Conditions: Leiomyoma Uterine Fibroids
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
PLUM evaluates the drug letrozole as a treatment for uterine fibroids. This study is a randomized, blinded, placebo-controlled trial of oral letrozole among premenopausal women with symptomatic uterine fibroids. Participants will be randomly assigned in a 1:1 ratio to either oral letrozole 2.5mg/day for 6 months (Group A) or intermittent dosing with letrozole 2.5mg/day and an identical placebo capsule (Group B).

Detailed description:

Arms:
arm 1: Oral letrozole 2.5mg/day arm 2: Intermittent oral letrozole 2.5mg/day for 2 months and an identical placebo capsule for 4 months

Interventions: intervention 1: Letrozole intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
The PLUM Study:  
Pilot of Letrozole for Uterine Myomas 
 
 
 
 
 
 
 
 
PI: Vanessa Jacoby, MD, MAS 
University of California, San Francisco 
Department of Obstetrics, Gynecology, and Reproductive Sciences 
 
 
Version Date: August 19, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
Table of Contents 
 
1.0 
BACKGROUND ................................................................................................................. 3 
2.0 
STUDY RATIONALE .......................................................................................................... 4 
3.0 
STUDY OVERVIEW ........................................................................................................... 5 
4.0 
STUDY OBJECTIVES ........................................................................................................ 5 
5.0 
STUDY POPULATION ....................................................................................................... 6 
5.1 
Participant Recruitment .................................................................................................. 6 
5.2 
Informed Consent ........................................................................................................... 7 
6.0 
MEASURED VARIABLES .................................................................................................. 7 
6.1. Outcome Variables ............................................................................................................. 7 
6.1.A Questionnaires to Assess Symptoms ........................................................................... 7 
6.1.B  Pelvic Ultrasound ........................................................................................................ 8 
6.1.C  Serum hormone levels ................................................................................................ 8 
6.1.D  Other Outcomes .......................................................................................................... 8 
6.1.D  Long-term storage of blood ......................................................................................... 9 
6.1.E   Schedule of Outcomes Assessment .......................................................................... 9 
6.2 ADDITIONAL MEASUREMENTS ....................................................................................... 9 
6.2.A    Preoperative Assessment, Study Participants .......................................................... 9 
7.0 
ADVERSE EVENTS ......................................................................................................... 10 
7.1 
Adverse Event Grading Scale ...................................................................................... 10 
7.2 
Reporting of Adverse Events ........................................................................................ 10 
8.0 
DATA AND SAFETY AND MONITORING PLAN ............................................................. 10 
9.0 
Participant Remuneration ............................................................................................. 11 
10.0 STATISTICAL CONSIDERATIONS ................................................................................. 11 
11.0 REFERENCES ................................................................................................................... 13 
 
 


3 
 
1.0 BACKGROUND 
 
Women with symptomatic uterine fibroids have limited treatment options. Uterine leiomyoma, or 
fibroids, are benign smooth muscle tumors that occur in 25% of premenopausal women and 
cause heavy bleeding, pelvic discomfort or pressure, urinary and bowel dysfunction, and 
adverse pregnancy outcomes. Major surgery (hysterectomy and myomectomy) is the most 
common treatment; uterine artery embolization is reserved for women who have completed 
childbearing, and magnetic resonance guided focused ultrasound ablation is in limited use 
under research protocols. Many women seek medical management, but there are no FDA 
approved drugs that decrease fibroid volume and symptoms without causing harm during long-
term use.  
 
Letrozole is an aromatase inhibitor (AI) that decreases the synthesis of estrogen by the 
aromatase enzyme in the ovary and peripheral tissues, including fibroid cells. Fibroids are 
hormonally responsive tumors that grow with exposure to systemic and local estrogen levels. 
Letrozole is FDA approved as adjuvant therapy for postmenopausal women with estrogen 
receptor positive breast cancer. However, letrozole has been used for treatment of a variety of 
gynecologic conditions including chronic pelvic pain among women with endometriosis and for 
ovulation induction among women with infertility. Six small studies of AIs have reported a 35-
55% decrease in fibroid volume over 8-12 weeks of oral AI treatment.1-6  In premenopausal 
women, low dose letrozole at 2.5mg/day may preferentially inhibit estrogen synthesis in fibroids 
more than the ovaries, thus avoiding undesirable side effects of systemic hypoestrogenism such 
as hot flashes and decreased bone density. Letrozole may therefore improve fibroid symptoms 
without impacting long-term health risks. 
   
Fibroids change volume rapidly in response to fluctuating estrogen levels. Fibroids shrink up to 
60% in 3 months among women treated with gonadotropin-releasing hormone agonists (GnRH) 
that markedly decrease overall serum estrogen by shutting down ovarian hormone production.7 
But the hypoestrogenism with GnRH use causes hot flashes and rapid loss of bone density. In 
addition, fibroids regrow to their original volume within 2-3 months after discontinuing GnRH.8,9 
Therefore, GnRH use is generally limited to short-term use to reduce fibroid volume prior to 
surgical intervention and cannot serve as long-term medical management. 
 
Fibroids produce estrogen that autoregulates fibroid growth. In premenopausal women, the 
ovary is the primary source of estrogen production. However, estrogen is also produced locally 
in fibroid cells through the conversion of androgen by aromatase cytochrome P450 enzyme 
activity.10-12 Estrogen has autocrine and paracrine action which results in fibroids demonstrating 
local control over their own growth.13,14 
 
Aromatase inhibitors rapidly decrease fibroid volume but this effect plateaus after 3 months. 
Letrozole is a type II, reversible, competitive aromatase inhibitor that rapidly blocks estrogen 
production in peripheral tissues.15,16 In the two trial of letrozole alone for treatment of fibroids, 
fibroid volume decreased by 45-46% after 3 months of treatment. However, 90% of that volume 
reduction occurred within 1 month after treatment. This growth pattern indicates that intermittent 
letrozole dosing may be a viable option for long-term treatment. 
 
Low dose daily letrozole in premenopausal women has few adverse effects. Long-term safety 
data on letrozole is derived from large trials and meta-analysis of postmenopausal women with 
estrogen-receptor-positive breast cancer on  letrozole for 5 years.17,18 In these studies, letrozole 
has been associated with slightly higher risks of hypercholesterolemia and fractures compared 
with women taking tamoxifen. 


4 
 
 
It is not appropriate to presume that these risks would be associated with letrozole use in 
premenopausal women. Letrozole use in postmenopausal women significantly reduces overall 
serum estrogen levels because postmenopausal women primarily derive estrogen from 
conversion in peripheral tissue via aromatase. However, estrogen in premenopausal women is 
primarily produced in the ovary with secondary production in peripheral tissue. In one study of 
16 women premenopausal women taking letrozole 5.0 mg/day for fibroid treatment, estrogen 
levels did drop significantly after 1 month, though remained in the normal range for 
premenopausa19-21l women1, but in a subsequent study of 33 women taking letrozole at a 
reduced dose of 2.5mg/day, there was no change in any hormone levels including estradiol, 
FSH, LH, or testosterone.3 Two studies of the AI anastrozol similarly showed no change in 
hormone levels among premenopausal women undergoing fibroid treatment.2,4 
 
There is some concern that daily letrozole will induce ovarian cysts because it successfully 
induces ovulation for women with the polycystic ovarian syndrome.19 This has led to the use of 
an oral progestin and/or combined oral contraceptive in addition to letrozole to prevent cysts in 
the treatment of endometriosis.22,23 However, fibroids are hormonally responsive tumors so use 
of exogenous hormones may counteract the beneficial  effect of letrozole. In addition, in the 
study of 33 women on letrozole 2.5mg monotherapy, there was no significant change in ovarian 
volume or development of ovarian cysts.3 
 
 
2.0 STUDY RATIONALE 
 
Although there is preliminary evidence to demonstrate a positive effect of AIs on reducing fibroid 
volume, current studies are insufficient to support widespread clinical use. There are only 2 
trials of letrozole monotherapy for fibroids with a total of 56 women; both are open-label, 
unblinded studies. A randomized, blinded, placebo-controlled trial is needed for an unbiased 
assessment of letrozole efficacy. In addition, most women with symptomatic fibroids are 35-50 
years old and may require many years of treatment until menopause when fibroids regress 
spontaneously with falling serum estrogen levels. All current AI studies are short-term with only 
2-3 months of drug delivery due to lingering concerns that AIs might induce hypoestrogenism 
among premenopausal women. There are also no studies that evaluate the rate of fibroid 
regrowth after stopping AIs when fibroid estrogen levels may rapidly rise. If fibroids regrow 
slowly over several months after stopping AIs, there may be a role for intermittent AI dosing to 
maximize benefit and minimize harm.  Studies are needed to assess the safety profile of 
letrozole for >3 months of use and to evaluate changes in fibroid volume after letrozole is 
discontinued. 
 
