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

Tracking Information
First Submitted Date ICMJE	March 22, 2007
First Posted Date ICMJE	March 23, 2007
Results First Submitted Date	January 20, 2016
Results First Posted Date	June 16, 2016
Last Update Posted Date	June 16, 2016
Study Start Date ICMJE	March 2007
Actual Primary Completion Date	July 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: May 10, 2016)	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.
Original Primary Outcome Measures ICMJE; (submitted: March 22, 2007)	Relapse Rate
Change History	Complete list of historical versions of study NCT00451204 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: May 10, 2016)	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 ]
Original Secondary Outcome Measures ICMJE; (submitted: March 22, 2007)	Relapse Related Secondary; "Relapse Event" Rate; time to first "Relapse"; time to first "Relapse Event"; proportion of subjects "Relapse" free at each year; proportion of subjects "Relapse Event" free at each year; number of "Relapses" per subject; number of "Relapse Events" per subject; severity of "Relapse" as assessed by degree of worsening of EDSS; severity of "Relapse Event" as assessed by degree of worsening of EDSS; severity of "Relapse" as assessed by degree of worsening of MSFC.; severity of "Relapse Event" as assessed by degree of worsening of MSFC.; number of times IV solumedrol was administered per subject for treatment of "Relapses."; number of times IV solumedrol was administered per subject for treatment of "Relapse Events."; Disability Related Secondary; Proportion of subjects with confirmed progression in EDSS (at least 1.0 point for at least 6 months on two exams) between baseline and conclusion; EDSS progression from baseline at conclusion; MSFC progression from baseline at conclusion; Improvement in PASAT scores between baseline and conclusion; Improvement in 7-24 Spatial Recall test scores between baseline and conclusion; Improvement in Selective Reminding Test scores between baseline and conclusion
Current Other Outcome Measures ICMJE; (submitted: May 10, 2016)	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.
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Combination Trial of Copaxone Plus Estriol in Relapsing Remitting Multiple Sclerosis (RRMS)
Official Title ICMJE	A Combination Trial of Copaxone Plus Estriol in RRMS
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.
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 ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition ICMJE	Relapsing Remitting Multiple Sclerosis
Intervention ICMJE	Drug: Estriol Estriol 8 mg capsule, once per day, duration of treatment is 2 years Other Names: E3 estrogen; 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
Study Arms	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. Interventions: Drug: Estriol Drug: Copaxone; 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. Interventions: Drug: Placebo Drug: Copaxone
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.; 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.; 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.; 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. 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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: May 15, 2014)	158
Original Enrollment ICMJE; (submitted: March 22, 2007)	150
Actual Study Completion Date	July 2014
Actual Primary Completion Date	July 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years to 50 Years (Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00451204
Other Study ID Numbers ICMJE	R01NS051591( U.S. NIH Grant/Contract ); R01NS051591 ( U.S. NIH Grant/Contract ); RG3915 ( Other Grant/Funding Number: NMSS )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
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.
Responsible Party	Rhonda Voskuhl, University of California, Los Angeles
Study Sponsor ICMJE	University of California, Los Angeles
Collaborators ICMJE	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, MN; Mayo Clinic; University of Colorado, Aurora; 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 ICMJE	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, MN Principal Investigator: Dean Wingerchuk, M.D. Mayo Clinic Principal Investigator: John Corboy, M.D. University of Colorado, Aurora 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
PRS Account	University of California, Los Angeles
Verification Date	May 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP