Clinical trial NCT03401918
Conditions: Recurrent Pregnancy Loss Unexplained Infertility
Sponsor: Stanford University
Start date: 2017-08-01; Completion date: 2021-07-01
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if patients with recurrent pregnancy loss or unexplained infertility have an altered uterine gene expression or uterine microbiome (micro-organism composition) during the window of embryo implantation. Furthermore we would like to assess for women with an abnormal uterine gene expression whether vaginal progesterone medication improves or alters gene expression and for women with an abnormal microbiome whether antibiotic treatment followed by probiotic treatment normalizes the microbiome.

Detailed description:
Recurrent pregnancy loss and unexplained infertility are emotional and difficult diagnoses. Despite a thorough medical investigation, many cases of recurrent pregnancy loss and infertility remain unexplained. Understanding endometrial factors that may contribute to these diseases may lead to improved treatment options in the future. The purpose of this study is to determine if patients with recurrent pregnancy loss or unexplained infertility have an altered uterine gene expression or uterine microbiome (micro-organism composition) during the window of embryo implantation. Furthermore we would like to assess for women with an abnormal uterine gene expression whether vaginal progesterone medication improves or alters gene expression and for women with an abnormal microbiome whether antibiotic treatment followed by probiotic treatment normalizes the microbiome.

A standard evaluation for infertility includes a uterine cavity evaluation, evaluation for ovarian reserve testing, and for patients with recurrent pregnancy loss parental testing for uterine infection, chromosome analysis, autoimmune and thyroid screening. This standard workup, however, does not include a molecular or microbial assessment of the endometrium. Endometrial factors may contribute to unexplained infertility or recurrent pregnancy loss however the extent of this is unknown.

We are recruiting patients who have recurrent pregnancy loss, unexplained infertility, and healthy control patients who have had a term delivery in order to compare differences between these groups.

Subjects will undergo an endometrial biopsy that will specifically test the receptivity of your endometrium as well as identify the bacterial composition of the uterine environment (microbiome). The endometrial receptivity array and microbiome testing will be performed at no cost. The endometrial receptivity array provides information on the receptivity of a patient's endometrium to the implantation of an embryo. This may yield additional information regarding the etiology of a patient's infertility and/or recurrent pregnancy loss. If this testing is abnormal we may repeat the biopsy after vaginal progesterone supplementation to see if this normalizes the results. If the microbiome is abnormal we may repeat the biopsy after oral antibiotics and vaginal probiotics to see if this normalizes your microbiome results.

Arms: arm 1: Patients with recurrent pregnancy loss or unexplained infertility will have an assessment of the uterine environment at the time of implantation, followed by testing of uterine endometrial gene expression using the ERA test and the uterine micro biome.

Those who have abnormal results (an abnormal microbiome or an abnormal ERA) will have the option to undergo treatment followed by retesting of the uterine environment. For an abnormal ERA suggesting a pre-receptive result, luteal phase vaginal progesterone supplementation will be offered prior to re-testing of the ERA. For an abnormal microbiome a combination of oral antibiotics and vaginal probiotics will be offered prior to re-testing the uterine microbiome. arm 2: Patients who have had a normal delivery and no history of infertility or recurrent pregnancy loss will have assessment of the uterine environment at the time of implantation.
Interventions: intervention 1: Uterine ERA and microbiome testing intervention 2: Oral antibiotics and vaginal probiotics
Intervention descriptions: intervention 1: Uterine fluid and endometrial biopsy collection to test uterine endometrial receptivity array and microbiome. intervention 2: For subjects with abnormal microbiome results, oral antibiotics and vaginal probiotic treatment will be offered followed by a repeat uterine microbiome biopsy.

Protocol documents:
ICF_001.pdf: 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 1 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
Print your name here: _____________________________________ 
Are you participating in any other research studies? _____ Yes _____No 
PURPOSE OF RESEARCH
You are invited to participate in a research study to assess the uterine 
environment in unexplained recurrent pregnancy loss and unexplained infertility.   
Recurrent pregnancy loss and unexplained infertility are emotional and difficult 
diagnoses. Despite a thorough medical investigation, many cases of recurrent 
pregnancy loss and infertility remain unexplained. Understanding endometrial 
factors that may contribute to these diseases may lead to improved treatment 
options in the future. The purpose of this study is to determine if patients with 
recurrent pregnancy loss or unexplained infertility have an altered uterine gene 
expression or uterine microbiome (micro-organism composition) during the 
window of embryo implantation. Furthermore we would like to assess for women 
with an abnormal uterine gene expression whether vaginal progesterone 
medication improves or alters gene expression.  
A standard evaluation for infertility includes a uterine cavity evaluation, evaluation 
for ovarian reserve testing, and for patients with recurrent pregnancy loss parental 
testing for uterine infection, chromosome analysis, autoimmune and thyroid 
screening.  This standard workup, however, does not include a molecular or 
microbial assessment of the endometrium.  Studies suggest that endometrial 
factors may contribute to unexplained infertility or recurrent pregnancy loss 
however the extent of this is unknown.
If you are enrolled in this study, you will undergo the standard evaluation of 
infertility and/or recurrent pregnancy loss that every patient seen in our office 
receives.  As part of this study, you will also have 1-2 endometrial biopsies to test 
for the molecular and genetic environment of your uterus. Each patient enrolled 
will be treated according to medical standard of care practice and no standard 
treatment will be withheld from you if you choose to participate in this study. 
If you decide to terminate your participation in this study, you should notify Dr. 
Sara Churchill at (650) 498-7911   
VOLUNTARY PARTICIPATION


