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

NCT01466114 | Unknown Phase 2

• 1 other identifier: 11-002055
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 4

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.

Conditions

Relapsing-remitting Multiple Sclerosis; Secondary-progressive Multiple Sclerosis; Primary-progressive Multiple Sclerosis

Keywords

multiple sclerosis; MS; relapsing remitting multiple sclerosis; RRMS; secondary progressive multiple sclerosis; SPMS; primary progressive multiple sclerosis; estrogen; estriol

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Change from baseline in cognitive function as assessed by cognitive evoked potentials, measured in milliseconds.

  1 year

• Change from baseline in standard MS outcome measures.

  1 year

• Determine safety by assessing the number of subjects with adverse events with combination treatment as compared to placebo.

  1 year

• Change from baseline in cognitive function as assessed by a brief battery of cognitive tests.

  1 year

Study Arms (2)

Group A: Estriol

EXPERIMENTAL

Standard MS Treatment + Estriol

Drug: estriol; Drug: Norethindrone

Group B: Placebo

PLACEBO COMPARATOR

Standard MS Treatment + Placebo

Other: Placebo; Other: Progestin Placebo

Interventions

estriol DRUG

4 capsules of 2 mg (total of 8 mg) PO QD

Also known as: Synapause

Group A: Estriol

Placebo OTHER

4 capsules PO QD

Group B: Placebo

Norethindrone DRUG

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.

Also known as: Progestin

Group A: Estriol

Progestin Placebo OTHER

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.

Group B: Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, Los Angeles: lead

Study Sites (4)

University of California Los Angeles

Los Angeles, California, 90095, United States

RECRUITING

The University of Colorado Denver

Aurora, Colorado, 80045, United States

COMPLETED

The University of New Mexico

Albuquerque, New Mexico, 87131, United States

COMPLETED

The University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

COMPLETED

Related Publications (11)

• 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.

  PMID: 22525427 BACKGROUND

• Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jan;15(1):35-46. doi: 10.1016/S1474-4422(15)00322-1. Epub 2015 Nov 29.

  PMID: 26621682 BACKGROUND

• Voskuhl R, Wang H, Elashoff RM. Why use sex hormones in relapsing-remitting multiple sclerosis? - Authors' reply. Lancet Neurol. 2016 Jul;15(8):790-791. doi: 10.1016/S1474-4422(16)00129-0. No abstract available.

  PMID: 27302354 BACKGROUND

• Voskuhl R, Patti F. Hormone replacement in menopausal women with multiple sclerosis: Looking back, thinking forward. Neurology. 2016 Oct 4;87(14):1430-1431. doi: 10.1212/WNL.0000000000003189. Epub 2016 Sep 7. No abstract available.

  PMID: 27605172 BACKGROUND

• Voskuhl R. Rebound Relapses After Ceasing Another Disease-Modifying Treatment in Patients With Multiple Sclerosis: Are There Lessons to Be Learned? JAMA Neurol. 2016 Jul 1;73(7):775-6. doi: 10.1001/jamaneurol.2016.0934. No abstract available.

  PMID: 27136400 BACKGROUND

• Itoh N, Kim R, Peng M, DiFilippo E, Johnsonbaugh H, MacKenzie-Graham A, Voskuhl RR. Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis. J Neuroimmunol. 2017 Mar 15;304:63-71. doi: 10.1016/j.jneuroim.2016.09.017. Epub 2016 Oct 3.

  PMID: 27771018 BACKGROUND

• Kim RY, Mangu D, Hoffman AS, Kavosh R, Jung E, Itoh N, Voskuhl R. Oestrogen receptor &beta; ligand acts on CD11c&plus; cells to mediate protection in experimental autoimmune encephalomyelitis. Brain. 2018 Jan 1;141(1):132-147. doi: 10.1093/brain/awx315.

  PMID: 29228214 BACKGROUND

• MacKenzie-Graham A, Brook J, Kurth F, Itoh Y, Meyer C, Montag MJ, Wang HJ, Elashoff R, Voskuhl RR. Estriol-mediated neuroprotection in multiple sclerosis localized by voxel-based morphometry. Brain Behav. 2018 Sep;8(9):e01086. doi: 10.1002/brb3.1086. Epub 2018 Aug 24.

  PMID: 30144306 BACKGROUND

• Voskuhl RR, Itoh N, Tassoni A, Matsukawa MA, Ren E, Tse V, Jang E, Suen TT, Itoh Y. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 May 14;116(20):10130-10139. doi: 10.1073/pnas.1821306116. Epub 2019 Apr 30.

  PMID: 31040210 BACKGROUND

• Voskuhl R. It is time to conduct phase 3 clinical trials of sex hormones in MS - Yes. Mult Scler. 2018 Oct;24(11):1413-1415. doi: 10.1177/1352458518768764. Epub 2018 Jul 30. No abstract available.

  PMID: 30058469 BACKGROUND

• Voskuhl R, Momtazee C. Pregnancy: Effect on Multiple Sclerosis, Treatment Considerations, and Breastfeeding. Neurotherapeutics. 2017 Oct;14(4):974-984. doi: 10.1007/s13311-017-0562-7.

  PMID: 28766273 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis

Interventions

Estriol; estriol succinate; Norethindrone; Progestins

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Norpregnenes; Norpregnanes; Norsteroids; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Rhonda Voskuhl, M.D.

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mike Montag, M.S.

CONTACT

(310)206-2176; MMontag@mednet.ucla.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Department of Neurology; Director Multiple Sclerosis Program

Study Record Dates

• First Submitted: October 31, 2011
• First Posted: November 7, 2011
• Study Start: October 1, 2011
• Primary Completion: December 1, 2021
• Study Completion: April 1, 2022
• Last Updated: November 6, 2019

Record last verified: 2019-11

Locations

US (4)