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

Overview

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.

Full Title of Study: “A Combination Trial of Copaxone Plus Estriol in RRMS”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: July 2014

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.

Interventions

  • Drug: Estriol
    • Estriol 8 mg capsule, once per day, duration of treatment is 2 years
  • Drug: Placebo
    • Placebo capsule, once a day, treatment duration is 2 years
  • Drug: Copaxone
    • Injection, once a day, all subjects

Arms, Groups and Cohorts

  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary 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 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

Participating in This Clinical Trial

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

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of California, Los Angeles
  • Collaborator
    • Washington University School of Medicine
  • Provider of Information About this Clinical Study
    • Principal Investigator: Rhonda Voskuhl, Professor, Department of Neurology; Director Multiple Sclerosis Program – University of California, Los Angeles
  • Overall Official(s)
    • Rhonda Voskuhl, M.D., Study Director, University of California, Los Angeles (UCLA), Los Angeles, CA
    • Anne Cross, M.D., Principal Investigator, Washington University, Saint Louis, MO
    • Elliot Frohman, M.D., Principal Investigator, University of Texas, Southwestern, Dallas, TX
    • Suhayl Dhib-Jalbut, M.D., Principal Investigator, Robert Wood Johnson Medical School, UMDNJ, New Brunswick, NJ
    • Michael Racke, M.D., Principal Investigator, Ohio State University
    • Anthony Reder, M.D., Principal Investigator, University of Chicago
    • John Rose, M.D., Principal Investigator, Western Institute for Biomedical Research, Salt Lake City, UT
    • Barbara Giesser, M.D., Principal Investigator, University of California, Los Angeles (UCLA), Los Angeles, CA
    • John Ratchford, M.D., Principal Investigator, Johns Hopkins, Baltimore, MD
    • Sharon Lynch, M.D., Principal Investigator, University of Kansas
    • Gareth Parry, M.D., Principal Investigator, University of Minnesota
    • Dean Wingerchuk, M.D., Principal Investigator, Mayo Clinic
    • John Corboy, M.D., Principal Investigator, University of Colorado, Denver
    • Corey Ford, M.D., Principal Investigator, University of New Mexico, Albuquerque
    • Dina Jacobs, M.D., Principal Investigator, University of Pennsylvania
    • Lloyd Kasper, M.D., Principal Investigator, Dartmouth University, Lebanon, NH

References

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.

Citations Reporting on 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.

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