Our ultimate goal is to conduct a multi-centered, randomized, trial of letrozole versus placebo 
among women with symptomatic fibroids. This trial will provide gold standard evidence to 
determine if letrozole results in symptom improvement but offers the advantages of less 
morbidity and lower rates of recurrence of fibroid symptoms.  
 
To prepare for a future multi-centered randomized trial of letrozole, we will first conduct a 
controlled pilot study (the PLUM study). The pilot will allow us to assess the feasibility of 
recruiting and retaining study participants to this drug intervention trial. We will also complete 
essential preparatory work for a future randomized trial; we will create and test study forms, a 
manual of operations, and a study database that can be easily adapted for a multi-site trial. The 
PLUM pilot study will lay the foundation for a successful future study of letrozole as a treatment 
for uterine fibroids. 
 


5 
 
The PLUM study will also provide preliminary data on the efficacy of letrozole in treating uterine 
fibroids. We will use PLUM outcome data to estimate effect sizes and standard deviations to 
calculate an appropriate sample size for a future randomized trial.  
 
3.0 STUDY OVERVIEW 
 
This is a randomized, blinded, placebo-controlled trial of oral letrozole among 20 
premenopausal women with symptomatic uterine fibroids. Participants will be randomly 
assigned in a 1:1 ratio to either oral letrozole 2.5mg/day for 6 months (Group A) or intermittent 
dosing with letrozole 2.5mg/day and an identical placebo capsule (Group B). Group B will 
receive medication dosing as follows: 2 months of placebo, then 2 months daily letrozole 
2.5mg/day, then 2 months of placeboday (Table 1). This dosing regimen in the two groups will 
allow for: 1) between group comparisions in month 1 and 2 to assess the efficacy of letrozole 
compared with a placebo, 2) within-group comparisions in month 3-6 in group B to evaluate the 
rate of fibroid regrowth after discontinuing letrozole to evaluate the possibility of intermediate 
dosing and 3) within-group comparisons in group A in month 1-6 to evaluate the safety of long-
term letrozole use. This pilot data will be critical for determining the appropriate long-term 
dosing regimen in a future, larger, full-scale trial of letrozole. 
 
We will assess changes in fibroid symptoms, quality of life, and 
sexual functioning monthly using standardized, validated 
questionnaires. In addition, at baseline, month 2, 4 and 6, we 
will assess changes in the following measures: 
1) fibroid and uterine volume assessed by pelvic ultrasound 
2) serum follicle stimulating hormone (FSH) and estradiol levels to determine ovarian function 
 
Study participants will be recruited at UCSF. All study data will be stored securely in a HIPAA 
compliant, secure database monitored by the UC San Francisco Coordinating Center. A data 
safety and monitoring board will oversee participant safety and protection.  
 
4.0 STUDY OBJECTIVES 
 
The PLUM study will collect essential preliminary data to guide and inform a future multi-
centered, randomized trial of letrozole versus placebo. The 3 primary study goals are:   
 
1. To assess the feasibility of conducting a randomized, placebo-controlled trial of letrozole 
for premenopausal women with fibroids.  
2. To collect pilot data that examines differences in fibroid symptoms, fibroid volume, and 
hormone levels among premenopausal women who take letrozole compared with a 
placebo.  
These will be between-group analyses in Months 1 and 2 (Group A vs. Group B) that 
serve as preliminary data on the efficacy of letrozole in a placebo-controlled trial. 
 
3. To collect pilot data that examines changes in fibroid symptoms, fibroid volume, and 
hormone levels among premenopausal women taking continuous and intermittent 
letrozole dosing. 
These will be within-group analyses as follows: Months 1-6 for Group A, Months 3-6 for 
Group B.  These data will provide preliminary information on the safety of letrozole use 
beyond 3 months (Group A) and the rate of fibroid regrowth after letrozole is 
discontinued (Group B). 
 
