or is currently taking any anti-coagulant or any antiplatelet agent.
  17. has evidence or history of any gastrointestinal surgery or gastrointestinal (GI) ulceration or perforation in the past six months, gastrointestinal bleeding in the past year; or evidence or history of inflammatory bowel disease
  18. is pregnant, actively trying to become pregnant, or breast feeding
  19. has evidence of alcohol or substance abuse within the last year or any concurrent medical or psychiatric condition which, in the investigator's judgment, will likely interfere with the study conduct, subject cooperation, or evaluation and interpretation of the study results, or which otherwise contraindicates participation in this clinical trial.
  20. has participated in an investigational drug trial within the previous four weeks or plans to participate in another study at any time during this study.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01329562

Locations
United States, Missouri
Clinvest
Springfield, Missouri, United States, 65807
United States, Ohio
University Internal Medicine Associates, Inc.
Cincinnati, Ohio, United States, 45267-0535
Sponsors and Collaborators
Cady, Roger, M.D.
GlaxoSmithKline
Investigators
Principal Investigator: Roger K Cady, MD Clinvest
  More Information

Publications:
Responsible Party: Cady, Roger, M.D.
ClinicalTrials.gov Identifier: NCT01329562     History of Changes
Other Study ID Numbers: 114680
Study First Received: March 17, 2011
Results First Received: October 8, 2013
Last Updated: March 11, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Cady, Roger, M.D.:
Menstrual migraine
Menstrually-related migraine
Treximet
CGRP
calcitonin gene-related peptide

Additional relevant MeSH terms:
Migraine Disorders
Headache Disorders, Primary
Headache Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Estrogens
Naproxen
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Gout Suppressants
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Central Nervous System Agents

ClinicalTrials.gov processed this record on September 30, 2014