Estriol Treatment in Multiple Sclerosis (MS): Effect on Cognition

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Double-Blind, Placebo Controlled Trial of Estriol Treatment in Women With Multiple Sclerosis: Effect on Cognition.

Conditions
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Relapsing-remitting Multiple Sclerosis, Secondary-progressive Multiple Sclerosis, Primary-progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: estriol
* Other: Placebo
* Drug: Norethindrone
* Other: Progestin Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Estriol<br>Standard MS Treatment + Estriol | Drug: estriol<br>* 4 capsules of 2 mg (total of 8 mg) PO QD<br>* Other names: Synapause;Drug: Norethindrone<br>* Starting at month 6, and at Months 9 and 12: subjects who are on estriol (Group A) take 0.7 mg PO QD for 2 weeks.<br>* Other names: Progestin;|
| Placebo Comparator: Group B: Placebo<br>Standard MS Treatment + Placebo | Other: Placebo<br>* 4 capsules PO QD<br>Other: Progestin Placebo<br>* Starting at Month 6 and at Months 9 and 12: subjects who are on placebo (Group B) take a second progestin placebo pill PO QD for 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cognitive function assessed by Paced Serial Addition Test (PASAT). | Processing speed will be assessed by PASAT. Numerical test scores (ranging from 0-60) will be acquired, then percent change for each subject at trial conclusion as compared to baseline will be determined. Whether greater improvement as expressed as percent change occurs in the estriol group as compared to the placebo group will be determined. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in cognitive function as assessed by cognitive evoked potentials, measured in milliseconds. | Cognitive evoked potentials will be recorded in msecs for each subject at baseline and conclusion. The percent improvement as conclusion as compared to baseline for each subject will be determined. Group comparisons will reveal whether the percent improvement is greater in the estriol treated group as compared to the placebo treated group. | 1 year | 
| Change from baseline in standard MS outcome measures. | Determine whether the combination treatment has an effect on standard MS outcome measures (relapses, EDSS, 25 foot walk test, 9 hole peg test, low contrast visual acuity, MS Quality of Life, Modified Fatigue Impact Scare, Beck Depression Inventory. | 1 year | 
| Determine safety by assessing the number of subjects with adverse events with combination treatment as compared to placebo. | Determine whether the combination treatment is safe (based on neurologic exams, laboratory tests (Chemistries, CBC), and gynecologic exams (breast and gynecologic exams). | 1 year | 
| Change from baseline in cognitive function as assessed by a brief battery of cognitive tests. | A brief battery of cognitive tests will be administered including: Processing speed: SDMT-hand written; Visual memory: 7/24 Spatial Recall Test, Benton Forms F & G; Verbal memory: Buschke Selective Reminding Test, Verbal Paired Associates; Language: Word List Generation. Each subject will be tested at baseline, month 6 and conclusion. Percent change at conclusion as compared to baseline will be determined in each subject. Group comparisons will reveal which cognitive test within the battery had greater improvement in the estriol treated group as compared to the placebo treated group. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, MS, relapsing remitting multiple sclerosis, RRMS, secondary progressive multiple sclerosis, SPMS, primary progressive multiple sclerosis, estrogen, estriol