Conditions: Menopause Multiple Sclerosis
Keywords: Hot flash Estrogen Women
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
Duavee is a hormone receptor modulator that has been approved for the treatment of menopausal symptoms in menopausal women. The goal of this 8-week randomized, double blind, placebo controlled pilot study, is to determine whether this medication alleviates menopausal symptoms in women with MS. The investigators will secondarily determine whether addressing menopausal symptoms ameliorates MS symptoms and, on MRIs, is not triggering worsening inflammation.

Detailed description:
Menopause in MS. Multiple sclerosis (MS) affects 3 times more women than men, and before age 50 in about 90% cases, i.e. prior to menopause. There is broad evidence for hormonal regulation of MS in animal models and in clinical cohorts. Around menopause, many clinical patients report symptom worsening associated with hot flashes, sleep disturbance or mood changes. Additionally, individuals at MS may be at increased risk of developing osteoporosis. Longer-term, an age-related decline in gonadal steroids might represent one sex-specific influence on the known age-related increases in disability and conversion to progressive course, which is marked by accelerated brain volume loss and neurodegeneration. Recent data suggest that MS disease severity may worsen after menopause.

* Hormone therapy (HT). Despite the benefits of HT (menopausal symptoms, bone density), very few women (\<30% of our cohort) are currently taking HT for menopausal symptoms; this is a result of risks such as (1) breast and endometrial cancer, and (2) stroke in older women in the Women's Health Initiative. Recent data on HT use in MS (Nurses Health Study) did not show any adverse effects on MS course, and women who used HT reported better physical function than women who did not (Bove et al, Neurology 2016).
* Study Drug: Duavee, a tissue selective estrogen complex (TSEC), combines conjugated estrogens (CE) with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA). BZA offsets estrogenic stimulation of endometrial and breast tissue, and CE 0.45mg/BZA 20mg is approved for menopausal symptom (hot flash) relief and osteoporosis prevention, with a favorable tolerability and safety profile.

In the current study, 24 women with MS and who are experiencing bothersome menopause symptoms will be enrolled and randomized to receive either 8 weeks of Duavee or 8 weeks of placebo. Visits will be: eligibility, baseline, and 2 month visit.

Arms:
arm 1: 1 Tablet of 0.45mg conjugated estrogens/20 mg bazedoxifene daily for 8 weeks arm 2: Placebo pill daily for 8 weeks.

Interventions: intervention 1: Tissue Selective Estrogen Complex intervention 2: Placebo
Intervention descriptions: intervention 1: Once-daily dosing of Duavee for 8 weeks. intervention 2: Once-daily dosing of placebo for 8 weeks

Protocol document:
Prot_000.pdf: 
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University of California, San Francisco
Dr. Riley Bove
Clinical Research Protocol
A placebo-controlled pilot trial evaluating the effect of a tissue selective estrogen complex on 
menopausal symptoms in women with multiple sclerosis
Protocol Number:
1
Version Date:
3/29/2016
Investigational Product:
Duavee
IND Number:
We believe this clinical investigation of a marketed drug meets all 
FDA IND exemption criteria, namely:
• The drug product is lawfully marketed in the United States. 
• The investigation is not intended to be reported to FDA as a 
well-controlled study in support of a new indication and there is 
no intent to use it to support any other significant change in the 
labeling of the drug. 
• The investigation of this prescription drug, is not intended to 
support a significant change in the advertising for the drug. 
• The investigation does not involve a route of administration, 
dose, patient population, or other factor that significantly increases 
the risk (or decreases the acceptability of the risk) associated with 
the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
• The investigation is conducted in compliance with the 
requirements for review by an IRB (21 CFR part 56) and with the 
requirements for informed consent (21 CFR part 50). 
• The investigation is conducted in compliance with the 
requirements of § 312.7 (i.e., the investigation is not intended to 
promote or commercialize the drug product). 
Development Phase:
Phase II
Sponsor:
Riley Bove
Sandler Neurosciences Center, 675 Nelson Rising Lane
San Francisco, CA
Funding Organization:
National Multiple Sclerosis Society 
Principal Investigator:
Name: Riley Bove
Telephone:
415 595 2795
Fax:
n/a
E-mail:
Riley.Bove@ucsf.edu
Medical Monitor:
Name:
N/A
Telephone:
Fax:
E-mail:
Coordinating Center:
N/A


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Approval:
12/16/2015
PI or Sponsor Signature (Name and Title) 
Date
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time.  The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure.  Subject to the foregoing, this information may be disclosed only to those persons 
involved in the study who have a need to know, with the obligation not to further 
disseminate this information.  


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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing the 
University of California, San Francisco with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures required 
to carry out the study in accordance with accepted GCP principles and to abide by the terms of this 
protocol.
Protocol Number:  15-18004
Protocol Title:  A placebo-controlled pilot trial evaluating the effect of a tissue selective 
estrogen complex on menopausal symptoms in women with multiple sclerosis
Protocol Date:  12/16/2015
12/16/2015
Investigator Signature 
Date
Riley Bove, MD    Assistant Professor of Neurology
Print Name and Title
Site #
Site Name
NCRU, UCSF Mission Bay
Address
675 Sandler Neurosciences Center
San Francisco, CA
Phone Number
415 595 2795


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TABLE OF CONTENTS
1
BACKGROUND ..................................................................................................................4
1.1
Overview of Non-Clinical Studies...............................................................................9
1.2
Overview of Clinical Studies .......................................................................................9
2
STUDY RATIONALE.........................................................................................................9
2.1
Risk / Benefit Assessment............................................................................................9
3
STUDY OBJECTIVES........................................................................................................9
3.1
Primary Objective ........................................................................................................9
3.2
Secondary Objectives...................................................................................................9
4
STUDY DESIGN..................................................................................................................9
4.1
Study Overview............................................................................................................9
5
CRITERIA FOR EVALUATION......................................................................................10
5.1
Primary Efficacy Endpoint...........................................................................................10
5.2
Secondary Efficacy Endpoints.....................................................................................10
5.3
Safety Evaluations........................................................................................................10
5.4
Other Evaluations (include only if applicable) ............................................................10
6
SUBJECT SELECTION .....................................................................................................10
6.1
Study Population..........................................................................................................10
6.2
Inclusion Criteria..........................................................................................................10
6.3
Exclusion Criteria ........................................................................................................11
7
CONCURRENT MEDICATIONS.....................................................................................11
7.1
Allowed........................................................................................................................11
7.2
Prohibited.....................................................................................................................11
8
STUDY TREATMENTS.....................................................................................................11
8.1
Method of Assigning Subjects to Treatment Groups...................................................11
8.2
Blinding........................................................................................................................11
8.3
Test and Control Formulation......................................................................................12
8.4
Supply of Study Medication at the Site .......................................................................13
8.5
Study Medication Accountability ................................................................................14
8.6
Measures of Treatment Compliance ............................................................................14
9
STUDY PROCEDURES AND GUIDELINES..................................................................14
9.1
Clinical Assessments....................................................................................................14
9.2
Clinical Laboratory Measurements (include sections as appropriate).........................15
9.3
Pharmacokinetic Measurements ..................................................................................16
9.4
Research Laboratory Measurements (include sections as appropriate) .......................16
10 EVALUATIONS BY VISIT................................................................................................16
10.1 Visit 1 (Day/Week/Month #) .......................................................................................16
10.2 Visit 2 (Day/Week/Month # include visit window).....................................................17
10.3 Visit 3 (Day/Week/Month # include visit window).....................................................17


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10.6 Early Withdrawal Visit ................................................................................................18
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................18
11.1 Adverse Events ............................................................................................................18
11.2 Serious Adverse Experiences (SAE)............................................................................20
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting.........20
11.4 Medical Monitoring .....................................................................................................20
11.5 Safety Management Plan .............................................................................................4
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ...................................20
12.1 Withdrawal of Subjects................................................................................................20
12.3 Replacement of Subjects..............................................................................................21
13 PROTOCOL VIOLATIONS..............................................................................................22
14 DATA SAFETY MONITORING (OPTIONAL SECTION – INCLUDE WHEN 
APPROPRIATE)........................................................................................................................22
15 STATISTICAL METHODS AND CONSIDERATIONS................................................22
15.1 Data Sets Analyzed ......................................................................................................22
15.2 Demographic and Baseline Characteristics..................................................................22
15.3 Analysis of Primary Endpoint......................................................................................23
15.4 Analysis of Secondary Endpoints ................................................................................23
15.5 Interim Analysis...........................................................................................................23
15.6 Sample Size and Randomization..................................................................................23
16 DATA COLLECTION, RETENTION AND MONITORING........................................23
16.1 Data Collection Instruments.........................................................................................23
16.2 Data Management Procedures .....................................................................................24
16.3 Data Quality Control and Reporting ............................................................................24
16.4 Archival of Data...........................................................................................................24
16.5 Availability and Retention of Investigational Records ................................................24
16.6 Monitoring ...................................................................................................................25
16.7 Subject Confidentiality ................................................................................................25
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS...................25
17.1 Protocol Amendments..................................................................................................25
17.2 Institutional Review Boards and Independent Ethics Committees..............................25
17.3 Informed Consent Form...............................................................................................26
17.4 Publications..................................................................................................................26
17.5 Investigator Responsibilities........................................................................................27


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CE
CFR
Conjugated estrogen
Code of Federal Regulations
CRF
case report form
DMC
Data Monitoring Committee
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
intravenous
mEq
milliequivalent
MS
mg
NAMS
PI
Multiple sclerosis
milligram
North American Menopause Society
Principal Investigator
SAE
serious adverse experience
SERM
SGOT
Selective estrogen receptor modulator
serum glutamic oxaloacetic transaminase
SGPT
TSEC
serum glutamate pyruvate transaminase
tissue selective estrogen complex


