Estriol Treatment in Multiple Sclerosis (MS): Effect on Cognition
Estriol Treatment in Multiple Sclerosis (MS): Effect on Cognition
Approximately 50% of people diagnosed with Multiple Sclerosis (MS) will develop problems with
 cognition. Currently, there are no FDA-approved treatments targeting cognitive function in
 Multiple Sclerosis. This trial will ascertain whether treatment with an estrogen pill, used
 in combination with standard MS anti-inflammatory drugs, can improve cognitive testing as
 compared to treatment with a placebo pill in combination with standard anti-inflammatory
 drugs in women with MS.
Approximately 50% of people diagnosed with Multiple Sclerosis (MS) will develop problems with
 cognition. Currently, there are no FDA-approved treatments for cognitive function in Multiple
 Sclerosis. Multiple sclerosis relapses are known to be significantly decreased by
 approximately 80% during late pregnancy. This disease improvement may be due to estriol, an
 estrogen unique to pregnancy. Estriol blood levels go from undetectable levels prior to
 pregnancy, increase during pregnancy and reach highest levels during late pregnancy. Further,
 estrogen treatment has been shown to have favorable effects on cognition in animal models of
 other neurological diseases. This proposal will establish whether oral treatment with
 estriol, induces an improvement in cognitive functioning in subjects with multiple sclerosis
 when used in combination with the major FDA-approved standard treatments for MS, (Betaseron®
 (or Extavia®), Rebif®, Avonex®, Copaxone®, Gilenya®, Aubagio®, Tecfidera®, or Ocrevus®).

 The combination of standard MS treatment plus estriol pill (8 mg per day) will be compared to
 standard MS treatment plus placebo in a double-blinded fashion. The duration of treatment
 will be one year and the primary outcome measure will be cognitive testing processing speed
 ability.

 Secondary outcomes will be improvement in other cognitive tests, brain MRIs, cognitive evoked
 potentials, as well as relapse rates and disability measures (EDSS, 25 foot walk, 9 hole peg
 test, low contrast visual acuity, MS Quality of Life, Modified Fatigue Impact Scale, Beck
 Depression Inventory, Level of Activity using accelerometry). Safety measures (blood tests
 and gynecologic evaluations) will also be followed. The overall goal of this study will be
 the development of an oral treatment, estriol, to improve cognitive function in MS.
Inclusion Criteria:

 -  Diagnosis of clinically definite or MacDonald criteria relapsing-remitting multiple
 sclerosis, secondary-progressive multiple sclerosis or primary-progressive multiple
 sclerosis.

 -  No relapse within 30 days before day of trial enrollment (month 0 visit). If steroids
 given for relapse, then the month 0 visit must be 30 days after last steroid dose.

 -  Females age 18 to 55, inclusive.

 -  Expanded Disability Status Score (EDSS) = 0.0 to 6.0.

 -  Screening PASAT (3-second) score 25-50, inclusive.

 -  Must be mentally competent enough to comply with study guidelines and give informed
 consent.

 -  Must be willing and able to travel to the study center at frequencies in the protocol
 for a total period of 12 months.

 -  Patients must be on no treatment or be on a stable dose of one of the following agents
 for a minimum of 3 months duration prior to the month 0 visit: Copaxone®, Betaseron®
 (or Extavia®), Rebif®, Avonex®, PLEGRITY®, Ocrelizumab, Rituximab, Gilenya®, Aubagio®,
 or Tecfidera®. The time spent in the screening period may serve as part of this
 3-month period.

 -  Patients who are currently being treated with ACTH, corticosteroids, intravenous
 immunoglobulins (IVIG), plasma exchange, Lipitor® or minocycline may be included.

 -  If patients plan to start treatment with Copaxone® or an interferon [Betaseron® (or
 Extavia®), Rebif®, Avonex®, PLEGRITY®], Ocrelizumab, Rituximabor an oral agent
 [Gilenya®, Aubagio® or Tecfidera®] and then they must be on for at least 3 months
 prior to month 0 (as above).

 Exclusion Criteria:

 -  Males

 -  Subjects on oral contraceptives (OCP), hormone replacement therapy (HRT) other sex
 hormones during screening and during the 12-month study period (Mirena® IUD is
 permitted).

 -  Females who are pregnant or who plan to become pregnant during the 12 months of
 enrollment, who wish to become pregnant within 3 months following completion of the
 study, or who will be within 6 months post partum at the day of first enrollment visit
 (month 0).

 -  Females who plan to breastfeed after first enrollment visit (month 0).

 -  Fertile sexually active women who are unwilling to practice reliable barrier methods
 of contraception other than oral contraceptives (i.e. condom, diaphragm, IUDs Note:
 Hormonal IUD [Mirena®] is permitted).

 -  Patients with surgical ovariectomy with no hormone replacement for 1 year or more.

 -  Menopause with no hormone replacement for 3 years or more prior to the first
 enrollment visit.

 -  Patients who smoke at any time during screening or during the 12 month study period.

 -  Patients who have serious pulmonary, renal, gastrointestinal, hepatic, immunologic,
 infectious, neoplastic, major psychiatric disease (major depression, schizophrenia),
 endocrine disease (including major diabetes, thyroid disease), or gynecologic disease,
 including but not limited to those with: Thrombophlebitis or thromboembolic disorders,
 a past history of deep vein thrombophlebitis or thromboembolic disorders, cerebral
 vascular or coronary artery disease, migraine with focal aura, known or suspected
 carcinoma of the breast, carcinoma of the endometrium or other known or suspected
 estrogen-dependent neoplasia, undiagnosed abnormal genital bleeding, polycystic ovary
 disease, amenorrhea of unknown etiology, cholestatic jaundice of pregnancy or jaundice
 with prior birth control pill use, acute or chronic hepatocellular disease with
 abnormal liver function, hepatic adenomas or carcinomas, known or suspected pregnancy,
 known hypersensitivity to birth control pill Copaxone or Betaseron use.

 -  B12 level < 200.

 -  Drug abuse within the past five years.

 -  Conditions that would interfere with assessing neurologic functions such as deforming
 arthritis or a major amputation.

 -  Have at any time been treated with total lymphoid irradiation, monoclonal antibody, T
 cell vaccination, cladribine, bone marrow transplantation, azathioprine,
 cyclophosphamide, methotrexate, mitoxantrone, or cyclosporine.

 -  Have been treated with natalizumab (Tysabri®) in the 6 months prior to screening.

 -  Positive titers to HIV in the past.

 -  Previous serious adverse effects with estrogen treatment.

 -  Patients who participated in the previous multi-center estriol trial for RRMS ("A
 Combination Trial of Copaxone plus Estriol in RRMS").