- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00451204
A Combination Trial of Copaxone Plus Estriol in Relapsing Remitting Multiple Sclerosis (RRMS) (Estriol-MS)
May 10, 2016 updated by: Rhonda Voskuhl, University of California, Los Angeles
A Combination Trial of Copaxone Plus Estriol in RRMS
This is a double-blinded, placebo controlled study of estriol pills versus placebo pills in relapsing remitting multiple sclerosis.
The study treatment will be an added on to Copaxone injections in all subjects.
The primary outcome measure is a reduction in relapses.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
Detailed Description
Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy.
This proposal will establish whether oral treatment with estriol, the major estrogen of pregnancy, induces a decrease in relapses in relapsing remitting multiple sclerosis (RRMS) subjects when used in combination with injectable Copaxone.
Previously, in a pilot study, it has been demonstrated that treatment of RRMS subjects with oral estriol for six months resulted in a significant reduction in gadolinium enhancing lesions on serial brain MRIs (Annals of Neurology, 2002; 52:421-428) and caused a favorable shift in immune responses (Journal of Immunology, 2003; 171:6267-6274).
This is an add-on study aiming to extend these previous findings by treating longer and focusing on clinical outcomes.
The combination of Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a double blind trial.
The duration of treatment will be two years and the primary outcome measure will be relapse rate.
Other outcomes will include disability measures and brain MRI outcomes.
Safety measures (blood tests and gynecologic evaluations) will also be followed and correlations will be made between serum estriol levels with efficacy and safety.
The overall goal of this study will be the development of a new oral treatment, estriol, for RRMS.
Study Type
Interventional
Enrollment (Actual)
158
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Montreal, Canada
- Montreal Neurological Institute
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Arizona
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Scottsdale, Arizona, United States, 85259
- Mayo Clinic
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California
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Los Angeles, California, United States, 90095
- University of California, Los Angeles
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Colorado
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Aurora, Colorado, United States, 80045
- University of Colorado
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Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago
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Kansas
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Kansas City, Kansas, United States, 66160
- University of Kansas
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Maryland
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Baltimore, Maryland, United States, 21287-6965
- Johns Hopkins University
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Minnesota
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Minneapolis, Minnesota, United States, 55455
- University of Minnesota
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Missouri
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Saint Louis, Missouri, United States, 63110
- Washington University
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New Hampshire
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Lebanon, New Hampshire, United States, 03765
- Dartmouth Medical School
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New Jersey
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New Brunswick, New Jersey, United States, 08901
- UMDNJ-Robert Wood Johnson Medical Center
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New Mexico
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Albuquerque, New Mexico, United States, 87131
- University of New Mexico
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Ohio
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Columbus, Ohio, United States, 43221
- Ohio State University
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- University of Pennsylvania
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Texas
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Dallas, Texas, United States, 75390-8575
- University of Texas Southwestern
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Utah
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Salt Lake City, Utah, United States, 84158
- Western Institute for Biomedical Research
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 50 years (Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
Female
Description
Inclusion Criteria:
- Diagnosis of relapsing remitting multiple sclerosis
- At least one relapse in the last two years
Exclusion Criteria:
- Patients treated in the past with total lymphoid irradiation, monoclonal antibody, T cell vaccination, cladribine, bone marrow transplantation, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, cyclosporin or Tysabri
- Clinically significant diseases other than multiple sclerosis
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: Estriol plus Copaxone injections QD
Estriol Capsules (daily) plus Copaxone injections (daily).
Progestin capsules given for 2 weeks every 3 months to avoid unopposed estrogens.
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Estriol 8 mg capsule, once per day, duration of treatment is 2 years
Other Names:
Injection, once a day, all subjects
Other Names:
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Placebo Comparator: Placebo plus Copaxone injections QD
Placebo Capsules (daily) plus Copaxone injections (daily).
A second placebo capsule given for 2 weeks every 3 months.