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PROTOCOL SYNOPSIS
TITLE
A placebo-controlled pilot trial evaluating the effect of a tissue selective estrogen 
complex on menopausal symptoms in women with multiple sclerosis
SPONSOR
University of California, San Francisco
FUNDING 
ORGANIZATION
National Multiple Sclerosis Society
NUMBER OF SITES
1
RATIONALE
Multiple sclerosis (MS) is a chronic neurologic disorder characterized by 
inflammation and neurodegeneration that affects 3 times more women than men 
and, in 90% cases, women before the age of 50, i.e. prior to menopause. 
Given evidence for hormonal regulation of MS, a symptomatic worsening of MS 
symptoms at menopause due to hot flashes and other phenomena, as well as 
recent data suggesting that MS disease severity may worsen after menopause, we 
propose to pilot hormonal therapies in peri-menopausal women.  
Increasing evidence suggests that estrogen is neuroprotective, and that hormonal 
modulation after menopause may be an important strategy to combat cognitive 
decline. 
Given the potential complications of hormone replacement therapies (HT), tissue 
selective estrogen complex (TSEC)s have been developed to combine the 
beneficial effects of estrogen with the tissue-specific agonistic and 
antagonistic properties of selective estrogen receptor modulators (SERMs). 
Here, we propose a pilot single-center randomized double blind placebo 
controlled trial to investigate the effectiveness of the TSEC Duavee (conjugated 
estrogen + SERM bazedoxifene), vs. placebo, for 8 weeks on (1) tolerability, (2) 
patient-reported symptoms (menopausal: hot flashes, sleep, cognition) and (3) 
MS-related safety (MS symptoms, MRI). 
Our team consists of experts in MS translational research, and hormonal 
therapies.  
STUDY DESIGN
A pilot, 2-month, double blind, 1:1 randomized placebo controlled clinical trial 
investigating the effect of a tissue-selective estrogen modulator (TSEC) (Duavee, 
which is FDA approved for the treatment of menopausal symptoms in women in 
the general population) on tolerability and menopausal symptoms in 
perimenopausal women with MS.
PRIMARY 
OBJECTIVE
To test the hypothesis that a TSEC (CE+BZA) will be well tolerated in women 
with MS, and will alleviate their menopausal symptoms. In relieving hot flashes 
and subsequent sleep and mood disruption, MS symptoms will also be 
ameliorated.
SECONDARY 
OBJECTIVES
 - To explore the hypothesis that CE+BZA improves menopausal symptoms in 
MS women.
- To explore the hypothesis that CE+BZA results in improvement in MS-related 
outcomes.
- To explore the hypothesis that CE+BZA for 8 weeks is tolerable in women 
with MS.
NUMBER OF 
SUBJECTS
24


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SUBJECT 
SELECTION
CRITERIA
Inclusion Criteria:
Women aged 40-62 who carry a diagnosis of MS that is stable and are 
perimenopausal (we will use the widely used criterion of 6 months of 
amenorrhea as this corresponds to either the late menopausal transition or early 
postmenopause).
Exclusion Criteria:
Known hypersensitivity or contraindications to estrogen, use of any prescribed 
therapy that is taken specifically for hot flashes in the past 1 month, steroids in 
the past 1 month, clinical relapse in last 3 months, evidence of other structural 
brain disorder, pregnancy, intending pregnancy, or breast feeding, drug or 
alcohol abuse in the past 1 year, or other considerations to ensure the safety of 
the patients.
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
DUAVEE (0.45mg conjugated estrogens/20 mg bazedoxifene) tablets.
Product will be taken orally by patient every day for two months.
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
Microcrystalline cellulose placebo
Product will be taken orally by patient every day for two months.
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY
Subjects will be on study for up to 70 days
Screening:  2 weeks
Treatment:  2 months
CONCOMMITANT 
MEDICATIONS
Allowed: MS disease modifying and symptomatic therapies, antidepressants 
(no adjustments within 2 months of baseline visit)
Prohibited: hormone therapies (estrogen, testosterone, progesterone), hot flash 
therapies; lamotrigine, oxcarbazepine
EFFICACY 
EVALUATIONS
PRIMARY 
ENDPOINT
The primary measure will be the daily number of hot flashes averaged over 3 
days (daily diary)
SECONDARY 
ENDPOINTS

sleep quality (ISI questionnaire)

Treatment Satisfaction Questionnaire for Medications (TSQM) global 
score

MS Rating Scale (MSRS) global score

SF36 PCS (physical component score). 

MRI: number of new or enhancing lesions
OTHER 
EVALUATIONS

Safety labs: LFTs

Exploratory measures: corpus callosum tract integrity on DTI, cognitive 
function, other QOL outcomes (fatigue, mood)

Blood samples stored for hormone levels (estradiol, testosterone, sex 
hormone binding globulin) and for immunology.


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SAFETY 
EVALUATIONS
Phone call at week 6 to see if patient is experiencing any unacceptable side 
effects.
When approximately 50% of patients have completed the study through Study 
Visit 2 (total visit 3), an interim analysis for safety will be conducted by the PI. 
Serious adverse events will be monitored by the committee on an ongoing basis 
throughout the study.
Incidence of adverse events.
PLANNED INTERIM 
ANALYSES 
When approximately 50% of patients have completed the study through Study 
Visit 2 (total visit 3), an interim analysis for safety will be conducted by the PI. 
Serious adverse events will be monitored by the committee on an ongoing basis 
throughout the study.
STATISTICS
Primary Analysis 
Plan
We will perform t-tests comparing the absolute changes in outcomes from the 
baseline to the 2-month visit in the two treatment groups.
Aim 1. Effect of CE+BZA on menopausal symptoms. The primary measure will 
be the daily number of hot flashes averaged over 3 days (daily diary), and the 
secondary measure will be sleep quality (ISI questionnaire).
Aim 2. Effect of CE+BZA on MS outcomes. The primary measure will be the 
MS Rating Scale (MSRS) global score, and the secondary measure will be the 
SF36 PCS (physical component score). Exploratory measures will include 
corpus callosum tract integrity on DTI, cognitive function (SDMT), and other 
QOL outcomes (MFIS, SF36 sub-scales, depression scale).
Aim 3. Tolerability of CE+BZA. The primary measure will be the percentage of 
subjects reporting side effects on the Treatment Satisfaction Questionnaire for 
Medications (TSQM) global score, and the MS-specific secondary measure will 
be the number of new or enhancing lesions on MRI.
Rationale for Number 
of Subjects
Given this is a pilot study, we will view the study as a success if the observed 
mean change in the treatment group is larger by any amount compared to the 
placebo group (“play the winner” approach). In healthy women treated with 
estradiol for 8 weeks,(Joffe et al., 2014) VMS decreased by 2.2 daily in the 
placebo group and 4.5 in the estradiol group and the SD for the change was 3.4. 
Assuming same differences and SD, we will have 80% power to find the 
treatment arm mean difference to be larger with our proposed sample size.


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1
BACKGROUND
Menopause in MS. Multiple sclerosis (MS) affects 3 times more women than men, and before age 
50 in about 90% cases, i.e. prior to menopause (Bove et al., 2012). There is broad evidence for 
hormonal regulation of MS in animal models (Gold & Voskuhl, 2009) and in clinical cohorts (e.g. 
pregnancy (Bove & Chitnis, 2014)).
Around menopause, many clinical patients report symptom worsening associated with hot flashes, 
sleep disturbance or mood changes. Longer-term, an age-related decline in gonadal steroids might 
represent one sex-specific influence (Clayton & Collins, 2014) on the known age-related increases 
in disability and conversion to progressive course (Tutuncu et al., 2013), which is marked by 
accelerated brain volume loss and neurodegeneration. Recent data suggest that MS disease 
severity may worsen after menopause (Bove & al., 2014; Bove et al., 2015).
Hormone therapy (HT). In healthy women, after the abrupt decline in estradiol occurring with 
early oophorectomy, there is an increased risk for cognitive decline and dementia (Coppus et al., 
2010; Corbo et al., 2011; Henderson & Sherwin, 2007; Phung et al., 2010; Rocca et al., 2007; 
Vearncombe & Pachana, 2009; Zhou et al., 2011) and gray matter (GM) loss in functionally 
important regions (e.g. hippocampus)(Goto et al., 2011). HT, when taken within a perimenopausal 
“window of opportunity” (5 years), may protect against neurodegeneration, (Bove et al., 2014b; 
Henderson, 2013; Rocca et al., 2011; Shao et al., 2012) perhaps due to sparing effects on regional 
GM atrophy (Boccardi et al., 2006; Lord et al., 2010; Robertson et al., 2009). 
Despite the benefits of HT (menopausal symptoms, bone density), very few women (<30% of our 
cohort) are currently taking HT for menopausal symptoms; this is a result of risks such as (1) 
breast and endometrial cancer, and (2) stroke in older women in the Women’s Health Initiative 
(NAMS; Langer et al., 2012; Rapp et al., 2003). 
INNOVATION: To date, there are no objective assessments of the impact of HT on MS disease 
course. In an initial pilot designed at providing HT to women with MS, we plan to investigate the 
tolerability of Duavee in treating menopausal symptoms in women with MS.
Our treatment, Duavee, has been approved by the FDA for the following indications:
1.    Treatment of moderate to severe vasomotor symptoms associated with menopause
2.    Prevention of postmenopausal osteoporosis
(http://www.accessdata.fda.gov/drugsatfdadocs/label/2006/004782s147lbl.pdf)
Duavee is commercially available.
1.1
Overview of Non-Clinical Studies
SERMs in MS animal models. 
Estrogen receptor (ER) α and β and membrane (m)ERs are present on oligodendrocyte lineage 
cells. In an animal model of MS, experimental autoimmune encephalomyelitis (EAE), SERMs 
have been explored for their potential in stimulating endogenous myelination and sparing axonal 
degeneration. Bebo et al found that both tamoxifen and raloxifene (two commercially available 
SERMs) suppressed myelin antigen specific T-cell proliferation, with tamoxifen being more 
effective. Tamoxifen treatment reduced the induction of major histocompatibility complex II by 


