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 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®, or Tecfidera®).

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").