Clinical trial NCT00451204: A Combination Trial of Copaxone Plus Estriol in Relapsing Remitting Multiple Sclerosis (RRMS)
Official title: A Combination Trial of Copaxone Plus Estriol in RRMS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Multiple sclerosis
estrogen
estriol
progesterone
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: Washington University School of Medicine
name: University of Texas Southwestern Medical Center
name: Ohio State University
name: University of Medicine and Dentistry of New Jersey
name: University of Chicago
name: University of Utah
name: Johns Hopkins University
name: University of Kansas Medical Center
name: University of Minnesota
name: Mayo Clinic
name: University of Colorado, Denver
name: University of New Mexico
name: University of Pennsylvania
name: Dartmouth-Hitchcock Medical Center
name: National Multiple Sclerosis Society
name: National Institutes of Health (NIH)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2007-03-23
Enrollment: 158
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Confirmed Relapse, Annualized Relapse Rate
timeFrame: 24 months
Secondary outcomes:
measure: Relapse Event, Annualized Relapse Rate
timeFrame: 24 months
measure: Confirmed Relapse, Probability of First Relapse
timeFrame: 24 months
measure: Relapse Event, Probability of First Relapse Event
timeFrame: 24 months
Other outcomes:
measure: Confirmed Relapse, Annualized Relapse Rate
timeFrame: 12 months
measure: Relapse Event, Annualized Relapse Rate
timeFrame: 12 months
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Medical School
state: New Hampshire
city: New Brunswick
country: United States
facility: UMDNJ-Robert Wood Johnson Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Salt Lake City
country: United States
facility: Western Institute for Biomedical Research
state: Utah
city: Montreal
country: Canada
facility: Montreal Neurological Institute
Study officials:
affiliation: University of California, Los Angeles (UCLA), Los Angeles, CA
name: Rhonda Voskuhl, M.D.
role: STUDY_DIRECTOR
affiliation: Washington University, Saint Louis, MO
name: Anne Cross, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern, Dallas, TX
name: Elliot Frohman, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Robert Wood Johnson Medical School, UMDNJ, New Brunswick, NJ
name: Suhayl Dhib-Jalbut, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ohio State University
name: Michael Racke, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Anthony Reder, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Western Institute for Biomedical Research, Salt Lake City, UT
name: John Rose, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles (UCLA), Los Angeles, CA
name: Barbara Giesser, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins, Baltimore, MD
name: John Ratchford, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kansas
name: Sharon Lynch, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Gareth Parry, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Dean Wingerchuk, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: John Corboy, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico, Albuquerque
name: Corey Ford, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Dina Jacobs, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Dartmouth University, Lebanon, NH
name: Lloyd Kasper, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.