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 2 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
Your participation in this study is entirely voluntary.  Your decision not to 
participate will not have any negative effect on you or your medical care.  You 
can decide to participate now, but withdraw your consent later and stop being in 
the study without any loss of benefits or medical care to which you are entitled.
DURATION OF STUDY INVOLVEMENT  
This research study is expected to take approximately 5 years from the date of 
your enrollment.  This length of time is anticipated to complete a thorough 
fertility and medical evaluation in addition to following the outcome of your 
subsequent pregnancies. 
PROCEDURES 
If you choose to participate, Dr. Sara Churchill and her research study staff will 
consent you for the following: 
You will undergo a standard infertility OR recurrent pregnancy loss evaluation 
that includes ovarian reserve testing, hormonal analyses (blood tests), 
ultrasound(s), a uterine cavity evaluation, genetic testing (blood work), 
autoimmune testing (blood work) and thyroid screening (blood work).  
As a study participant, you will be offered an endometrial biopsy that will 
specifically test the receptivity of your endometrium as well as identify the 
bacterial composition of the uterine environment (microbiome).  The endometrial 
receptivity array (ERA) and microbiome testing will be performed by Ivigen at no 
extra costs. The ERA provides information on the receptivity of a patient's 
endometrium to the implantation of an embryo.  This may yield additional 
information regarding the etiology of a patient’s infertility and/or recurrent 
pregnancy loss.  If your ERA is abnormal we will repeat the biopsy after vaginal 
progesterone supplementation to see if this normalizes the ERA results.   
Your follow up visits and treatment regimens will be determined by the treating 
physician according to the standard of care treatment of infertility or other 
medical comorbidity.  Repeat laboratory testing may be recommended if any lab 
abnormalities are identified and treated while you are receiving care in our clinic.  
We will track your clinical outcomes without intervening with your treatments 
until you have a successful pregnancy and for a minimum of one year after 
enrollment.  If your outcomes are not in your medical record you may be 
contacted by phone for additional follow up information. 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 3 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
Your clinical data and pregnancy outcomes will be entered into a secure 
database.  No publications as a result of this study will have any patient 
identifiers. 
Tissue Sampling for Research  
Research using tissues is an important way to try to understand human disease.  
You have been given this information because the investigators want to include 
your tissues in a research project and because they want to save the samples for 
future research.  There are several things you should know before allowing your 
tissues to be studied.   
Your tissues will be stored in a locked freezer under your medical record number 
in order to protect your identity.  
You have the right to refuse to allow your tissues to be studied now or saved for 
future study.  You may withdraw from this study at any time.  The investigators 
might retain the identified samples, e.g., as part of your routine clinical care, but 
not for additional research.  
Because your samples will not be linked to your name after they are stored, you 
cannot withdraw your consent to the use of the samples after they are taken.   
You will be told the results of tests that are part of your clinical care, but you will not 
be told the results of the research tests, including any future research tests.  
 
_____ I consent to my samples being saved for future research 
 
_____ I do not consent to my samples being saved for future research 
Any of your samples which are used in research may result in new products, 
tests or discoveries. In some instances, these may have potential commercial 
value and may be developed and owned by the Investigators, Stanford University 
and/or others.  However, donors of samples do not retain any property rights to 
the materials.  Therefore, you would not share in any financial benefits from 
these products, tests or discoveries. 
PARTICIPANT RESPONSIBILITIES           