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lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific 
T-cells. At lower doses, tamoxifen also increased the levels of Th2 transcription factors and 
induced a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of 
demyelination were less severe in mice treated with tamoxifen than in control mice.1 
In subsequent work, the estrogen receptor (ER) β ligand 2,3-bis(4-hydroxyphenyl)-propionitrile 
(DPN) has been found to reduce clinical disease, be neuroprotective, stimulate endogenous 
myelination, and improve axon conduction without altering peripheral cytokine production or 
reducing central nervous system (CNS) inflammation. Both prophylactic and therapeutic 
treatments with DPN during EAE were found to improve remyelination-induced axon conduction, 
suggesting adirect effect of treatment on oligodendrocytes. DPN treatment of EAE animals 
resulted in phosphorylated ERβ and activated the phosphatidylinositol 3-kinase (PI3K)/serine-
threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling 
pathway, a pathway required for oligodendrocyte survival and axon myelination.2 Altogether, 
these studies suggest that SERMs may exert beneficial effects on neuroprotection through ER-beta 
modulation.
1.2 Overview of Clinical Studies
HT: What is the evidence? 
Hormone therapy (HT) during menopause is an area of active inquiry. HT typically consists of 
estrogen therapy (ET) or combined estrogen-protestogen (EPT) therapy, either administered orally 
(ET and EPT), vaginally (ET) or transdermally (low dose estrogen). While HT has been proven to 
alleviate many menopausal symptoms, it is also associated with risks.[68] Currently, the North 
American Menopause Society (NAMS) recommends individualized HT treatment based on a 
patient’s risk profile, for the shortest possible duration and at the lowest possible dose.[68] 
General benefits and Risks. 
Benefits. According to the NAMS 2012 consensus statement, HT is the most effective treatment 
for menopause-related vasomotor symptoms (ET with or without progestogen) and for moderate 
to severe symptoms of vulvar and vaginal atrophy (local vaginal ET, systemic HT). Additionally, 
P HT is effective against overactive bladder (local ET; systemic HT may provoke or worsen stress 
incontinence), reduces the risk of recurrent UTIs (vaginal ET), improves health-related quality of 
life (HQOL) in symptomatic menopausal women, and may reduce the diagnosis of new onset type 
2 diabetes mellitus. At low doses, HT maintains or improves bone mass density (BMD) and at 
standard doses, reduces postmenopausal osteoporotic fractures even in women without 
osteoporosis. Additionally, in observational studies at least, HT was associated with lower risks of 
venous thromboembolism and stroke (transdermal and low-dose ET). There is to date no report of 
significant improvement in libido associated with HT, although low dose local ET may improve 
vaginal symptoms such as lubrication, blood flow and sensation.[68]  
Risks: Unopposed systemic ET in postmenopausal women with an intact uterus is associated with 
increased endometrial cancer risk; concomittant progestogen is therefore recommended. In 
addition, EPT initiated close to the onset of menopause may be associated be an increased risk of 
breast cancer; this increased risk has not been observed in ET. HT use in breast cancer survivors 
may be associated with an increased risk of recurrence. EPT use for longer than 5-10 years may be 
associated with an increased risk of ovarian cancer, although the incidence rate is rare. There may 
also be increased risk of lung cancer, or of more aggressive lung cancer, particularly in smokers. 


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Currently, HT is considered primarily in women ages 50-59, within 10 years of menopause. In this 
age group, HT used for menopausal symptoms is not felt to increase the risk of CHD events, and 
in fact ET initiated early postmenopausally may reduce coronary artery disease and CHD risk.[68] 
HT and neuroprotection.
Observational studies have suggested that HT, when taken within a “window of opportunity” 
relative to menopause (operationally defined as 5 years), may be protective against cognitive 
decline including Alzheimer’s disease.[69] Beyond this, perhaps due to estrogen receptor down-
regulation, HT may even be harmful, leading to increased risk of stroke and dementia. This 
hypothesis appears to explain findings from the Women’s Health Initiative Memory Study 
(WHIMS), a subset of the Women’s Health Initiative, a landmark longitudinal study that included 
randomized controlled trials evaluating the effects of (1) unopposed estrogen and (2) EPT 
compared with placebo on a diverse set of health outcomes. In WHIMS, HT when initiated in 
women aged 65 or above was associated with an increased risk of dementia of any cause and of 
cognitive decline [70]. Longitudinal placebo-controlled trials of the effects of HT, initiated within 
the “window of opportunity,” on long-term risk of cognitive decline are awaited. HT 
considerations in MS. Given the initially negative findings from the Women’s Health Initiative, 
very few women who are currently perimenopausal are treated with HT,5 limiting the power of 
longitudinal observational studies. Of particular importance in MS, are the long-term effects of HT 
on neuroprotection, altered immune regulation, and osteoporosis, which are more common in 
women with MS than in healthy women in study populations. Therefore, the benefit:risk ratio in 
these patients may be different from those in the general population. Additionally, because many 
women with MS are at increased risk of premature ovarian failure due to their exposure to 
cyclophosphamide and novantrone, the benefits to them of a longer duration of HT exposure are 
unknown. Longitudinal studies are required to uncover the effect that HT may have, if any, on the 
aggregate balance of neuroinflammation and neurodegeneration seen in MS, as well as in patients’ 
experiences and quality of life (QOL).  
As a response to the mixture of desirable and undesirable effects of estrogen formulations on 
various tissues, through a combination of agonistic, neutral and antagonistic effects, selective 
estrogen receptor modulators (SERMs) have been developed, with a wide range of effects.  
TSECs: Focus on CE/BZA. One important consideration of treating human females with 
SERMs, again, is the impact of these compounds on various tissues. Tamoxifen, despite its 
promising effects in EAE, induces hot flashes, which may severely limit its immediate 
tolerability in perimenopausal MS women, who in our experience worsening of symptoms, 
perhaps through the Uhthoff phenomenon.3 
More recently, tissue selective estrogen complexes (TSECs) have been developed to combine 
the benefits of estrogen with SERMs’ tissue-specific properties.4  TSECs provide a progestin-
free alternative to traditional estrogen-progestin therapy (EPT) in women with a uterus. 
Specifically, the effects on breast and endometrial proliferation, as well as venous 
thromboembolism, observed with estrogens were not noted when estrogen was combined 
with bazefoxifene, and in fact, BZA appears to mitigate the effects of the estrogen.4  
The following provides a summary of pre-clinical and clinical data that highlight the 
safety of the medication, and in contrast to purely estrogen compounds. 4   


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Effect of menopause in MS. In individuals with MS onset after age 50 there are fewer sex 
differences (1) in disease type or (2) in time to an EDSS of 6 than there are in individuals with MS 
onset prior to age 50. This suggests that changes around age 50 (menopause) may contribute to a 
narrowing of sex differences (Bove et al., 2012).
In a cohort of postmenopausal women, 124 had been prospectively followed through their 
menopause during CLIMB. In these women, we noted an inflection point in subjects’ disease 
severity at the time of menopause (Bove et al, MS Journal 2015, in press). The rate of EDSS 
change increased from 0.047 units per year before, to 0.15 units per year after menopause 
(difference of 0.10 units; 95% CI: 0.03, 0.17, p=0.005). A similar effect was observed in both the 
natural and surgical menopause groups. When women with only post-menopausal measurements 
(n=267) were also included in the model, the estimated increase in the average yearly change was 
0.052 units per year (95% CI: 0.005, 0.098, p=0.029). These women were followed for a mean 
duration of 10 years (SD 2.6, range 0.9-16.6), and have both pre- and post-menopausal serial MRI 
and blood samples available.
These data were substantiated by results from a patient-powered online research platform, 
PatientsLikeMe, Inc (PLM).(Bove et al., 2013c) Using results from a reproductive survey 
deployed to “active users”, we compared prospectively collected disease severity scores (MS 
Rating Score (MSRS), good correlation with EDSS(Bove et al., 2013c)) according to reproductive 
status. The mean (SD) MSRS at the time of the questionnaire was higher in the surgical 
menopause group (13.1 (5.4)) than in the natural menopause (9.6 (5.1)) or cycling (8.9 (5.5)) 
groups (age, disease duration and category-adjusted difference for surgical vs. pre=3.27; 
p<0.0001; surgical vs. natural=3.44; p<0.0001). A significant effect of menopausal age was 
observed when this was included in the model (p<0.001). Interestingly, we found associations of 
menopausal status with MS symptoms for the global MSRS score as well as for individual MSRS 


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domains not typically overlapping with menopausal symptoms (Bove et al, MS and Related 
Diseases 2015). Despite the obvious biases in online research, these findings are suggestive 
because of the biologically plausible associations with early, surgical menopause.
Effect of sex and gonadal steroids in MS neuroimaging. Our first set of preliminary data come 
from a comparison of BPFs in 4 cohorts: men and women, aged less than (38-46) and greater than 
(54-62) 50 years, and followed for 2 years. In that study, we found that both the older and male 
cohorts had significantly greater rates of BPF atrophy than the younger and female cohorts (Table 
3). Men had lower BPF in a generalized linear model adjusting for age, disease type and duration 
(p<0.0001). We assessed a sex*age interaction to determine whether there were sex –specific 
changes occurring after age 50, and this was negative. A very important limitation is that 
menopausal status in these cohorts was not known at the time, and therefore it is possible that a 
subset of the women aged under 50 had already experienced early, surgical menopause.(R. Bove 
et al., 2013b) 
In a preliminary analysis related to our neuroimaging measure, the corpus callosum (CC), we 
measured crosssectional area of the CC (as detailed in Aim 1b) for 228 MRI scans where subject 
menopausal status was known (RB training set). We found that CC area was significantly 
associated with timing of menopause (est= -3 mm2 per year since menopause, p=0.0066) but not 
with age at MRI (p=0.57), when both were included in a model.
Hormonal trials.
Trials of estrogen treatment in healthy perimenopausal women:
Recent approaches to treating VMS have compared low-dose oral 17β-estradiol (0.5 mg/d) (n=97), 
with SSRI/SNRIs (E.g. low-dose venlafaxine hydrochloride extended release (75 mg/d) (n=96)) or 
placebo (n=146) for 8 weeks. Estradiol reduced the frequency of symptoms by 2.3 more per day 
than placebo (P<.001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day 
than placebo (P=.005). Importantly, within 8 weeks, significant reduction in VMS were noted with 
both therapies (Joffe et al., 2014).
HT in women with MS. Using data from the Nurses Health Study (NHS), the PI and 
collaborators examined the association between perimenopausal HT use and a physical 
functioning assessment (PF10; subscale of the Short Form 36 (SF-36) QOL survey) at a timepoint 
between 3 and 10 years after their final menstrual period (early postmenopause) (Bove et al, under 
review). We assessed the association between HT use at this timepoint (never vs. at least 12 
months of systemic estrogen with/without progestin) and both PF10 and the SF-36 Physical 
Component Scale (PCS). We employed a linear regression model adjusted for age, MS duration, 
and menopause type and duration, and further for other significant covariates (ancestry). HT users 
had average PF10 scores that were 23 points higher than non-HT users (adjusted p=0.004), and 
average PCS scores that were 9.15 points higher in the subset of 59 women with these available 
(adjusted p=0.021). Duration of HT use showed a similar trend for PF10 (adjusted p=0.057). 
While this study cannot establish causality, it does suggest that HT may not result in excess 
adverse outcomes in women with MS.
2
STUDY RATIONALE
Duavee is an approved medication for menopausal symptoms.
The risks of Duavee are shown to be extremely minimal by FDA reports on previous 
clinical trials and by their approval of the drug. These minimal risks may be 


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outweighed by the therapeutic potential of Duavee in menopausal women with MS.
2.1
Risk / Benefit Assessment
Information from this study will benefit others because the medical community will gain more 
knowledge on hot flashes in MS patients, and responses to the study medication. Due to the low 
risks associated with participation in this study, the potential benefits of self-monitoring hot 
flashes outweigh the risks.
3
STUDY OBJECTIVES
3.1
Primary Objective
The goal of this pilot grant is to assess the tolerability of Duavee in a cohort of MS women, and to 
obtain preliminary data regarding its impact on MS outcomes (advanced neuroimaging, patient-
reported measures).  
3.2
Secondary Objectives
Aim 1. To explore the hypothesis that CE+BZA improves menopausal symptoms in MS 
women.
Aim 2. To explore the hypothesis that CE+BZA results in improvement in MS-related 
outcomes.
Aim 3. To explore the hypothesis that CE+BZA for 8 weeks is tolerable in women with MS.
4
STUDY DESIGN
4.1
Study Overview
Women will be randomized to treatment with Duavee (conjugated estrogens + bazedoxifene) vs. 
conjugated estrogen vs. placebo. They will undergo MRI with DTI and fMRI both at baseline and 
again after 2 months of treatment. While our primary comparisons of interest are Duavee vs. 
placebo, the premarin arm is included in order to provide preliminary data to dissect out an effect 
of estrogen vs.bazedoxifene.
Participation will include a screening visit, 2 study visits, 2 phone calls, and taking Duavee or the 
placebo once daily for two months as well as keeping daily hot flash and sleep diaries throughout 
participation in the study.
The Screening visit will occur at the MS Clinic. Eligible subjects will then be contacted to return 
to enroll. Enrollement/Study Visit 1 and Study Visit 2 will be separated by 2 months and consist 
of neuroimaging, PROs, blood draws and neuropsychological testing.  Between visits 1 and 2, 
subjects will complete diaries. They will also be contacted at 1 week and 4 weeks. After Visit 2, 
subjects will be contacted for follow up and at their 6M regularly scheduled clinic visit.
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study. 
Total duration of subject participation will be ten weeks.  


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5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
Three primary measurements to assess each of the three aims:
- The number of daily vasomotor symptoms (VMS), obtained from the patient diary. In healthy 
women, this was shown to significantly decrease with estradiol treatment at 8 weeks (Joffe et al., 
2014). Power calculation: Given this is a pilot study, we will view the study as a success if the 
observed mean change in the treatment group is larger by any amount compared to the placebo 
group (“play the winner” approach). In healthy women treated with estradiol for 8 weeks (Joffe et 
al., 2014), VMS decreased by 2.2 daily in the placebo group and 4.5 in the estradiol group and the 
SD for the change was 3.4. Assuming same differences and SD, we will have 80% power to find 
the treatment arm mean difference to be larger with our proposed sample size. This will explore 
the hypothesis that CE+BZA improves menopausal symptoms in MS women.
- The MSRS, a global score capturing patient impressions of MS severity across eight function 
domains, and which in a tertiary care referral clinic population has shown good correlation with 
the EDSS. (Bove et al., 2013, Wicks et al., 2012) This will explore the hypothesis that CE+BZA 
results in improvement in MS-related outcomes.
- The percentage of subjects reporting side effects on the Satisfaction Questionnaire for 
Medication (TSQM) (Atkinson et al., 2004), which is commonly used in MS treatment studies 
(e.g. Calkwood et al., 2014). This will explore the hypothesis that CE+BZA for 8 weeks is 
tolerable in women with MS.
5.2
Secondary Efficacy Endpoints
-  Our secondary endpoints to test the hypothesis that CE+BZA improves menopausal symptoms 
in MS women will be sleep quality from sleep diary.  
- Our secondary endpoints to test the hypothesis that CE+BZA results in improvement in MS-
related outcomes will include MSQOL54 composite score (primary), measures of mood (CES-D), 
fatigue (MFIS), cognition (MSNQ), and bladder (MSQLI BLCS).
- Our secondary endpoints to test the hypothesis that CE+BZA for 8 weeks is tolerable in women 
with MS will be number of missed doses, and the number of new or enhancing lesions on 8-week 
MRI, to verify that CE+BZA does not yield any marked changes in inflammatory activity. 
5.3
Safety Evaluations
We will have 3 formal means of evaluating safety concerns during the course of the study:
(1) All patients receive an interim phone call at week 6 to see if patient is experiencing any 
unacceptable side effects. We will compare rates in the 2 groups. 
(2) When approximately 50% of patients have completed the study through Study Visit 2 
(total visit 3), an interim analysis for safety will be conducted by the PI, including clinical 
measures as well as effects on liver function. Serious adverse events will be monitored by 
the committee on an ongoing basis throughout the study.
(3) Also, we will compare MRI outcomes in the first 12 patients, in order to ensure that there 
is no increased MRI signal. 


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At the end of the study, we will perform a comparison of liver tests, chemistry, hematology, 
treatment satisfaction, and clinical reported AEs, across the whole group. We will compare uring 
t-tests. 
6
SUBJECT SELECTION
6.1
Study Population
Subjects with a diagnosis of multiple sclerosis who meet the inclusion and exclusion criteria will 
be eligible for participation in this study.  
6.2
Inclusion Criteria
Menopause/HT considerations:

Women aged 40-62 years.

Perimenopausal: We will use the widely used criterion of 6 months of amenorrhea (this 
corresponds to either the late menopausal transition (periods separated by at least 60d) or 
early postmenopause (LMP within 2Y) (STRAW +10; Figure 1; [8]).
o
This can include

Women who have had a bi-lateral oöphorectomy;

Women without a uterus and who still have one or both ovaries, with FSH 
level > 20 mIU/mL and estradiol ≤ 50 pg/mL (on at least one of two 
blood draws two weeks apart);

Women with a uterus who have skipped 2 or more menstrual cycles with 
an amenorrhea interval >=6 months in the past 12 months;

Women who are using the Mirena IUD or who have had an endometrial 
ablation and who still have one or both ovaries, with FSH level > 20 
mIU/mL and estradiol ≤ 50 pg/mL (on at least one of two blood draws 
two weeks apart).

A mean of two or more hot flashes/night sweats per day (24 hrs) as reported on daily hot 
flash diaries collected over 2 weeks.

Hot flashes/night sweats rated as bothersome (‘moderately’ to ‘a lot’) and/or severe 
(‘moderate’ to ‘severe’) on 4 or more 12 hour (day/night) blocks of times in each of the 2 
weeks of diary completion.  This criterion must be met on at least one of the 4 scales on 
the symptom reports (daytime severity, nighttime severity, daytime bother, nighttime 
bother).

In general good health as determined by medical history, blood pressure, and heart rate.

Absence of uncontrolled hypertension (>160/95 mmHg);

Resting heart rate <110/minute;

No history of myocardial infarction, angina, or cerebrovascular events;

No symptoms consistent with or history of thrombo-embolism, deep vein thrombosis, 
congestive heart failure;

No history of endometrial, ovarian, or breast cancer;

No abnormal mammogram in the last 2 years. Women with an abnormal screening 
mammogram that was found to be benign after additional evaluation are eligible. If a 
participant has not had a mammogram in the last 2 years, she will be encouraged to 
schedule one but will not be excluded from study participation if she declines;


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
Normal physical and breast exam in the last two years. (If a participant has not had a 
physical exam in the last 2 years, she will be required to schedule one before 
randomization.)

Absence of any current severe or unstable medical illness.

Signed informed consent.
MS considerations:

Documentation of a multiple sclerosis diagnosis as evidenced by one or more clinical 
features consistent with the multiple sclerosis phenotype, and one or more of the following 
criteria: 
o
If using psychotropic medications (SSRIs, SNRIs, MAOIs, and other 
antidepressants) and anxiolytics, no change in the past 3 months.
o
If on DMT, no change in past 6 months.
o
Normal vitamin D levels (20-50 ng/mL).
6.3
Exclusion Criteria
HT considerations

BMI >30 kg/m2 as higher BMI may affect PK/PD

Use of hormone therapy or hormonal contraceptives (with the exception of the Mirena 
IUD) during the 2 months before enrollment.  Vaginal postmenopausal estrogens allowed, 
with the exception of vaginal creams used >3 times a week.

