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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01466114
Recruitment Status : Unknown
Verified November 2019 by Rhonda Voskuhl, University of California, Los Angeles.
Recruitment status was:  Recruiting
First Posted : November 6, 2011
Last Update Posted : November 6, 2019
Information provided by (Responsible Party):
Rhonda Voskuhl, University of California, Los Angeles

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Relapsing-remitting Multiple Sclerosis Secondary-progressive Multiple Sclerosis Primary-progressive Multiple Sclerosis Drug: estriol Other: Placebo Drug: Norethindrone Other: Progestin Placebo Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-Blind, Placebo Controlled Trial of Estriol Treatment in Women With Multiple Sclerosis: Effect on Cognition.
Study Start Date : October 2011
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Estriol

Arm Intervention/treatment
Experimental: Group A: Estriol
Standard MS Treatment + Estriol
Drug: estriol
4 capsules of 2 mg (total of 8 mg) PO QD
Other Name: Synapause

Drug: Norethindrone
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.
Other Name: Progestin

Placebo Comparator: Group B: Placebo
Standard MS Treatment + Placebo
Other: Placebo
4 capsules PO QD

Other: Progestin Placebo
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.

Primary Outcome Measures :
  1. Change from baseline in cognitive function assessed by Paced Serial Addition Test (PASAT). [ Time Frame: 1 year ]
    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.

Secondary Outcome Measures :
  1. Change from baseline in cognitive function as assessed by cognitive evoked potentials, measured in milliseconds. [ Time Frame: 1 year ]
    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.

  2. Change from baseline in standard MS outcome measures. [ Time Frame: 1 year ]
    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.

  3. Determine safety by assessing the number of subjects with adverse events with combination treatment as compared to placebo. [ Time Frame: 1 year ]
    Determine whether the combination treatment is safe (based on neurologic exams, laboratory tests (Chemistries, CBC), and gynecologic exams (breast and gynecologic exams).

  4. Change from baseline in cognitive function as assessed by a brief battery of cognitive tests. [ Time Frame: 1 year ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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").

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01466114

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Contact: Mike Montag, M.S. (310)206-2176

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United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Mike Montag, M.S.    310-206-2176   
Sub-Investigator: Barbara Giesser, MD         
Sub-Investigator: Callene Momtazee, MD         
United States, Colorado
The University of Colorado Denver Completed
Aurora, Colorado, United States, 80045
United States, New Mexico
The University of New Mexico Completed
Albuquerque, New Mexico, United States, 87131
United States, Pennsylvania
The University of Pennsylvania Completed
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of California, Los Angeles
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Principal Investigator: Rhonda Voskuhl, M.D. University of California, Los Angeles

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Responsible Party: Rhonda Voskuhl, Professor, Department of Neurology; Director Multiple Sclerosis Program, University of California, Los Angeles Identifier: NCT01466114    
Other Study ID Numbers: 11-002055
First Posted: November 6, 2011    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: November 2019
Keywords provided by Rhonda Voskuhl, University of California, Los Angeles:
multiple sclerosis
relapsing remitting multiple sclerosis
secondary progressive multiple sclerosis
primary progressive multiple sclerosis
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Norethindrone Acetate
Contraceptives, Oral, Hormonal
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptive Agents, Hormonal
Contraceptives, Oral, Synthetic
Hormones, Hormone Substitutes, and Hormone Antagonists