Table 1. Trial Design 
Month 
1 
2 
3 4
5 
6 
Group A  L  L 
L 
L
L 
L 
Group B  P P 
L  L
P
P


6 
 
5.0 STUDY POPULATION 
 
We will recruit women with symptomatic fibroids who meet the following criteria: 
 
 INCLUSION CRITERIA 
1. ≥21 years old 
2. Premenopausal (at least one menses in last 3 months) 
3. Symptomatic fibroids (fibroids visualized on ultrasound or MRI and heavy uterine 
bleeding, pelvic pressure or discomfort, urinary or bowel abnormalities, dyspareunia) 
4. Fibroids that are ≤4 in total number or Fibroids that are ≤7 in total number if all fibroids 
are less than 4cm (40 mm) each. 
5. Fibroids that are ≤7cm (70mm) in maximum diameter, on screening imaging, if ≤4 
fibroids in total number. (fibroid is defined as any mass with radiographic characteristics 
of fibroid >2cm or 20mm)  
6. Up to date in Pap smear screening and surveillance 
7. Endometrial biopsy (required if age>45 years with irregular bleeding) does not indicate 
premalignant or malignant cells 
8. Agree to use non-hormonal barrier method of contraception during study period if at risk 
for pregnancy 
9. Has primary care provider or gynecologist 
10. Agrees not to start new medications/treatments for fibroids during the study 
11. Able to give informed consent 
 
EXCLUSION CRITERIA 
1. Fibroids treated by surgery, radiologic procedure, or GnRH agonist or antagonist in the 
last 3 months 
2. Any submucosal fibroid ≥2cm (20mm) that is  >50% in uterine cavity (FIGO Type 0 or 
Type 1 fibroids) amenable to hysteroscopic resection 
3. Use of exogenous estrogen and/or progestin in the last month. (for 3 month long-acting 
depoprovera injection, no use in last 3 months) 
4. Pregnant, lactating, or planning to become pregnant in the next 6 months 
5. Hematocrit <27% or visit to emergency room or hospitalization for fibroid symptoms in 
the last 3 months (cannot be safely randomized to a placebo) 
6. History of osteopenia or osteoporosis 
7. History of hyperlipidemia 
8. Current liver or kidney disease 
9. History of breast cancer or current breast cancer 
10. Unable or unwilling to attend 4 study visits 
11. Pelvic imaging concerning for gynecologic cancer or cancer of the genitourinary or 
gastrointestinal system 
12. Does not have primary care provider or gynecologist 
 
5.1 Participant Recruitment 
 
We will identify potentially eligible participants with symptomatic fibroids who present to the 
UCSF Women’s Health Center and the UCSF Comprehensive Fibroid Center (CFC) where Dr. 
Jacoby sees patients. The CFC is a high volume specialty clinic that offers the full range of 
available surgical and nonsurgical treatments. Many women come to the CFC seeking minimally 
invasive interventions because of our ongoing trials of new and emerging fibroid treatments as 
described in Preliminary Data. There are 20-25 new fibroid consultations per week among the 
CFC physicians; many of these patients inquire about the availability of medical management of 


7 
 
their symptoms. The patient population is racially and ethnically diverse with a general 
enthusiasm for supporting fibroid studies. Therefore, we believe it is feasible to recruit 20 
women to this pilot trial over 6 months in this pilot study.  
 
Participants will also be recruited from the greater San Francisco Bay Area community.  The 
investigative team will use a multi-component IRB-approved recruitment approach, including 
contacting a database of women with fibroids who have given permission to be contacted about 
future research opportunities, direct community-based media efforts (newspaper notices, radio 
advertising, brochures in local clinics, talks to local community groups, notices in churches), 
social media/networking sites).  Recruitment efforts will be based at UCSF.  To facilitate 
recruitment. 
 
5.2 Informed Consent 
 
Before entering the study, all study procedures, time requirements, risks and potential benefits 
will be explained to each potential study participant using the information in the UCSF IRB-
approved informed consent form.  The potential study participant will be given adequate time to 
read the informed consent document and ask questions. Eligible participants who choose to 
enter the study will sign the inform consent form and Health Insurance Portability and 
Accountability Act (HIPAA) form prior to beginning the study intervention.  Each participant will 
be given a copy of the signed documents and the original will be a part of the research record.  
All study-specific data will be kept confidential and stored in locked files at the clinical center. 
 
6.0 MEASURED VARIABLES 
 
6.1. Outcome Variables 
 
Outcomes will be measured at baseline prior to randomization and at multiple time points for 6 
months. Questionnaires will be administered to evaluate patient-reported fibroid symptoms, 
study medication compliance, adverse events, and the rate of recurrence for fibroid symptoms. 
In the following section, outcome measurements are described in detail.  
 
6.1.A Questionnaires to Assess Symptoms 
These are validated questionnaires to assess the change in symptoms over time.  
 
1. Uterine Fibroid Symptom-Quality of Life (UFS-QOL): The Uterine Fibroid Symptom and 
Quality of Life Questionnaire (UFS-QOL) will be the primary outcome to assess fibroid 
symptoms. The UFS-QOL is a validated fibroid-specific questionnaire that assesses 
fibroid symptoms and their impact on quality-of-life.20,21 
 
2. EuroQoL 5-D: The EuroQoL 5D is a widely used, validated questionnaire to assess 
overall quality of quality of life across a broad spectrum of diseases.  
 
3. Menstrual Impact Questionnaire (MIQ): The MIQ is a 12-question, validated 
questionnaire to determine the impact of heavy menstrual bleeding on a woman’s quality 
of life.24 The MIQ has been used in trials of heavy bleeding that includes women with 
uterine fibroids.  
 


8 
 
6.1.B  Pelvic Ultrasound 
Pelvic ultrasound including trans-abdominal and trans-vaginal images will be used to assess 
changes in uterine volume as well as fibroid number, size, and volume from baseline to the end 
of month 2, 4 and 6. All pelvic ultrasound will be performed by either Dr. Heather Huddleston or 
Dr. Evelyn Mok-Lin, faculty members in the Division of Reproductive Endocrinology and 
Infertility (REI)  in the Department of Obstetrics, Gynecology, and Reproductive Sciences. Dr. 
Huddleston and Mok-Lin have specialty training in performing pelvic ultrasound to assess 
uterine fibroids as well as ovarian cysts. They perform up to 100 pelvic ultrasounds every week 
in their clinical practice and their expertise in this area will be invaluable. All pelvic ultrasound 
will be performed in a private room within the Ob/Gyn Division of Reproductive Medicine clinical 
space located adjacent to Mission Bay Hospital at 499 Illinois St or Mt Zion Women's Health. 
6.1.C  Serum hormone levels  
Estradiol and follicle-stimulating hormone (FSH) levels will be measured at baseline and the end 
of month 2, 4 and 6. These hormones will detect the development of hypoestrogenism and 
assess changes in the hypothalamic-pituitary-ovarian axis that regulate normal menstrual 
function. All blood draws will be performed by certified phlebotomists in the REI practice. 
 
6.1.D  Total Cholesterol 
Since hyperlipidemia is a rare side effect of letrozole, total cholesterol will be measured at 
baseline and month 6. All blood draws will be performed by certified phlebotomists in the REI 
practice. Approximately 5 ml (1 tsp) will be drawn at Baseline and Month 6 for this test. 
 
6.1.E  Other Outcomes 
Other outcomes related to study intervention and fibroid symptoms will include measures 
related to: 
 
Treatment Failure: We will ask participants to report any additional fibroid treatments including 
medical management for fibroid-related symptoms, myomectomy, hysterectomy, uterine artery 
embolization, MR Guided Focused Ultrasound, endometrial ablation, dilation and curettage, or 
any new and emerging fibroid treatments. 
 
Adverse Events  
This is the first trial of letrozole monotherapy for >12 weeks among premenopausal women. 
Therefore, a full range of adverse events will be assessed every 2 months for all body systems 
including known potential side effects such as hot flashes, myalgias, and fatigue as well as 
unknown side effects that will be identified by using the open ended question “Have you had 
any changes to your health that impact your ability to perform your normal activities?”. In 
addition to assessing adverse events monthly during the trial, we will query participants about 
adverse events 30 days after completing the last dose of medication. 
 
