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

Relapsing Remitting Multiple Sclerosis Clinical Trial

— Estriol in MS  

Official title:

A Combination Trial of Copaxone Plus Estriol in RRMS

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00451204
• Other study ID #: RO1-NS051591
• Secondary ID: NIH grant RO1-NS
• Status: Completed
• Phase: Phase 2
• First received: March 22, 2007
• Last updated: December 18, 2014
• Start date: March 2007
• Est. completion date: July 2014

Study information

• Verified date: December 2014
• Source: University of California, Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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. Secondary and exploratory outcomes will include disability measures (MSFC, EDSS, Quality of Life, Fatigue and Depression testing) and MRI as a biomarker (white matter enhancing lesion number and volume, T2 lesion volume). 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 158
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing Remitting Multiple Sclerosis
• Sclerosis

Intervention

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

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern	Dallas	Texas
United States	University of Kansas	Kansas City	Kansas
United States	Dartmouth Medical School	Lebanon	New Hampshire
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	UMDNJ-Robert Wood Johnson Medical Center	New Brunswick	New Jersey
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	Western Institute for Biomedical Research	Salt Lake City	Utah
United States	Mayo Clinic	Scottsdale	Arizona

Sponsors (18)

Lead Sponsor

Collaborator

University of California, Los Angeles

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

Country where clinical trial is conducted

United States, 

References & Publications (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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. Epub 2007 Sep 4. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relapse Rate		2 years	Yes
Secondary	severity of "Relapse" as assessed by degree of worsening of Expanded Disability Status Scale (EDSS)		2 years	No
Secondary	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		2 years	No
Secondary	Expanded Disability Status Scale (EDSS) progression from baseline at conclusion		2 years	No
Secondary	Improvement in Paced Serial Addition Test (PASAT) scores between baseline and conclusion		2 years	No
Secondary	Improvement in 7-24 Spatial Recall test scores between baseline and conclusion		2 years	No
Secondary	Improvement in Selective Reminding Test scores between baseline and conclusion		2 years	No
Secondary	Brain MRI enhancing lesions		2 years	No
Secondary	Time to first relapse	The number of days to relapse from month 0 will be assessed in each treatment group	2 years	No