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 4 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
As a participant, your responsibilities include: 
x
Follow the instructions of the Protocol Director and study staff. 
x
Keep your study appointments.  If it is necessary to miss an appointment, 
please contact the Protocol Director or research study staff to reschedule 
as soon as you know you will miss the appointment. 
x
Tell the Protocol Director or research study staff about any side effects, 
doctor visits, or hospitalizations that you may have. 
x
Complete your questionnaires as instructed. 
x
Ask questions as you think of them. 
x
Tell the Protocol Director or research staff if you change your mind about 
staying in the study. 
WITHDRAWAL FROM STUDY 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your 
decision will not affect your ability to receive medical care for your disease and 
you will not lose any benefits to which you would otherwise be entitled.  
If you decide to withdraw your consent to participate in this study, you should 
notify Dr. Sara Churchill at (650) 498-7911.
If you withdraw from the study, there will be no health consequences to you.
The Protocol Director may also withdraw you from the study without your 
consent for one or more of the following reasons: 
o
Failure to follow the instructions of the Protocol Director and 
study staff. 
o
You need treatment not allowed in the study. 
o
The study is cancelled.  
o
Other administrative reasons. 
o
Unanticipated circumstances. 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES 
There are risks, discomforts, and inconveniences associated with any research 
study.  These deserve careful thought.  You should talk with the Protocol 
Director if you have any questions. 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 5 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
A uterine cavity evaluation consists of either a saline sonohysterogram or 
hysteroscopy.  These procedures involve placing saline within the endometrial 
cavity to allow complete visualization of the shape and contour of the cavity.  
This procedure is performed under sterile conditions and involves a rare risk of 
infection and vaginal bleeding after the procedure.  Some patients experience 
cramping during the procedure that resolves shortly upon completion of the 
procedure. 
The endometrial biopsy is performed under sterile conditions with minimal risk 
however some patients do experience cramping during the procedure.  Although 
this is a sterile procedure, there is a rare risk of infection and vaginal bleeding 
after the procedure. 
Blood draws are routinely performed for our patients and pose minimal risks to 
participants.  Drawing blood may cause some discomfort, bleeding or bruising 
where the needle enters the skin and there is a small risk of infection.   
Patient who have been on vaginal progesterone have reported side effects such 
as abdominal pain, nausea, abdominal bloating, constipation, vomiting, fatigue, 
urinary tract infections, headache and vaginal bleeding. Vaginal progesterone 
may also have similar side effects compared to other drugs containing 
progesterone including breast tenderness, mood swings, irritability, and 
drowsiness. If you were to experience bothersome side effects that are not easily 
treated we would stop vaginal progesterone treatment and these side effects 
would not be expected to persist.  
Please let your physician know if you experience any of these complications. 
POTENTIAL BENEFITS                              
Information about the endometrial receptivity and uterine microbiome 
obtained during the study will be shared with you.  However, we cannot and 
do not guarantee or promise that you will receive any benefits from this 
study. 
ALTERNATIVES 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 6 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
The alternative to participating in this study is to not participate and to undergo 
testing and treatment based on your doctor’s clinical reccomendations.  
PARTICIPANT’S RIGHTS 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell 
the Protocol Director.   
You will be told of any important new information that is learned during the 
course of this research study, which might affect your condition or your 
willingness to continue participation in this study. 
ClinicalTrials.gov 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web site will not 
include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
CONFIDENTIALITY
Your identity will be kept as confidential as possible as required by law.  Your 
personal health information related to this study: name, medical record number, 
date of birth  that is required for processing laboratory specimens may be 
disclosed as authorized by you.  Your research records may be disclosed outside 
of Stanford, but in this case, you will be identified only by a unique code number.  
Information about the code will be kept in a secure location and access limited to 
research study personnel.   
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  However, your identity will not be 
disclosed.  
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect 
research records and learn your identity if this study falls within its jurisdiction. 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 7 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
Authorization To Use Your Health Information 
For Research Purposes
Because information about you and your health is personal and 
private, it generally cannot be used in this research study without 
your written authorization.  If you sign this form, it will provide that 
authorization.  The form is intended to inform you about how your 
health information will be used or disclosed in the study.  Your 
information will only be used in accordance with this authorization 
form and the informed consent form and as required or allowed by 
law.  Please read it carefully before signing it.   
What is the purpose of this research study and how will my 
health information be utilized in the study? 
The investigators of this study hope to identify which prognostic 
factors are most clearly correlated with poorer outcomes in the obese 
infertile population.  As a participant, in addition to receiving 
standard of care treatment of infertility, you will receive additional 
information regarding the receptivity of your endometrium as a 
possible explanation for your infertility.  The results of the screening 
examinations in the overweight/obese population will allow for 
comparison of different prognostic factors that may be contributing 
to the cause of infertility, response to assisted reproductive 
technologies, and pregnancy outcomes.
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, 
you will not be able to participate in this research study.  Signing the 
form is not a condition for receiving any medical care outside the 
study. 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your 
authorization regarding the use and disclosure of your health 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 8 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
information (and to discontinue any other participation in the study) 
at any time.  After any revocation, your health information will no 
longer be used or disclosed in the study, except to the extent that 
the law allows us to continue using your information (e.g., necessary 
to maintain integrity of research).  If you wish to revoke your 
authorization for the research use or disclosure of your health 
information in this study, you must write to: Dr. Ruth Lathi at 
Stanford University Medical Center, Reproductive Endocrinology, 900 
Welch Road, Suite 350, Palo Alto, CA 94304. 
What Personal Information Will Be Obtained, Used or 
Disclosed?
Your health information related to this study may be used or 
disclosed in connection with this research study, including, but not 
limited to patient name, your age, date of birth, medical record 
number, previous infertility  
treatment, obstetrical history, results of laboratory testing, and 
outcome of pregnancy.
Who May Use or Disclose the Information?
The following parties are authorized to use and/or disclose your 
health information in connection with this research study: 
x
The Protocol Director: Dr. Sara Churchill
x
The Stanford University Administrative Panel on Human 
Subjects in Medical Research and any other unit of Stanford 
University as necessary 
Who May Receive or Use the Information?
The parties listed in the preceding paragraph may disclose your 
health information to the following persons and organizations for 
their use in connection with this research study:  
x
The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
x
The Stanford Research Staff 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 9 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
x
The Federal Drug Administration 
x
Ivigen 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
When will my authorization expire?
Your authorization for the use and/or disclosure of your health 
information will end on February 28, 2050 or when the research 
project ends, whichever is earlier. 
________________________________            ______________
Signature of Participant                                           Date 
________________________________            
Print Name of Participant                                           
FINANCIAL CONSIDERATIONS 
Payment 
You will not be paid to participate in this research study.
Costs 
If you participate in this study, there may be additional costs to you.  These 
include the personal time it will take to come to all of the study visits.   
The study will pay for those services, supplies, procedures, and care associated 
with this study that are not a part of your routine medical care.   
Your insurance will be billed for the cost of the standard infertility evaluation.  
The study will pay for the endometrial receptivity array (ERA) that is associated 
with this study and is not a part of your routine medical care.   
Participation in this study is not a substitute for health insurance.  You and/or 
your health insurance must pay for those services, supplies, procedures, and 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 10 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
care that you require during this study for routine medical care.  You will be 
responsible for any co-payments and/or deductibles as required by 
your insurance.   
Sponsor 
Ivigen is providing the endometrial receptivity array (ERA) and microbiome 
testing for this study.  
COMPENSATION for Research-Related Injury 
All forms of medical diagnosis and treatment – whether routine or experimental 
– involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications 
arise, the Protocol Director and the research study staff will assist you in 
obtaining appropriate medical treatment.  In the event that you have an injury or 
illness that is directly caused by your participation in this study, reimbursement 
for all related costs of care first will be sought from your insurer, managed care 
plan, or other benefits program.  You will be responsible for any associated 
co-payments or deductibles as required by your insurance. 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these 
costs.  If you are unable to pay for such costs, the Protocol Director will assist 
you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
You do not waive any liability rights for personal injury by signing this form. 
CONTACT INFORMATION  
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Dr. Sara 
Churchill. You may contact her now or later at (650) 498-7911.
Injury Notification:  If you feel you have been hurt by being a part of this study, 
please contact the Protocol Director.  
Independent Contact:  If you are not satisfied with how this study is being 
conducted, or if you have any concerns, complaints, or general questions about 