Use of any prescribed therapy that is taken specifically for hot flashes in the past 1 month.

Use of any over-the-counter or herbal therapies that are taken specifically for hot flashes 
in the past 2 weeks.

Use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors during the 
2 months before enrollment.

Known hypersensitivity or contraindications to estrogen.

Not using a medically approved method of birth control, if sexually active and not 12 or 
more months since last menstrual period.

Drug or alcohol abuse in the past 1 year.

Depression: moderate or severe (HAD score > 8)

Other psychiatric disease meeting DSM-IV criteria (bipolar disorder, obsessive 
compulsive disorder, or schizophrenia

Lifetime diagnosis of psychosis or bipolar disorder.

Pregnancy, intending pregnancy, or breast feeding.

Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver; 
coadministration with UGT inducers (lamotrigine, oxcarbazepine) may reduce 
bazedoxifene exposure/efficacy and therefore increase risk of endometrial hyperplasia

History of any of the following, as determined by clinician review of the potential 
participant’s medical history:
o
Pre-breast cancer or high-risk breast cancer condition;
o
Abnormal bleeding suggestive of endometrial pre-cancer;
o
Endometrial hyperplasia.
o
Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable or 
under medical management
o
Active or past history of venous or arterial thromboembolism
o
History of gallstones IF gallbladder intact


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o
Known or suspected estrogen-dependent neoplasia
o
History of coronary artery disease
o
Hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any 
ingredients
o
Known hepatic impairment or disease
o
Thyroid dysfunction on thyroid medications
o
Known hypoparathyroidism

Blood test results indicating:  
o
Liver function tests: AST >2.5 times upper limit of normal; ALT >2.5 times upper 
limit of normal; total bilirubin 1.5 times upper limit of normal;
o
Kidney test: creatinine >1.5 mg/dL;
o
Blood count:  hematocrit <30%;
o
Hemoglobin <8 g/dL.

Current participation in another drug trial or intervention study.

Inability or unwillingness to complete the study procedures.
MS considerations:

Clinical relapse within the last three months (to ensure disease stability)

Steroid treatment in prior 1 month

Evidence of other structural brain disease (e.g. prior stroke)
MRI considerations:

Left handed

Metal implants

Prior head trauma

Claustrophobia requiring anxiolytic or sedation, or other contraindication to MRI.
7
CONCURRENT MEDICATIONS
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies.
7.1
Allowed Medications and Treatments
Standard therapy for Multiple Sclerosis is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below.  
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be considered a 
protocol violation: other hormone therapies, other hot flash therapies, UGT inducers (lamotrigine, 
oxcarbazepine).
8
STUDY TREATMENTS
8.1
Method of Assigning Subjects to Treatment Groups
Up to 24 eligible patients will be randomly assigned to DUAVEE or placebo treatment groups in a 
1:1 ratio using a SAS-based computer-generated randomization scheme developed by the study 


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data management provider. The CTSI statistician advising the PI will complete a randomization 
worksheet.
8.2
Blinding
Due to the objectives of the study, the identity of test and control treatments will not be known to 
investigators, research staff, or patients.  The following study procedures will be in place to ensure 
double-blind administration of study treatments.  
- Access to the randomization code will be strictly controlled.  
- The CTSI statistician advising the PI will perform the randomization/blinding chart and provide 
this to the Compounding Pharmacy. They will perform interim safety analysis without umblinding 
the study, and will only unblind the study to the investigators at the end of study. 
- Packaging and labeling of test and control treatments will be identical to maintain the blind. 
- Packaging and labeling will be done by pharmacy personnel who are not involved in analysis of 
study data.
The study blind will be broken on completion of the clinical study and after the study database has 
been locked. The investigators will be given the randomization worksheet from the CTSI 
statistician after the last participant has completed their study.
During the study, the blind may be broken only in emergencies when knowledge of the patient’s 
treatment group is necessary for further patient management. When possible, the Investigator 
should discuss the emergency with Dr. Ari Green prior to unblinding.  
8.3
Formulation of Test and Control Products
8.3.1
Formulation of Test Product
DUAVEE (conjugated estrogens/bazedoxifene) tablets, 0.45 mg/20 mg will be manufactured by 
Pfizer, Inc.
Duavee is an oral, biconvex, pink tablet branded with “0.45/20” in black ink on one side. 
For blinding, it will be made into encapsulated into a gelatin capsule and fill remaining space with 
microcrystalline cellulose, by the Safeway Compounding Pharmacy (Dr. Jack Castaldo) at:
Compounding Pharmacist/BHRT Consultant
Safeway Compounding Pharmacy
6100 Hellyer Ave #100
San Jose, Ca. 95138. 
Table X: Formulation and Measured pH of Duavee and Placebo
Duavee
Placebo
Active 
Ingredient, 
mg/mL
Conjugated estrogens, 0.45 mg (mixture of sodium 
estrone sulfate and sodium equilin sulfate and other 
components, including sodium sulfate conjugates, 
17α-dihydroequilin, 17α-estradiol, and 17β-
dihydroequilin.)


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Bazedoxifene, 20 mg
Other 
ingredient, 
mg/mL
calcium phosphate tribasic, hydroxypropyl cellulose, 
microcrystalline cellulose, powdered cellulose, 
hypromellose, lactose monohydrate, magnesium 
stearate, polyethylene glycol, sucrose, ascorbic acid, 
sucrose palmitic acid ester, hydroxyethylcellulose, 
titanium dioxide, red iron oxide, yellow iron oxide, 
black iron oxide, povidone, polydextrose, maltitol, 
poloxamer 188, propylene glycol, isopropyl alcohol.
microcrystalline 
cellulose
pH
8.3.2
Formulation of Control Product
Placebo is: Microcrystalline cellulose, encapsulated into a gelatin capsule, taken daily. 
8.3.3
Packaging and Labeling
Both the drug and the placebo will be single use daily tablets packaged into monthly blister packs. 
Each carton (kit) of study drug will be labeled with the required FDA warning statement, the 
protocol number, a treatment number, the name of the sponsors, and directions for patient use and 
storage.
8.4
Supply of Study Drug at the Site
The Sponsor (or designee) will ship Study Drug to the investigational pharmacy.  The initial study 
drug shipment will be shipped after site activation (i.e., all required regulatory documentation has 
been received by the Sponsor and a contract has been executed). Subsequent study drug shipments 
will be made after site request for resupply.
The randomization and blinding chart will be provided by CTSI statistician to the pharmacy 
personnel. The Safeway Compounding Pharmacy then ship the study drug to the PI, and the 
research team (PI or research coordinator) will give the 8-week package to participants at their 
Visit 1.
8.4.1
Dosage/Dosage Regimen
The medication (Duavee or placebo) will be taken once daily, in the morning, for 8 weeks. The 
Duavee dosing is: 0.45mg conjugated estrogens/20 mg bazedoxifene.
8.4.2
Dispensing
The Safeway Compounding pharmacy will ship the drugs to study personnel, who will then give 
the samples to the study participants at their Visit 1.
8.4.3
Administration Instructions 
Patients will take this tablet orally once a day.


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8.5
Supply of Study Drug at the Site
Study personnel will receive the Study Drug/placebo shipment from the Safeway Compounding 
Pharmacy and maintain it under locked conditions in the Sandler Neurosciences Center. Subjects 
will be randomized and provided the study drug on the same day.
8.5.1
Storage
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59 to 
86ºF). Subjects will be instructed to store the medication in blister packaging at room temperature 
according to the instructions outlined on the Drug Administration Instructions.
8.6
Study Drug Accountability
An accurate and current accounting of the dispensing and return of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff.  The number of study drug 
dispensed and returned by the subject will be recorded on the Investigational Drug Accountability 
Record.  The study monitor will verify these documents throughout the course of the study.
8.7
Measures of Treatment Compliance
Subjects will be asked to keep a patient diary noting the day and date they take their study drug 
and any adverse events. They will be asked to bring their patient diary to each study visit along 
with all used and unused study drug containers.
9
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the duration 
of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the 
subject.  If appropriate, assent must also be obtained prior to conducting any study-related 
activities.
9.1
Clinical Assessments
9.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at Screening and at the 
first Study Visit on Week 2, at final Visit on Week 10, and at early termination when applicable.  
Dose, route, unit frequency of administration, and indication for administration and dates of 
medication will be captured.
9.1.2
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.
9.1.3
Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at Screening.


