A Combination Trial of Copaxone Plus Estriol in Relapsing Remitting Multiple Sclerosis (RRMS) (Estriol-MS)

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ClinicalTrials.gov Identifier: NCT00451204

Recruitment Status : Completed

First Posted : March 23, 2007

Results First Posted : June 16, 2016

Last Update Posted : June 16, 2016

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

Washington University School of Medicine

University of Texas Southwestern Medical Center

Ohio State University

University of Medicine and Dentistry of New Jersey

University of Chicago

University of Utah

Johns Hopkins University

University of Kansas Medical Center

University of Minnesota

Mayo Clinic

University of Colorado, Denver

University of New Mexico

University of Pennsylvania

Dartmouth-Hitchcock Medical Center

National Multiple Sclerosis Society

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Information provided by (Responsible Party):

Rhonda Voskuhl, University of California, Los Angeles

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Relapsing Remitting Multiple Sclerosis	Drug: Estriol Drug: Placebo Drug: Copaxone	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	158 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	A Combination Trial of Copaxone Plus Estriol in RRMS
Study Start Date :	March 2007
Actual Primary Completion Date :	July 2014
Actual Study Completion Date :	July 2014

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Multiple sclerosis

MedlinePlus related topics: Multiple Sclerosis

Drug Information available for: Estriol Glatiramer Glatiramer acetate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Estriol Estriol 8 mg capsule, once per day, duration of treatment is 2 years Other Names: E3 estrogen Drug: Copaxone Injection, once a day, all subjects Other Name: glatiramer acetate
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.	Drug: Placebo Placebo capsule, once a day, treatment duration is 2 years Other Name: "sugar pill" Drug: Copaxone Injection, once a day, all subjects Other Name: glatiramer acetate

Outcome Measures

Primary Outcome Measures :

Confirmed Relapse, Annualized Relapse Rate [ Time Frame: 24 months ]
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.

Secondary Outcome Measures :

Relapse Event, Annualized Relapse Rate [ Time Frame: 24 months ]
Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
Confirmed Relapse, Probability of First Relapse [ Time Frame: 24 months ]
Relapse Event, Probability of First Relapse Event [ Time Frame: 24 months ]

Other Outcome Measures:

Confirmed Relapse, Annualized Relapse Rate [ Time Frame: 12 months ]
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.
Relapse Event, Annualized Relapse Rate [ Time Frame: 12 months ]
Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00451204

Locations

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United States, Arizona
Mayo Clinic
Scottsdale, Arizona, United States, 85259
United States, California
University of California, Los Angeles
Los Angeles, California, United States, 90095
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Kansas
University of Kansas
Kansas City, Kansas, United States, 66160
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-6965
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New Hampshire
Dartmouth Medical School
Lebanon, New Hampshire, United States, 03765
United States, New Jersey
UMDNJ-Robert Wood Johnson Medical Center
New Brunswick, New Jersey, United States, 08901
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43221
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States, 75390-8575
United States, Utah
Western Institute for Biomedical Research
Salt Lake City, Utah, United States, 84158
Canada
Montreal Neurological Institute
Montreal, Canada

Sponsors and Collaborators

University of California, Los Angeles

Washington University School of Medicine

University of Texas Southwestern Medical Center

Ohio State University

University of Medicine and Dentistry of New Jersey

University of Chicago

University of Utah

Johns Hopkins University

University of Kansas Medical Center

University of Minnesota

Mayo Clinic

University of Colorado, Denver

University of New Mexico

University of Pennsylvania

Dartmouth-Hitchcock Medical Center

National Multiple Sclerosis Society

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

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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

More Information

Publications of Results:

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.

Other Publications:

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.

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.

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.

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Responsible Party:	Rhonda Voskuhl, Professor, Department of Neurology; Director Multiple Sclerosis Program, University of California, Los Angeles
ClinicalTrials.gov Identifier:	NCT00451204
Other Study ID Numbers:	R01NS051591 ( U.S. NIH Grant/Contract ) R01NS051591 ( U.S. NIH Grant/Contract ) RG3915 ( Other Grant/Funding Number: NMSS )
First Posted:	March 23, 2007 Key Record Dates
Results First Posted:	June 16, 2016
Last Update Posted:	June 16, 2016
Last Verified:	May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Investigators interested in further research using the data should contact Dr. Voskuhl with proposed plans and request.

Keywords provided by Rhonda Voskuhl, University of California, Los Angeles:


Multiple sclerosis estrogen estriol progesterone

Additional relevant MeSH terms:

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Multiple Sclerosis Multiple Sclerosis, Relapsing-Remitting Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases	Glatiramer Acetate Estrogens (T,G)-A-L Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Adjuvants, Immunologic Immunologic Factors Immunosuppressive Agents Antirheumatic Agents

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