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 11 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
the research or your rights as a participant, please contact the Stanford 
Institutional Review Board (IRB) to speak to someone independent of the 
research team at (650)-723-5244 or toll free at 1-866-680-2906.  You can also 
write to the Stanford IRB, Stanford University, 3000 El Camino Real, Five Palo 
Alto Square, 4th Floor, Palo Alto, CA 94306.
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
As a research participant you have the following rights.  These rights include but 
are not limited to the participant's right to: 
x
be informed of the nature and purpose of the experiment;  
x
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
x
be given a description of any attendant discomforts and risks reasonably 
to be expected;  
x
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
x
be given a disclosure of any appropriate alternatives, drugs or devices 
that might be advantageous to the subject, their relative risks and 
benefits; 
x
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
x
be given an opportunity to ask questions concerning the experiment or 
the procedures involved;  
x
be instructed that consent to participate in the medical experiment may 
be withdrawn at any time and the subject may discontinue participation 
without prejudice;  
x
be given a copy of the signed and dated consent form; and  
x
be given the opportunity to decide to consent or not to consent to a 
medical experiment without the intervention of any element of force, 
fraud, deceit, duress, coercion or undue influence on the subject's 
decision. 
May we contact you about future studies that may be of interest to you?    
____ Yes  ____ No 
Signing your name means you agree to be in this study and that you were given 
a copy of this signed and dated consent form.


STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Dr. Sara Churchill  
Protocol Title:   Assessing the endometrial environment in recurrent pregnancy loss and unexplained 
infertility 
Page 12 of 12 
SUSampCons_CA_Privacy rev 8/30/13
IRB Use Only
Approval Date:   July 12, 2017 
Expiration Date: July 12, 2018 
Participant ID: 
_____________________________________ 
Printed Name of Participant 
_____________________________________                ____________ 
Signature of Adult Participant 
 
 
 
   
   Date 
____________________________________ 
Printed Name of Person Obtaining Consent 
____________________________________                   _____________ 
Signature of Person Obtaining Consent  
 
            Date 

Prot_000.pdf: 
 
Assessing the Endometrial Environment in Recurrent  
Pregnancy Loss and Unexplained Infertility   
NCT03401918 
August 21, 2020 
Ruth Bunker Lathi, Principal Investigator 
Stanford University 
Stanford, California 94305 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
Recurrent pregnancy loss and unexplained infertility are emotionaland difficult diagnoses 
for patients. Despite a thorough medicalinvestigation, most cases of recurrent pregnancy 
loss remainunexplained and unexplained infertility is by definition so.Understanding 
endometrial factors that may contribute to recurrentpregnancy loss and unexplained 
infertility are of increasinginterest. The purpose of this study was to determine if 
patientswith recurrent pregnancy loss or unexplained infertility havealtered gene 
expression in the uterus, or an altered microbiome,during the window of implantation and 
to assess whether lutealphase progesterone supplementation improves or alters 
geneexpression and to assess whether oral antibiotics followed by vaginal 
probioticsimproves an altered microbiome. 
b. 
Objectives 
The investigators hope to determine if endometrial gene expression is altered in recurrent 
pregnancy loss or unexplained infertility patients compared to healthy controls. 
Furthermore the investigators hope to learn if luteal phase progesterone support 
normalizes women with altered endometrial gene expression and if oral antibiotics and 
over the counter vaginal probiotics improve an altered uterine microbiome. This would 
give us better evidence to justify using progesterone support which is often done 
empirically without strong evidence for or against and suggest a uterine mechanism of an 
altered microbiome in infertility and recurrent pregnancy loss. This knowledge would 
provide a better means to counsel patients in these populations. 
c. 
Rationale for Research in Humans 
Human subjects must be used for this study as the purpose of the study is to understand 
human endometrial genetic expression and the human microbiome in an unexplained 
recurrent pregnancy loss and unexplained infertility patient populations. Furthermore this 
is a minimal risk study where patients are already undergoing endometrial biopsies as a 