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9.1.4
Physical Examination
A complete physical examination will be performed by either the investigator or a sub-investigator 
who is a physician at the Screening Visit. Qualified staff (MD, NP, RN, and PA) may complete 
the abbreviated physical exam at all other visits.  New abnormal physical exam findings must be 
documented and will be followed by a physician or other qualified staff at the next scheduled visit.
9.1.5
Vital Signs
Body temperature, blood pressure, pulse and respirations will be performed after resting for 
5 minutes at all Study Visits.
9.1.6
Other Clinical Procedures
Neurological examination:
Expanded Disability Status Scale (EDSS): EDSS Score will be determined, based on neurological 
examination, by a trained certified EDSS rater at scheduled visits according to the Schedule Table, 
using the validated Neurostatus scoring system. Individual patients will have EDSS performed by 
same rater on each visit. The EDSS is an ordinal scale used for assessing neurological impairment 
of MS based on a neurological examination. It consists of scores in each of seven functional 
systems (FS) and an ambulation score that are then combined to determine the EDSS [ranging 
from 0 (normal) to 10 (death due to MS)]. The FSs are the Visual, Brain Stem, Pyramidal, 
Cerebellar, Sensory, Bowel & Bladder, and Cerebral functions. The FSs and EDSS steps will be 
assessed in a standardized manner. EDSS is a widely used and accepted instrument to evaluate 
disability status at a given time and longitudinally, to assess disability progression in clinical 
studies in MS.
T25W: The Timed 25-foot Walk will be assessed according to the schedule in the Table. The 
Timed Walk is an objective quantitative test of neurological function, and is one of three 
components of the Multiple Sclerosis Functional Composite (MSFC), a composite measure 
assessing upper extremity function, ambulation and cognitive function (Fisher et al. 1999). The 
Timed Walk is an ambulation measurement: a walk of 25 feet (7.62 meters): time taken in 
seconds. The Timed Walk test will be administered either by the Independent EDSS Rater or by 
another qualified individual not involved in the treatment of the patients.
Patient-reported Outcomes:
MSQOL 54: The Multiple Sclerosis Quality of Life- 54 (MSQOL-54) was the first MS-specific 
QOL measure.(1, 2) It includes a 36 generic instrument as well as 18 additional items, for a total 
of 54 items. (3) It is graded on 12 subscales and 2 summary scores: the Physical Health and 
Mental Health Composite Summaries.
MFIS: The Modified Fatigue Impact Scale (MFIS)(4) is a 21-item fatigue scale that measures the 
physical, cognitive, and psychosocial aspects of fatigue.
HAD: Hospital Anxiety and Depression Scale (HADS)(5) cutoff is 8 for anxiety, depression.
MS Rating Score-Revised: (MSRS, free under Creative Commons License), patients rate their 
disability on a 0-4 scale in 8 areas (walking, use of upper extremities, speech disturbance, vision, 
dysphagia, cognitive or affective disturbance, sensory disturbance and bowel/bladder). Composite 
scores range from 0-32. The patient-reported MSRS has shown high internal consistency, 


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concordant validity with the NARCOMS Patient-Determined Disease Step, and demonstrated 
adequate known-groups validity (6). In a clinic population, the previous version (MSRS) has 
demonstrated good correlations with physician-derived EDSS (MSRS composite score rs=0.61, 
MSRS walking domain rs =0.74)(7).
Bladder Control (MSQLI version): This questionnaire assesses bladder symptoms and has been 
validated in MS (8).
MSNQ: MS Neuropsychological Screening questionnaire (9).
Neuropsychological Tests:
Symbol Digit Modalities Test (SDMT):
The SDMT is a sensitive and specific test to assess processing speed and working memory which 
are typically affected domains in cognitively impaired MS patients. The SDMT has been found to 
accurately categorize 72% of MS subjects as cognitively impaired based on a longer, 
comprehensive test battery.
During the administration of the SDMT, only the examiner and the patient should be in the testing 
room. The examiner can be the study coordinator, independent EDSS Rater or a qualified 
individual not involved in the treatment of the patients who has been instructed in the appropriate 
administration of the test. Patients are presented with a test instrument at the top of which there is 
a row of nine numbers paired with unique symbols. Below this part of the test instrument is an 
array of symbols paired with empty spaces, the patient’s task is to verbally match the number for 
each symbol as quickly as possible. The test takes approximately 5 minutes to administer. The test 
scoring is calculated based on the number of correct answers in 90 seconds. (Partmenter et al, Mult 
Scler 2007;13:52-57).
Letter Number Sequencing Subtest: LNS, from the Wechsler Memory Scale (verbal working 
memory). This test, of 5 minute duration, will be used to assess verbal working memory. We will 
use the recall score.
9.1.7
Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to study 
drug will be recorded on the case report form (CRF).
9.2
Clinical Laboratory Measurements 
9.2.1
Hematology
Blood will be obtained and sent to each site’s clinical hematology lab for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell 
differential, and platelet count).
9.2.2
Blood Chemistry Profile
Blood will be obtained and sent to each site’s clinical chemistry lab for determination of serum 
sodium, potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase, 
total bilirubin, direct bilirubin.


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Additionally, the following hormones will be measured: 

antimullerian hormone (AMH)

follicle stimulating hormone (FSH)

luteinizing hormone (LH)

estradiol (E2)

progesterone (P)

testosterone (total and free)

sex hormone binding globulin (SHBG)

vitamin D.

estrone (E1)
9.2.3
Pregnancy Test
A serum pregnancy test will be obtained from female subjects who are of childbearing age prior to 
their participation in the study.
9.3
Research Laboratory Measurements (include sections as appropriate)
9.3.1 Peripheral blood mononuclear cells (PBMCs). These will be stored for future use. Should 
there be any significant hormonal changes observed during the study, then we will pursue 
immunology testing to probe
correlations between hormonal and immunological changes.
9.3.2. MRI
There will be an MRI exam at Visit 1 and 2, for a subset of the first 12 participants.
Prior to the MRI, each participant will be asked a number of questions concerning his or health, 
lack of metal implants and absence of claustrophobia.
They will then be asked to lie down on a narrow bed that will then be moved into a tunnel that is 6 
feet by 2.5 feet. Each person will need to lie there quietly for about one hour during which time 
machine-like banging noises will occur. Earplugs will be provided to reduce the sound level. 
Communication with the technologists outside will be possible at all times by a microphone and 
loudspeaker. If the participant wishes to be removed from the magnet, this will be done 
immediately. Towards the end of the exam, an injection of gadolinium contrast will be performed 
by a registered nurse or MR technologist, just as is done for many routine clinical exams. If 
necessary, an I.V. (intravenous) line may be set up during or prior to the exam to allow the 
injection of this compound during the MRI acquisition. I.V. access is the placing of a small Teflon 
catheter or small needle into one of the veins, preferably in the arm. A small amount of fluid, 
usually normal saline (salt water) or dextrose (sugar) 5% in water is dripped in to prevent the 
catheter from clogging.
The MRI scan performed for the study will be reviewed by a neuroradiologist. The Primary 
Treating Physician must be contacted in case of unexpected findings (not consistent with MS) 
detected on the MRI scan for safety actions and Adverse Event reporting. During the study the 
scan will be assessed by the blinded trained physician  from the NIC MS MRI team. Upon 
acquisition MRI will be evaluated for quality, completeness, and adherence to the manual. 
Confirmation of MRI quality or a description of the quality problems, if detected, will be 
communicated to the investigators. If scan is incomplete or incorrectly performed, the study center 
will be asked to repeat it as soon as possible. After completion of the quality check, all scans will 
be analyzed according to a standardized procedure.


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10
EVALUATIONS BY VISIT
10.1
Visit 1 (Week 0) - SCREENING
1.
Review the study with the subject and obtain written informed consent and HIPAA 
authorization and assent, if appropriate.
2.
Assign the subject a unique screening number.
3.
Record demographics data.
4.
Record medical history, including a history of MS, diagnosis date, and prior MS treatments, 
as well as  reproductive and menopausal history.
5.
Record concomitant medications.
6.
Perform a complete physical examination.
7.
Perform and record vital signs.
8.
Perform and record results of blood pressure testing.
9.
Collect blood for clinical laboratory tests (chemistry, hematology, pregnancy test, 
hormones).
10.
Initiate subject diary
11.
Schedule subject for Visit 2 in 14 days +/-2.
10.2
Visit 2 (Day 14)
1.
Concomitant medications review.
2.
Perform abbreviated physical examination.
3.
Perform neurological examination.
4.
Obtain patient reported outcomes
5.
Perform neuropsychological testing
6.
Perform and record vital signs.
7.
Randomize subject, Dispense study drug
8.
Collect blood for research laboratory tests 
9.
MRI in ½ subjects.
10.3
Visit 3 (Week 8)
1.
Record any Adverse Experiences and/or Review subject diary for adverse experiences and 
dosing compliance.
2.
Record changes to concomitant medications.
3.
Perform abbreviated physical examination.
4.
Perform neurological examination.
5.
Obtain patient reported outcomes
6.
Perform neuropsychological testing


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7.
Perform and record vital signs.
8.
Randomize subject, Dispense study drug
9.
Collect blood for research laboratory tests 
10.
MRI in first ½ subjects.
10.4
Early Withdrawal Visit
1.
Record any Adverse Experiences and/or Review subject diary for adverse experiences and 
exclusionary medication use.
2.
Record changes to concomitant medications.
3.
Perform complete physical examination.
4.
Perform and record vital signs.
5.
Collect blood for clinical laboratory tests:  Chemistry, Hematology, Urinalysis, hormones.
11
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
11.1
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment. An AE is therefore any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product. An unexpected 
AE is one of a type not identified in nature, severity, or frequency in the current Investigator’s 
Brochure or of greater severity or frequency than expected based on the information in the 
Investigator’s Brochure.
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates 
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause.
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should 
be used to grade severity.  It should be pointed out that the term “severe” is a measure of intensity 
and that a severe AE is not necessarily serious.