Pregnancy and pregnancy outcomes: In this study pregnancy is considered a Serios 
Adverse Event. Participants will report all known pregnancies while receiving study 
medication. For each pregnancy, we will query participants about whether the pregnancy 
resulted in a miscarriage, abortion, or continued pregnancy. For continued pregnancies, 
we will ask participants to report obstetric outcomes including gestational age at birth, 
mode of delivery (vaginal or cesarean), and complications (e.g. placenta previa, 
placental abruption, preeclampsia).  


9 
 
6.1.F  Long-term storage of blood  
During blood draws at baseline and month 2, 4, and 6, we will ask participants if they are willing 
to allow long-term storage of their blood (serum) for future fibroid studies. Participants may 
decline this long term storage and still participate in the study. Specimens will be stored long-
term in the Specimen Bank within the UCSF Reproductive Medicine Lab.  
6.1.G   Schedule of Outcomes Assessment  
Outcomes will be assessed at varying timepoints from Baseline to 6 months (Table 2). In-person 
study visits will occur prior to randomization at the Baseline Visit (BV), Month 2, Month 4, and 
Month 6. All other visit data will be collected through mailed or on-line questionnaires, and/or 
phone interviews.  
*Optional 
6.2 ADDITIONAL MEASUREMENTS  
We will collect additional subjective and objective measurements that will be used to:  
1) describe the study population and 2) serve as confounding factors in multivariable analysis of 
the change in fibroid-related symptoms over time.  
6.2.A    Pre-Enrollment Assessment, Study Participants 
 
At baseline, we will query women about their general and reproductive health and obtain 
baseline data on fibroid size, number, and location as outlined in Table 3. 
 
Table 3. Baseline Assessment, Study Participants 
 
 
Participant-Reported Baseline 
Measures 
 
Demographic characteristics (age, race/ethnicity, 
education) 
 
Medical and surgical history 
 
Reproductive history (including pregnancy and 
pregnancy outcomes) 
 
Medication use 
 
Complementary and alternative therapy use 
 
Desire for future fertility 
 
Objective Baseline Measures 
 
Weight 
 
Height 
 
Vital signs 
 
Uterine size by trans-vaginal ultrasound 
Table 2. Schedule of Measurements 
 
BV 
Mo 1 
2 
3 
4 
5 
6 
7 
Symptom questionnaires 
X 
X 
X 
X 
X 
X 
X 
 
EQ5D questionnaire 
X 
 
X 
 
X 
 
X 
 
Pelvic ultrasound 
X 
 
X 
 
X 
 
X 
 
Hormone levels 
X 
 
X 
 
X 
 
X 
 
Total Cholesterol 
X 
 
 
 
 
 
X 
 
Adverse event assessment 
 
X 
X 
X 
X 
X 
X 
X 
Specimen Storage* 
X 
 
X 
 
X 
 
X 
 
Compensation 
$25 
 
$25 
 
$25 
 
$25 
 


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 
Fibroid characteristics on ultrasound 
       *Total number 
       *Location of each fibroid 
       * dimensions in mm of each fibroid 
       * dimensions in mm of each ovary 
       *Presence of ovarian cysts and sizes 
 
 
7.0 ADVERSE EVENTS 
 
This is the first trial of letrozole monotherapy for >12 weeks among premenopausal women. 
Therefore, a full range of adverse events will be assessed by using the open ended question 
“Have you had any changes to your health that impact your ability to perform your normal 
activities?”. In addition to assessing adverse events monthly during the trial, we will query 
participants about adverse events 30 days after completing the last dose of medication.  
 
7.1 Adverse Event Grading Scale 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) and Common Toxicity Criteria (CTC), version 4. Using this system, adverse events 
are classified as follows: 
 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self  
care activities of daily living 
Grade 4  
Life-threatening consequences; urgent intervention indicated. 
Grade 5  
Death related to Adverse Event 
 
. 
7.2 
Reporting of Adverse Events 
 
Grade 4 or 5 adverse events will be reported to the respective institution’s Institutional Review 
Board (IRB) and the UCSF Coordinating Center within 24 hours. The UCSF Coordinating 
Center will notify the study sponsor, the UCSF IRB, and the Data and Safety Monitoring Board 
(DSMB) Chair within 24 hours of the adverse event. The DSMB will receive a report of all 
adverse events every 4 months, categorized with the appropriate severity grading. The DSMB 
report will include details of the adverse event as reported in the Adverse Event Case Report 
Form.  
 