August 21, 2020 
 
Page 2 of 11 
standard of care to rule out endometrial infection. For healthy controls this is a minimal 
risk study as the endometrial biopsy is a minimal procedure. The benefit to the healthy 
controls would be access to the information which may be relevant to them in their future 
reproductive attempts. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
Patients enrolled in the study will be those presenting to the clinic for evaluation and 
treatment of recurrent pregnancy loss and infertility. Healthy controls will be patients 
presenting for elective egg freezing and elective sex selection and recruited from the 
general population by way of flier. 
 
Recurrent pregnancy loss and infertility patients will undergo the routine clinical standard 
evaluation including a uterine cavity evaluation, evaluation for endometritis, ovarian 
reserve testing, and for patients with recurrent pregnancy loss also parental chromosome 
analysis, antiphospholipid antibody blood testing and thyroid screening. Egg freezing 
patients will undergo routine clinical evaluation which includes uterine ultrasound 
evaluation and ovarian reserve testing and elective sex selection patients will undergo a 
routine evaluation which includes a uterine cavity evaluation, ovarian reserve testing and 
blood testing. 
 
For new patients presenting with no prior evaluation we will perform the uterine cavity 
evaluation as per standard of care in the follicular phase of the menstrual cycle. The 
endometrial biopsy is typically done during this same appointment however the 
endometrial biopsy will be deferred for the purposes of the study in order to perform the 
endometrial biopsy during the window of implantation after ovulation. This endometrial 
biopsy will be sent to pathology to rule out endometritis as per clinical standard of care 
and will allow us to evaluate endometrial gene expression during the window of 
implantation. The endometrial sample will be sent to Ivigen for an endometrial 
receptivity array (ERA)and microbiome analysis at no extra cost to the patient. The ERA 
provides information on the receptivity of a patient's endometrium to the implantation of 
an embryo. It is hypothesized that unexplained recurrent pregnancy loss and unexplained 
infertility patients are more likely to have a nonreceptive endometrium then healthy 
historic controls. 
 
For return patients with prior standard evaluation they will be invited to participate in the 
study. These patients will undergo an endometrial biopsy as above. The endometrial 
sample will be sent to Ivigen to our collaborators (Dr. Carlos Simon) for an endometrial 
receptivity array (ERA)and microbiome analysis at no extra cost to the patient. Dr. 
Simon's group will perform the analysis of the sample. 
 
For patients whose ERA shows a non receptive endometrium in the subsequent menstrual 
cycle, vaginal progesterone medication which is often prescribed empirically for 
recurrent pregnancy loss will be prescribed to start 3 days after ovulation detected by 
home urine LH kits. A second endometrial biopsy will be sent for a repeat ERA at not 


August 21, 2020 
 
Page 3 of 11 
extra cost to the patient. The patient will still be able to participate in the study if they 
decline this second biopsy. 
 
For patients who microbiome is altered, a 2 week course of oral doxycycline will be 
prescribed followed by 2 weeks of over the counter vaginal probiotics. A second 
endometrial biopsy will be sent for a repeat microbiome at not extra cost to the patient. 
The patient will still be able to participate in the study if they decline this second biopsy. 
 
If on the first biopsy there is endometritis the patient will first be treated based on 
standard of care practice with routine use of oral antibiotics prior to undergoing a second 
endometrial biopsy which is also routine practice. If the microbiome or ERA is also 
abnormal (It would be for example EXPECTED that the microbiome will be altered in all 
endometritis patients) for an abnormal ERA- vaginal progesterone would be added prior 
to rebiopsy and/or vaginal probiotics would be added. 
 
The patients' follow up visits and treatment regimens will be determined by the treating 
physician according to the standard of care treatment of recurrent pregnancy loss, 
unexplained infertility or other medical comorbidities. 
 
These patients are not required to consent to any additional testing or drug treatments 
outside of that which is standard treatment of their condition(s). They will consent to 
follow up communication (phone call or email) for up to 5 years after enrollment in the 
study to allow for completion of data collection and pregnancy outcomes except for the 
healthy controls who will be followed for 1 year. 
 
The only procedures which would be considered entirely research would be sending the 
endometrial biopsy tissue for ERA testing (currently endometrial biopsy is a standard of 
care for recurrent pregnancy loss and unexplained infertility) however this is not sent for 
ERA testing. 
 
Emperic use of vaginal progesterone is often used in the setting of recurrent pregnancy 
loss and unexplained fertility however doing a repeat biopsy in this setting would be 
considered research- not standard of care. 
 
