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

• severity of "Relapse" as assessed by degree of worsening of Expanded Disability Status Scale (EDSS) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• severity of "Relapse" as assessed by degree of worsening of Multiple Sclerosis Functional Composite (MSFC) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Proportion of subjects with confirmed progression in Expanded Disability Status Scale (EDSS) (at least 1.0 point for at least 6 months on two exams) between baseline and conclusion [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Expanded Disability Status Scale (EDSS) progression from baseline at conclusion [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Multiple Sclerosis Functional Composite (MSFC) progression from baseline at conclusion [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Improvement in Paced Serial Addition Test (PASAT) scores between baseline and conclusion [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Improvement in 7-24 Spatial Recall test scores between baseline and conclusion [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Improvement in Selective Reminding Test scores between baseline and conclusion [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Brain MRI enhancing lesions [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Brain atrophy on MRI [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

• 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

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.

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. Secondary outcomes will include disability measures (MSFC, EDSS, Quality of Life, Fatigue and Depression testing) and a surrogate marker for disability (cerebral MRI for whole brain volume, gray matter atrophy and T1 holes). Safety measures (blood tests and gynecologic evaluations) will also be followed. The overall goal of this study will be the development of an oral anti-inflammatory treatment, estriol, for RRMS.

• 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

• Active Comparator: 1
  Estriol Pills plus Copaxone injections
  Intervention: Drug: Estriol
• Placebo Comparator: 2
  Placebo pills plus Copaxone injections
  Intervention: Drug: Placebo

• 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.

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

• Washington University School of Medicine
• University of Texas Southwestern Medical Center
• Ohio State University
• University of Medicine and Dentistry New Jersey
• University of Chicago
• Western Institute for Biomedical Research, Salt Lake City, UT
• Johns Hopkins University
• University of Kansas
• University of Minnesota - Clinical and Translational Science Institute
• Mayo Clinic
• University of Colorado, Aurora
• University of New Mexico
• University of Pennsylvania
• Dartmouth Medical School, Lebanon, NH
• National Multiple Sclerosis Society
• National Institutes of Health (NIH)
• Adeona Pharmaceuticals, Ann Arnor, MI