 
8.0 
DATA AND SAFETY AND MONITORING PLAN 
 
The Data and Safety and Monitoring Board will consist of a single Data Safety Monitor (DSM), 
an obstetrician/gynecologist with expertise in clinical studies of gynecologic interventions and 
the conduct of clinical trials. 
 


11 
 
The DSM will be charged with overseeing participant safety and monitoring the scientific validity 
of the trial. Prior to initiating the study, the DSM will review and approve the study protocol.  
 
Assessment and Reporting of Adverse Events: The DSM will receive updates on adverse 
events every 3 months during the study. These will be presented to her by study group in a 
blinded fashion. All serious adverse events will be reported to the DSM within 24 hours of 
notification to the investigator.  
 
Assessment and Reporting of Study Conduct: Every 3 months, we will report to Dr. Goldman 
updated data on the number of potential participants screened, excluded, and enrolled in the 
study. We will also report adherence to study visits and medication. 
  
Interim Analysis and Stopping rules: This is a small pilot study of 20 women with a short 
duration of 6 months. Therefore, the sample size and length of study is not appropriate for an 
interim analysis. In addition, we do not believe a stopping rule is indicated in this small pilot. 
 
Full details of the DSMB are described in the PLUM DSMB Charter.  
 
9.0 Participant Remuneration  
 
Study participants will be provided with small values of debit or gift cards for their time and 
commitment to the study as follows: $25 at the Baseline, Month 2, Month 4, and Month 6 visits. 
Participants will also be paid for the cost of parking and transportation for study related 
activities.  
 
 
10.0 STATISTICAL CONSIDERATIONS 
 
Data analysis plan: We will use descriptive statistics to characterize the feasibility and process 
measures listed in Table 5, with 95% confidence intervals. Changes in UFS-QOL scores, the 
primary outcome, as well as secondary outcomes including hormone levels and fibroid volume, 
will be compared using linear mixed models for repeated measures, adjusting for baseline. We 
will estimate 1) between-group differences in change from baseline to months 1 and 2; 2) 
changes from baseline to months 1-3 and 4-6 in group A; and 3) changes from month 3 to 
months 5 and 6 within group B. 
 
Sample size calculations: This is a pilot study with the aim of assessing the feasibility of 
implementing a definitive letrozole trial. Therefore, we chose a sample size that would be large 
enough to assess feasibility, but small enough to complete the pilot within a the1 year timeframe 
and with a limited budget.  Accordingly, the study will not have power to detect small treatment 
effects. In the PROMISe pilot study discussed in Preliminary Studies, the standard deviation of 
the UFS-QOL SSS was 20, and correlation of baseline with follow-up scores declined from 0.5 
at 1 month to nearly zero at 3 months. In the analysis for AIM 2 of between-group differences in 
the change in UFS-QOL from baseline to 2 months , the sample size of 20 will provide 80% 
power to detect a between-group difference of 13.4 points in average SSS scores at months 1 
and 2, after accounting for short term attrition of 10%.  In the analysis for AIM 3, assessing 
longer term changes in SSS scores within group A, the sample of 15 women have 80% power 
to detect average changes from baseline to months 1-3 and 4-6 of 16.0 points.  In additional 
analysis for AIM 3, assessing changes from month 3 to months 5-6 in group B, the 
corresponding minimum detectable effect will be 18 points. Effects of this magnitude are 


12 
 
clinically relevant because 15-20 points is the mean difference in SSS between women with 
symptomatic fibroids and women without fibroids. 


13 
 
11.0 REFERENCES 
 
 
1. 
Gurates B, Parmaksiz C, Kilic G, Celik H, Kumru S, Simsek M. Treatment of symptomatic uterine 
leiomyoma with letrozole. Reproductive biomedicine online. Oct 2008;17(4):569‐574. 
2. 
Hilario SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of 
uterine leiomyoma in perimenopausal patients. Fertility and sterility. Jan 2009;91(1):240‐243. 
3. 
Parsanezhad ME, Azmoon M, Alborzi S, et al. A randomized, controlled clinical trial comparing 
the effects of aromatase inhibitor (letrozole) and gonadotropin‐releasing hormone agonist 
(triptorelin) on uterine leiomyoma volume and hormonal status. Fertility and sterility. Jan 
2010;93(1):192‐198. 
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