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Injection, once a day, all subjects
Other Names:
Placebo capsule, once a day, treatment duration is 2 years
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Confirmed Relapse, Annualized Relapse Rate
Time Frame: 24 months
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A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
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24 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Relapse Event, Annualized Relapse Rate
Time Frame: 24 months
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Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
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24 months
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Confirmed Relapse, Probability of First Relapse
Time Frame: 24 months
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24 months
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Relapse Event, Probability of First Relapse Event
Time Frame: 24 months
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24 months
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Confirmed Relapse, Annualized Relapse Rate
Time Frame: 12 months
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A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
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12 months
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Relapse Event, Annualized Relapse Rate
Time Frame: 12 months
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Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
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12 months
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Investigators
- Study Director: Rhonda Voskuhl, M.D., University of California, Los Angeles (UCLA), Los Angeles, CA
- Principal Investigator: Anne Cross, M.D., Washington University, Saint Louis, MO
- Principal Investigator: Elliot Frohman, M.D., University of Texas, Southwestern, Dallas, TX
- Principal Investigator: Suhayl Dhib-Jalbut, M.D., Robert Wood Johnson Medical School, UMDNJ, New Brunswick, NJ
- Principal Investigator: Michael Racke, M.D., Ohio State University
- Principal Investigator: Anthony Reder, M.D., University of Chicago
- Principal Investigator: John Rose, M.D., Western Institute for Biomedical Research, Salt Lake City, UT
- Principal Investigator: Barbara Giesser, M.D., University of California, Los Angeles (UCLA), Los Angeles, CA
- Principal Investigator: John Ratchford, M.D., Johns Hopkins, Baltimore, MD
- Principal Investigator: Sharon Lynch, M.D., University of Kansas
- Principal Investigator: Gareth Parry, M.D., University of Minnesota
- Principal Investigator: Dean Wingerchuk, M.D., Mayo Clinic
- Principal Investigator: John Corboy, M.D., University of Colorado, Denver
- Principal Investigator: Corey Ford, M.D., University of New Mexico, Albuquerque
- Principal Investigator: Dina Jacobs, M.D., University of Pennsylvania
- Principal Investigator: Lloyd Kasper, M.D., Dartmouth University, Lebanon, NH
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, Shattuck DW, Hull L, Wang HJ, Elashoff RM, Swerdloff RS, Voskuhl RR. Testosterone treatment in multiple sclerosis: a pilot study. Arch Neurol. 2007 May;64(5):683-8. doi: 10.1001/archneur.64.5.683.
- Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu TC, Voskuhl RR. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 2002 Oct;52(4):421-8. doi: 10.1002/ana.10301.
- Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003 Dec 1;171(11):6267-74. doi: 10.4049/jimmunol.171.11.6267.
- Morales LB, Loo KK, Liu HB, Peterson C, Tiwari-Woodruff S, Voskuhl RR. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis. J Neurosci. 2006 Jun 21;26(25):6823-33. doi: 10.1523/JNEUROSCI.0453-06.2006.
- Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. doi: 10.1073/pnas.0703783104. Epub 2007 Sep 4.
- Gold SM, Sasidhar MV, Morales LB, Du S, Sicotte NL, Tiwari-Woodruff SK, Voskuhl RR. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha). Lab Invest. 2009 Oct;89(10):1076-83. doi: 10.1038/labinvest.2009.79. Epub 2009 Aug 10.
- Ziehn MO, Avedisian AA, Dervin SM, O'Dell TJ, Voskuhl RR. Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Lab Invest. 2012 Aug;92(8):1234-45. doi: 10.1038/labinvest.2012.76. Epub 2012 Apr 23.
- Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, Cao Y, Bondar G, Lam J, Ao Y, Sandoval F, Suriany S, Sofroniew MV, Voskuhl RR. Neuroprotection mediated through estrogen receptor-alpha in astrocytes. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8867-72. doi: 10.1073/pnas.1103833108. Epub 2011 May 9.
- Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35-46. doi: 10.1016/S1474-4422(15)00322-1. Epub 2015 Nov 29.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
March 1, 2007
Primary Completion (Actual)
July 1, 2014
Study Completion (Actual)
July 1, 2014
Study Registration Dates
First Submitted
March 22, 2007
First Submitted That Met QC Criteria
March 22, 2007
First Posted (Estimate)
March 23, 2007
Study Record Updates
Last Update Posted (Estimate)
June 16, 2016
Last Update Submitted That Met QC Criteria
May 10, 2016
Last Verified
May 1, 2016
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Multiple Sclerosis
- Sclerosis
- Multiple Sclerosis, Relapsing-Remitting
- Physiological Effects of Drugs
- Antirheumatic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Adjuvants, Immunologic
- Estrogens
- Glatiramer Acetate
- (T,G)-A-L
Other Study ID Numbers
- R01NS051591 (U.S. NIH Grant/Contract)
- RG3915 (Other Grant/Funding Number: NMSS)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
Investigators interested in further research using the data should contact Dr. Voskuhl with proposed plans and request.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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