Use of antibiotics is often used in the setting of non-specific findings for endometritis in 
recurrent pregnancy and unexplained fertility however using this in the setting of an 
abnormal microbiome in combination with over the counter vaginal probiotics would be 
considered research. 
b. 
Procedure Risks 
New patients will not be exposed to any additional researchprocedures outside the 
standard of care. For return patients theywill undergo a simple uterine biopsy that they 
will have theknowledge ahead of time about as they have already undergone thesame 
procedure previously. For the healthy controls they will undergo one minorprocedure any 
may benefit from the testing in the future. The endometrial biopsy ingeneral is a low risk 
procedure with a risk of complications of less than 1 in1,000 with the most common side 


August 21, 2020 
 
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effects of short lived (lasting afew minutes at most)of mild cramping and mild 
spottingUse of Deception in the Study 
Deception will not be used. 
d. 
Use of Audio and Video Recordings 
There will be no audio or video recording. 
e. 
Alternative Procedures or Courses of Treatment 
For unexplained recurrent pregnancy loss and unexplained infertility patients there is no 
standard of care treatment. Empirical treatment includes supplementing with 
progesterone in a subsequent pregnancy started in the luteal phase or with the first 
pregnancy test however there is little evidence based medicine behind these options. At 
most this would be a 1-2 month delay of starting this empiric treatment for patients who 
fall in the abnormal group who had the option for treatment with progesterone or 
antibiotics/probiotics and subsequent biopsy. 
 
Another option we review with our recurrent pregnancy loss patients is in vitro 
fertilization with PGS (pre-implantation genetic screening) however this has not been 
shown to improve time to live birth and is very expensive. Again if patients decided to 
have this treatment the study would only again delay this by 1-2 months and have no 
effect on the patient's success rate of the treatment itself given a minor time delay. 
Furthermore it may allow us to better time an embryo transfer for these patients as ERA 
has been used to identify the best window of implantation after IVF. 
 
For unexplained infertility treatments in include oral fertility medications (clomid) plus 
insemination cycles or in-vitro fertilization cycles. Again this would be at most a 1-2 
month delay which we do not anticipate would change their overall prognosis or outcome 
for pregnancy. Again if patients proceed to IVF and embryo transfer the knowledge from 
the study could be used to better time an embryo transfer. 
 
For the healthy controls there is at least a 1-2 month set up to proceed with egg 
harvesting. The biopsy would be done during this set up time and would not cause a 
clinically significant delay. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
As there is no standard treatment of unexplained recurrent pregnancy loss, all therapy as 
described about will be possible for these patients. For unexplained infertility the 
standard appropriate therapy will resumed after the conclusion of the study. 
g. 
Study Endpoint(s) 
For patients who are found to have a receptive endometrium, the study end point will be 
after the standard medical evaluation as described. For patients who are found to have a 
non receptive endometrium or abnormal microbiome the study end point will be after the 
second endometrium biopsy. Participants will be allowed to continue any standard 


August 21, 2020 
 
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medically indicated treatments throughout the study. For healthy controls the study end 
point will be after the first endometrial biopsy and we will not plan a repeat biopsy. The 
study will end once the anticipated total number of participants is met to complete an 
adequate power analysis. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Recurrent pregnancy loss is a difficult clinical diagnoses defined as when women have 
>2 unexplained miscarriages (not accounted for by genetically abnormal fetal tissue) <10 
weeks. After a full evaluation for genetic, endocrine, anatomic, immunologic, infectious 
and autoimmune conditions, the majority of cases remain unexplained. In unexplained 
infertility normal sperm, normal ovulatory function and patent fallopian tubes are 
documented and the reason for infertility remains unexplained. The role of endometrial 
factors in pregnancy loss and unexplained infertility is becoming of increasing interest. 
Studies have identified differences in the endometrium in protein expression and 
endometrial glandular development in women with unexplained recurrent pregnancy loss. 
Some studies have suggested that luteal phase progesterone may change the endometrial 
environment. Therefore the purpose of this study was to look at a more comprehensive 
genetic expression profile and the microbiome atmosphere during the window of 
implantation and to evaluate if luteal phase progesterone support normalizes this genetic 
expression profile for RPL patients who are found to have non- receptive endometrial 
biopsies. Understanding the genetic expression profile of the endometrium and the 
microbiome atmosphere during the window of implantation for unexplained infertility 
may help identify a previously unknown uterine factor in unexplained infertility. Prior 
studies have shown that a non receptive ERA and an abnormal microbiome (lactobacilli 
non dominant) is associated with decreased implantation rate, pregnancy rate and live 
birth rates in women undergoing IVF. 
b. 
Findings from Past Animal Experiments 
None 
4. 
DEVICES USED IN THE STUDY 
a. 
IDE-Exempt Devices 
IND-Exempt Device 1 
Name: 
ERA: Endometrial receptivity array (IVIGEN) 
Description: 
The ERA is a diagnostic tool used to evaluate the endometrial receptivity 
of a patient that determines whether or not an embryo is capable of 
implanting in the uterus.   
IND-Exempt Device 2 
Name: 
Vaginal progesterone (endometrin) (Ferring Pharmaceuticals Inc.) 
Description: 
Vaginal progesterone supplementation   
IND-Exempt Device 3 
Name: 
Doxycyline (Generic) 
Description: 
Doxycyline 
 