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Table 1.  AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.
Severe (3)
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible.
Life-threatening (4)
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 2.
Table 2.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
11.2
Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes:

death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity


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
a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed. 
11.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per UCSF 
CHR Guidelines.  The collection period for all SAEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed.
All adverse reporting guidelines will be followed carefully. There are no procedures in this 
protocol that are considered to be high risk or pose physical harm to subjects. Nevertheless, 
unforeseen adverse events may occur. Any adverse event will be reported in writing to the IRB 
within 24 hours of the event. We will then provide a full written report to the Partners Human 
Studies Committees within 10 working days/14 calendar days. Study staff members will meet 
together weekly in a private room with the Principal Investigator to review subject-related issues 
or data problems. The Study Coordinator takes notes from the weekly meetings and records them 
into minutes which are kept on file. All information gathered in this study is reviewed and cross-
checked for accuracy and completeness by the PI. Study staff will also ensure the adherence to the 
IRB-approved protocol and integrity of the data by monitoring active case reports for missing data 
or errors, including the completeness of consent forms, on a weekly basis. If any information is 
missing or errors are found, study staff will notify the Principal Investigator and work with her to 
develop a plan of corrective action. 
All Human Subjects Committees will be notified in writing if missing data or errors are 
determined to be a protocol deviation/violation within 24 hours. 
For more urgent and severe adverse events, the PI will be notified immediately and a plan of 
action will be developed according to the policies and protocols developed over many years. The 
IRB will be notified as described above. 
In accordance with the standard operating procedures and policies of the local Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the 
IRB/IEC.  
11.3
Medical Monitoring
Dr. Riley Bove should be contacted directly at these numbers to report medical concerns or 
questions regarding safety.
Phone: (415) 595 2795
Pager: (415) 443 0871
  
12
DISCONTINUATION AND REPLACEMENT OF SUBJECTS
12.1
Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  The following is a list of 
possible reasons for study treatment discontinuation: 


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
Subject withdrawal of consent (or assent)

Subject is not compliant with study procedures

Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment:
o
Uterine bleeding, venous thromboembolic event

Protocol violation requiring discontinuation of study treatment

Lost to follow-up

Sponsor request for early termination of study

Positive pregnancy test
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or stabilized.  
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures.
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents Refer to Section 10 for early termination procedures.
12.3
Withdrawal of Subjects from the Study
A subject may be withdrawn from the study at any time if the subject, the investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue.  
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents.  As noted above, subjects who discontinue study treatment early (i.e., they withdraw 
prior to Visit 3) should have an early discontinuation visit. Refer to Section 10 for early 
termination procedures.  
12.4
Replacement of Subjects
Subjects who withdraw from the study treatment prior to Visit 3 will be replaced.  
Subjects who withdraw from the study will be replaced.  
13
PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria.  
Protocol violations for this study include, but are not limited to, the following:
Failure to meet inclusion/exclusion criteria


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Use of a prohibited concomitant medication
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The PI will determine if a protocol violation will result in withdrawal of a subject.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a Sponsor 
representative and the Investigator. A copy of the form will be filed in the site’s regulatory binder 
and in the Sponsor’s files.
14
DATA SAFETY MONITORING 
Safety Data Monitoring throughout the trial: Since this trial is a single-site trial and the overseeing 
PI will be present throughout the trial, a Data and Safety Monitoring Board is not deemed 
necessary. 
The study investigator will be responsible for monitoring safety data and adverse events recorded 
in the patient file and will be responsible for reporting such events to the CHR. 

In addition to the PI, a staff neurologist (Dr. Ari Green, a senior clinician with expertise in MS 
clinical trials) and a staff obstetrician/gynecologist (Dr. Robin Lamar) will review together the 
interim safety analyses to be conducted after (1) 12 patients have completed the entire trial, 
including MRI (2) each patient has completed the week 6 phone call, and (3) any AEs are 
reported. 
o
STOPPING RULE:

MRI: 2-fold increase in new T2 or gado enhancing lesions in 
treatment compared to placebo group
o
PATIENT WITHDRAWAL RULE:

Abnormal uterine bleeding

Thromboembolic event (DVT, PE, other)

Further details regarding the timing and content of the interim reviews is included in the 
statistical section below.
Safety assessments will be throughout patient visits to ensure patient welfare and safety in daily 
activities. Such assessments will include:

Physical Examination

Vital Signs

Height and Weight measurements

Pregnancy and Assessments of Fertility

Fatigue Assessment

Health Status Questionnaire

Blood tests to assess potential abnormal increase of liver enzymes and serum triglycerides

Lab tests to assess hormone levels.

MRIs


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The Investigator will meet with the study staff biweekly to review safety as well as efficacy data 
collected from patient visits and assess the safety of the visits and study outcomes.
Patient withdrawal from the study / Stopping rules: Study treatment must be discontinued for any 
patient if the investigator determines that continuing would result in a significant risk for that 
patient. The following conditions/events may be considered sufficient to support a decision about 
the study drug discontinuation in individual cases:

Adverse event/serious adverse event

Abnormal laboratory value(s) or abnormal test result(s)

Withdrawal of informed consent

Pregnancy

Use of prohibited other investigational medications

Deviations from the prescribed dose regimen for the study drug

Any other protocol deviation that results in a significant risk to the patient’s safety
Discontinuation of the study drug must be recorded along with the patient information in 
REDCap, giving the date and primary and secondary reasons for stopping study treatment. The 
investigator must also contact the Committee on Human Research at the study site (University of 
California at San Francisco Multiple Sclerosis Center) to register the patient’s discontinuation 
from randomized study drug. Patients may voluntarily withdraw from the study for any reason at 
any time. They may be considered withdrawn if they state an intention to withdraw, fail to return 
for visits, or become lost to follow-up for any other reason. For patients who are lost to follow-up 
(i.e. those patients whose status is unclear because they fail to appear for study visits without 
stating an intention to withdraw), the investigator should show "due diligence" by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, registered 
letters, etc. If premature withdrawal occurs for any reason, the investigator must make every effort 
to determine the primary reason for a patient’s premature withdrawal from the study and record 
this information with the patient’s research data in REDCap as well as report this withdrawal to 
the Committee on Human Research if deemed necessary by the committee.
Patients will be considered to have completed the study if they attend all protocol specified visits 
and complete all assessments. A patient who discontinues the study medication for any reason, 
including an adverse event must complete a Safety Follow-Up visit. Any patient still in screening 
at the time 24 patients have been enrolled will be allowed to continue screening to determine if 
they will be eligible to enter the study, provided all screening assessments are complete and the 
randomization visit can occur on or before the designated end of subject recruitment date. The 
investigator must provide follow-up medical care for all patients who are prematurely withdrawn 
from the study or must refer them for appropriate ongoing care. The study can be terminated at 
any time for any reason by the investigator. Should this be necessary, each patient should be seen 
as soon as possible and treated as described for a prematurely withdrawn patient. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing the Committee on Human Research of the trial’s early termination.
15
STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed. The SAP will contain any modifications to 
the analysis plan described below.  


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15.1
Data Sets Analyzed
All eligible patients who are randomized into the study and receive at least one dose of the study 
drug (the Safety Population) will be included in the safety analysis.
15.2
Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized by treatment assignment: 
race, age, height and weight.  
15.3
Analysis of Primary Endpoint
We will compare outcomes at baseline and at 8 weeks, using t-tests, between women receiving 
TSEC vs. placebo. Then, regressions will be run to adjust for subject age, disease duration, and 
DMT (disease modifying therapy).
Primary endpoints:
Aim 1. To explore the hypothesis that CE+BZA improves menopausal symptoms in MS women.
Outcomes: Our primary measure will be the number of daily vasomotor symptoms (VMS), 
obtained from the patient diary. In healthy women, this was shown to significantly decrease with 
estradiol treatment at 8 weeks).(Joffe et al., 2014) 
Power calculation: Given this is a pilot study, we will view the study as a success if the observed 
mean change in the treatment group is larger by any amount compared to the placebo group (“play 
the winner” approach). In healthy women treated with estradiol for 8 weeks,(Joffe et al., 2014) 
VMS decreased by 2.2 daily in the placebo group and 4.5 in the estradiol group and the SD for the 
change was 3.4. Assuming same differences and SD, we will have 80% power to find the 
treatment arm mean difference to be larger with our proposed sample size.
Aim 2. To explore the hypothesis that CE+BZA results in improvement in MS-related outcomes.
Our primary outcome will be MSQOL54 composite score (primary).
Aim 3. To explore the hypothesis that CE+BZA for 8 weeks is tolerable in women with MS.
Our primary measure will be the percentage of subjects reporting side effects on the Satisfaction
Questionnaire for Medication (TSQM)(Atkinson et al., 2004), which is commonly used in MS 
treatment studies (e.g.(Calkwood et al., 2014)). 
15.4
Analysis of Secondary Endpoints
These methods will be the same as per primary endpoints.
Secondary endpoints are:
Aim 1. To explore the hypothesis that CE+BZA improves menopausal symptoms in MS women.
Our secondary measure will be sleep quality from sleep diary. 
Aim 2. To explore the hypothesis that CE+BZA results in improvement in MS-related outcomes.
Our secondary outcomes will be: measures of mood (CES-D), fatigue (MFIS), cognition (MSNQ), 
and bladder (MSQLI BLCS), and our primary outcome is the MSRS, a global score capturing 
patient impressions of MS severity across eight function domains.


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Aim 3. To explore the hypothesis that CE+BZA for 8 weeks is tolerable in women with MS.
Our secondary measures will be number of missed doses, and the number of new or enhancing 
lesions on 8-week MRI, to verify that CE+BZA does not yield any marked changes in 
inflammatory activity.
Safety and tolerability data will be summarized by treatment group.  
Adverse event rates will be coded by body system and MedDra classification term. Adverse events 
will be tabulated by treatment group and will include the number of patients for whom the event 
occurred, the rate of occurrence, and the severity and relationship to study drug.  
15.5
Interim Analysis
After each patient completes the Week 6 phone call, the side effects reported will be analyzed.
When 50% of patients have completed the study through Study Visit 2 (total visit 3), an interim 
analysis for safety will be conducted by the PI, with the collaboration of Drs. Green (neurology) 
and Dr. Lamar (Ob/Gyn).
Serious adverse events will be monitored by the committee on an ongoing basis throughout the 
study.
15.6
Sample Size and Randomization
The sample size for this protocol was determined by the following. Given this is a pilot study, we 
will view the study as a success if the observed mean change in the treatment group is larger by 
any amount compared to the placebo group (“play the winner” approach). In healthy women 
treated with estradiol for 8 weeks,(Joffe et al., 2014) VMS decreased by 2.2 daily in the placebo 
group and 4.5 in the estradiol group and the SD for the change was 3.4. Assuming same 
differences and SD, we will have 80% power to find the treatment arm mean difference to be 
larger with our proposed sample size.
Subjects will be 1:1 randomized.
16
DATA COLLECTION, RETENTION AND MONITORING
16.1
Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.  
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic Case Report Form (eCRF) when the information 
corresponding to that visit is available.  Subjects will not be identified by name in the study 
database or on any study documents to be collected by the Sponsor (or designee), but will be 
identified by a site number, subject number and initials.
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and creates an electronic audit trail.  
The Investigator is responsible for all information collected on subjects enrolled in this study.  All 
data collected during the course of this study must be reviewed and verified for completeness and 


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accuracy by the Investigator.  A copy of the CRF will remain at the Investigator’s site at the 
completion of the study.
16.2
Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database lock will 
occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials.
16.3
Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the EDC system directly. The study database will be updated in 
accordance with the resolved queries.  All changes to the study database will be documented.
16.4
Archival of Data
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained.  
Databases are backed up by the database administrator in conjunction with any updates or changes 
to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures.
16.5
Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon 
request.  A file for each subject must be maintained that includes the signed Informed Consent, 
HIPAA Authorization and Assent Form and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source documents from 
which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason.
16.6
Monitoring
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing this protocol, the 
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities 
to conduct on-site monitoring and/or auditing of all appropriate study documentation.