August 21, 2020 
 
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5. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
PurFem priobiotic (Bifodan A/S) 
Dosage: 
Dispense 1 capsule per vagina daily x 10 days 
New and different use? (Y/N) 
No 
Commercial Product 2 
Name: 
Probaclac Vaginal Probiotic (Nicar Laboratories) 
Dosage: 
apply 1 vaginal capsule oer vagina daily x 14 days 
New and different use? (Y/N) 
No 
Commercial Product 3 
Name: 
Lactogyn (JADRAN-GALENSKI LABORATORIJ d.d. JGL d.d) 
Dosage: 
1 application to vagina per day 
New and different use? (Y/N) 
No 
6. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 
 
7. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
The number of participate expected to be enrolled at Stanford Medicine Fertility and 
Reproductive Health Clinic is 100 patients per patient population (100 recurrent 
pregnancy loss patients, 100 unexplained infertility patients and 100 health controls). 
Any patients eligible for the study but desiring no intervention will be offered the 
alternative of being included as an observational group only without intervention in order 
to compare pregnancy outcomes without intervention. These patients will be recurrent 
pregnancy loss and unexplained infertility patients seeking treatment at our facility. 
healthy controls will be patients presenting for elective egg freezing and sex selection. 
b. 
Age, Gender, and Ethnic Background 
All participants enrolled in this study will be female and of reproductive age 18-45 years 
old that present to our clinic for routine evaluation and treatment. Enrollment will be 
open to women of all ethnic backgrounds. 
c. 
Vulnerable Populations 
N/A 
d. 
Rationale for Exclusion of Certain Populations 
Children will not be included as recurrent pregnancy loss and infertility does not occur in 
children. 
e. 
Stanford Populations 
None 


August 21, 2020 
 
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f. 
Healthy Volunteers 
None 
g. 
Recruitment Details 
The participants will be recruited by their treating physician if they meet the inclusion 
criteria for the study. The study be open to the public and women who are already 
presenting to Stanford Medicine Fertility and Reproductive Health clinic will be invited 
to participate. Participants will be treated the same whether or not they agree to 
enrollment in the study. Those consenting to study participation will be willing to allow 
physician follow up for up to 5 years for thorough data collection. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Subjects must fulfill the following inclusion criteria to be eligible to participate in the 
study: 
1. Have a diagnosis of recurrent pregnancy loss as defined as two or more 
unexplained pregnancy losses at less than 10 weeks (miscarriages with known 
chromosomal errors excluded) OR have a diagnosis of unexplained infertility defined 
as normal ovarian reserve testing, normal ovulatory function, normal semen analysis 
defined why WHO criteria and evidence of at least one patent fallopian tube. 
2. Agree to the standard of care testing for evaluation of recurrent pregnancy loss OR 
unexplained infertility OR routine testing for preparation for oocyte freezing or 
elective sex selection. 
3. Be at least 18 years old and less than 46 years old. 
4. Have menstrual cycles that occur in 25-35 day intervals 
5. Agree to follow up for 5 years from the date of enrollment 
ii. 
Exclusion Criteria 
1. Irregular menstrual cycles 
2. Presence of untreated submucosal fibroids or polyps 
3. an unligated hydrosalpinx 
4. non-ovulatory progesterone level on the day of endometrial biopsy 
5. Women <21 or >45 years old. 
i. 
Screening Procedures 
Study staff will invite women presenting for recurrent pregnancy loss or unexplained 
infertility or healthy controls to participate in this study. The staff will explain the 
purpose of the study to interested patients and the patients will then sign an informed 
consent for their enrollment. Patients will receive a thorough evaluation of their condition 
upon presentation. It will be emphasized that their participation is entirely voluntary and 
that they will receive the standard of care even if they choose not to enroll in the study or 
discontinue participation at any time. 


August 21, 2020 
 
Page 8 of 11 
j. 
Participation in Multiple Protocols 
Patients will be asked if they are participating in any other studies on their consent forms. 
They may be enrolled in other studies concurrently with this study as long as it does not 
impact the outcome of this study. 
k. 
Payments to Participants 
No payment will be provided. Patients are receiving standard of care evaluation and 
management of recurrent pregnancy loss and unexplained infertility. 
l. 
Costs to Participants 
Standard recurrent pregnancy loss and unexplained infertility evaluation and treatment 
costs will be charged to the patient or her insurance. Similarly standard evaluation prior 
to oocyte freezing or sex selection cycles will be charted to the patient or her insurance. 
m. 
Planned Duration of the Study 
The probable duration of the study will be approximately 3-5 years to complete the 
patient's treatment of recurrent pregnancy loss and unexplained infertility and follow up 
the outcome of their pregnancies (if applicable) for up to 5 years. 
8. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
The ERA and microbiome tests pose no risks or injury to the subject. Participants will 
receive standard of care at the study site which includes an endometrial biopsy. A portion 
of this specimen will be sent free of charge for the endometrial receptivity array and 
microbiome evaluation. 
ii. 
Investigational drugs 
N/A 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Vaginal progesterone supplementation is often used empirically as an available treatment 
for patients with recurrent pregnancy loss. This will be offered to all patients who desire 
this empirical treatment if their ERA shows a non-receptive endometrium. These patients 
will be offered a repeat ERA biopsy to determine whether progesterone improves their 
endometrial receptivity. 
Vaginal progesterone risks are considered minimal but patient's have reported in clinical 
trials to report symptoms such as abdominal pain (12%) nausea (8%) abdominal bloating 
(4%), constipation (2-3%) vomiting (3%), fatigue (2%), UTIs (2%) headache 4%, vaginal 
bleeding of 3%. Vaginal progesterone may also have similar side effects compared to 
other drugs containing progesterone including breast tenderness, bloating, mood swings, 
irritability, and drowsiness. If patients experience bothersome side effects that are not 
easily treated (for example a headache that resolves with a dose of Tylenol) we would 
stop vaginal progesterone treatment as is our current clinical practice. 