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16.7
Subject Confidentiality
In order to maintain subject confidentiality, only a subject number and subject initials will identify 
all study subjects on CRFs and other documentation submitted to the Sponsor.  Additional subject 
confidentiality issues (if applicable) are covered in the Clinical Study Agreement.
17
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the FDA.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC).
17.1
Protocol Amendments
Any amendment to the protocol will be written by the PI.  Protocol amendments cannot be 
implemented without prior written IRB/IEC approval except as necessary to eliminate immediate 
safety hazards to patients.  A protocol amendment intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRBs are notified within five 
working days.
17.2
Institutional Review Boards and Independent Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of causality 
will be reported to the IRB/IEC in accordance with the standard operating procedures and policies 
of the IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of the 
study.  The Investigator will obtain assurance of IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the informed 
consent form will be in the possession of the Investigator before the study is initiated.  The 
IRB/IECs unconditional approval statement will be transmitted by the Investigator to the Sponsor 
prior to the shipment of study supplies to the site.  This approval must refer to the study by exact 
protocol title and number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or 
when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely 


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the safety of the patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed.
17.3
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the 
IRB/IEC.  The consent form generated by the Investigator must be acceptable to the Sponsor and 
be approved by the IRB/IEC.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will also 
comply with local regulations. The Investigator will send an IRB/IEC-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file.
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects must be given ample opportunity to inquire about details of the study.  If appropriate and 
required by the local IRB/IEC, assent from the subject will also be obtained.  If a subject is unable 
to sign the informed consent form (ICF) and the HIPAA authorization, a legal representative may 
sign for the subject.   A copy of the signed consent form (and assent) will be given to the subject 
and the original will be maintained with the subject’s records.
17.4
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996. 
17.5
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee).


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7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.
8.
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects.
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312.


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Protocol Template © CFFT TDN   Effective: 12 SEP 2007
APPENDIX 1. SCHEDULE OF STUDY VISITS
SCREENING
VISIT 1
(Week 0)a
STUDY1
VISIT 2
(Week 2)a
STUDY2
VISIT 3
(Week 10)a
Informed Consent
X
Medical History
X
Complete Physical Exam
X
Abbreviated Physical Exam
X
X
Height 
X
Weight 
X
X
X
Vital Signs 
X
X
X
Chemistry
X
X
Pregnancy Test (Serum) 
X
Hematology
X
Hormone levels
X
Research blood stored
X
X
Neurological Exam
Questionnaires, testing
X
X
MRI (subset)
X
X
Randomization
X
Dispensing or Administration 
of Study Drug
X
Counting of Returned Study 
Drug
X
Initiate Subject Diary
X
Subject Diary Review
X
X
Concomitant Medication 
Review
X
X
X
Adverse Experiences
a 
2 day
Safety Phone call at Week 6. 
1.
Bebo BF, Jr., Dehghani B, Foster S, Kurniawan A, Lopez FJ, Sherman LS. Treatment with selective estrogen 
receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis. Glia 
2009;57:777-790.
2.
Kumar S, Patel R, Moore S, et al. Estrogen receptor beta ligand therapy activates PI3K/Akt/mTOR signaling in 
oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiology of disease 
2013;56:131-144.
3.
Bove R, Chitnis T, Houtchens M. Menopause in multiple sclerosis: therapeutic considerations. J Neurol 
2014;261:1257-1268.


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Protocol Template © CFFT TDN   Effective: 12 SEP 2007
4.
Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective 
estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 2014.

SAP_001.pdf: 
 
A TSEC for Symptom Management in Menopausal Women with Multiple Sclerosis 
NCT02710214 
September 19th, 2019 


SAP: A TSEC for Symptom Management in Menopausal Women with Multiple Sclerosis 
 
Data Cleaning/Testing of Assumptions: Prior to proceeding with the following data analysis plan, 
we will examine variable distributions for outliers and evaluate whether the necessary 
assumptions are met for the planned analyses (e.g., normality and homogeneity of variances, 
as applicable). If outliers are detected or assumptions are violated, I will consult with CTSI 
statistics regarding appropriate analytic methods and will consider distribution transformations, 
non-parametric analyses, and/or analyses methods more robust to such violations. All analyses 
will be performed according to the intention-to-treat principle (primary) then the per-protocol 
principle. 
 
Power calculation: Given this is a pilot study, we will view the study as a success if the observed 
mean change in the treatment group is larger by any amount compared to the placebo group 
(“play the winner” approach). In healthy women treated with estradiol for 8 weeks,(Joffe et al., 
2014) VMS decreased by 2.2 daily in the placebo group and 4.5 in the estradiol group and the 
SD for the change was 3.4. Assuming same differences and SD, we will have 80% power to find 
the treatment arm mean difference to be larger with our proposed sample size. 
 
Groups:  
1. Treatment (Duavee); N=12 
2. Placebo; N=12 
 
Timepoints:  
1. V1=baseline 
2. V2=8 wks, for efficacy 
3.  
Primary Predictor:  
Treatment group 
 
Other Predictors: 
4. Age 
5. Disease duration 
6. DMT 
 
Baseline Comparisons:  
1. Characteristics at baseline (compare using t-test): 
i. Age 
2. Characteristics at baseline (compare using chi-square test): 
i. Disease type 
ii. DMT 
3. Characteristics at baseline (compare using Fisher’s exact test): 
i. Race 
4. Functional measures at baseline (compare using Wilcoxon rank sum test):  
i. Functional System Scores (vision, brainstem, pyramidal, cerebellar, sensory, bowel 
and bladder, cerebral, ambulation) 
ii. EDSS Total  
iii. T25FW 
iv. SDMT (raw score) 
v. SDMT (z-score) 
vi. LNS 
5. Patient reported measures at baseline (compare using Wilcoxon rank sum test): 


i. MSQOL-54 (mental) 
ii. MSQOL-54 (physical) 
iii. MSQOL-54 (energy) 
iv. MSRS Composite 
v. MSNQ 
vi. BLCS 
vii. Hot Flashes (per 24 hours, from 2 wks diaries) 
viii. HFRDIS 
ix. ISI 
Outcomes: 
2. Menopausal symptoms  
a. Number of daily vasomotor symptoms (VMS) from diary 
(1) Compare groups using GEE for linear regression 
(2) Adjust model in (1) by age 
(3) Adjust model in (1) by disease duration   
 
b. Sleep quality from sleep diary (PSQI) 
(1) Compare between treatment groups at each time point 
(2) Calculate differences between two time points and compare between treatment groups 
using Wilcoxon rank sum test 
 
c. Insomnia severity post treatment with Duavee/placebo (from ISI both numeric and 
categorical values)  
       (1) Compare between treatment groups at each time point. (numeric)  
       (2) Compare treatment arms using chi-square test. (categorical) 
 
 
 
 
d. HFDRIS 
       (1) Take average of two measurements and compare averages between treatment groups 
using t-test. 
 
3. MS symptoms and MS QOL 
a. Change in clinical symptoms: 
i. Functional System Scores (vision, brainstem, pyramidal, cerebellar, sensory, 
bowel and bladder, cerebral, ambulation) 
ii. EDSS Total Score 
iii. T25FW 
       (1) Calculate difference between V1 and V2 measures for each group; compare groups 
using Wilcoxon rank sum test. 
 
b. TSEC Cognitive 
i. SDMT (raw score) 
ii. SDMT (z-score) 
iii. LNS 
      (1) Calculate difference between V1 and V2 measures for each group; compare groups 
using Wilcoxon rank sum test. (SDMT raw score and LNS) 
      (2) Calculate difference between V1 and V2 measures for each group; compare  groups 
using t- test. (SDMT z-score) 
 
c. QOL Surveys 
i. MSQOL-54 (mental) 
ii. MSQOL-54 (physical) 


       (1) Calculate difference between V1 and V2 measures for each group; compare groups 
using t-test. 
iii. BLCS 
iv. MSRS 
v. MSQOL-54 (mental) 
vi. MSQOL-54 (physical) 
vii. MSQOL-54 (energy) 
viii. MSNQ 
ix. BLCS 
x.  
       (1) Calculate difference between pre- and post- measures for each group; compare groups 
using Wilcoxon rank sum test. 
 
4. Tolerability  
a. Patient side effects: percentage reporting side effects on TSQM 
b. Scores in domains on TSQM (effectiveness, side effects, convenience, and global 
satisfaction) 
       (1) Compare two groups using t-test. 
 
c. Number of missed doses 
        (1) Compare groups using Wilcoxon rank sum test. 
 
d. Number of new inflammatory lesions on 8-wk MRI 
i. New T2 Lesions 
ii. New gadolinium enhancing lesions 
        (1) Compare groups using Wilcoxon rank sum test.