August 21, 2020 
 
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Oral doxycycline is considered minimal risk but patients have reported in clinical trials to 
report symptoms such as nausea, decreased appetite, vomiting, diarrhea, hives and 
anemia. If these symptoms developed and didn't resolved with minimal intervention 
(taking food with medicine) the treatment would be stopped as is our current clinical 
practice. 
iv. 
Procedures 
Minimal risk to patients with non-invasive procedures. Patients will only receive standard 
of care diagnostic testing during their duration of treatment in our office. This will 
include ultrasounds, blood tests and a uterine cavity evaluation. A patient may experience 
mild discomfort at the venipuncture site and some lower abdominal cramping and light 
bleeding (spotting) associated with a uterine cavity evaluation. There are extremely low 
risks of infection or other complications associated with these minimally invasive 
procedures. 
v. 
Radioisotopes/radiation-producing machines 
N/A 
vi. 
Physical well-being 
Minimal risks to a patient's physical well-being. Patients are receiving standard medical 
treatment. Repeat biopsies will be offered to patients whose initial testing is not 
receptive. The risk of the repeat biopsy is again minimal physical risk and patients will be 
allowed to decline the repeat testing. 
vii. 
Psychological well-being 
Minimal risks to a patient's psychological well-being. Potential improvement to 
psychological well being as the information from the ERA may help explain a previously 
unexplained diagnosis of recurrent pregnancy loss or unexplained infertility. 
viii. 
Economic well-being 
Participants will not be responsible for any costs associated with this study. The are 
receiving standard medical care and if they agree to the endometrial biopsy, the ERA and 
microbiome testing will be done for no additional cost. 
ix. 
Social well-being 
x. 
Participation in this study should not effect a patient's social well-being. Overall 
evaluation of risk 
Low 
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
Clinical study staff will explain all procedures thoroughly to consented subjects and why 
each diagnostic test is being done during their evaluation. There are no anticipated 


August 21, 2020 
 
Page 10 of 11 
additional risks to a patient who is involved in this study as compared to a 
nonparticipating patient in the same clinical setting. Subject identity will be kept 
confidential. 
d. 
Study Conclusion 
The study will terminate once the desired number of participants has been reached and 
each patient has been followed for 5 years from the date of enrollment. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
Since we will be performing endometrial biopsies in patients enrolled in this study, 
there is a small risk of bleeding and infection that can occur as result of this 
intervention (<1%) We will keep track of all patients that experience complications 
as a result of this procedure. 
 
For patients who use vaginal progesterone there is a small risk of side effects from 
systemic absorption of the progesterone: Bloating, stomach/abdominal pain, nausea, 
breast tenderness, headache, drowsiness, mood swings, irritability, or vaginal 
discomfort. In our experience we have found that <1% of our patients have 
bothersome side effects with vaginal progesterone which we routinely use for many 
infertility and recurrent pregnancy loss patients. We will keep track of all patients 
that experience side effects on this medication. 
 
For patients using oral doxycycline there is a small risk of side effects including 
decreased appetite, nausea, vomiting, diarrhea, allergic reaction and anemia. In our 
experiences we have found that <1% of our patients have bothersome side effects 
with oral doxycycline which we routinely use for many of these patients. . We will 
keep track of all patients that experience side effects on this medication. 
 
Vaginal probiotics is an over the counter supplement that is not expected to have side 
effects other then difficulty with insertion or change in typical vaginal discharge. 
None the less we will keep track if any patient reports any bothersome side effect and 
discontinue its use if there are any. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The protocol director will be monitoring all unanticipated problems and adverse 
events. 
iii. 
Frequency of DSMB meetings 
N/A 
iv. 
Specific triggers or stopping rules 
The risk of complications with an endometrial biopsy in the general population is 
approximately 1%. If we experience a higher complication rate then this we will 
terminate the procedure. 


August 21, 2020 
 
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If any patient reports persistent side effects while on vaginal progesterone this will be 
stopped for this patient as it would be based on standard of care practice. 
v. 
DSMB Reporting 
N/A 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Yes 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
No 
f. 
Risks to Special Populations 
N/A 
9. 
BENEFITS 
Participants will benefit by receiving a thorough evaluation of theirrecurrent pregnancy loss and 
unexplained infertility or baseline fertility testing for thoseundergoing egg freezing or sex 
selection. Participantswill be informed of their endometrial receptivity array andmicrobiome 
results which may lead to improvements in their futurecare. For example many of our patients do 
go on to have in vitrofertilization with subsequent embryo transfers (also the sex selection 
patients or thosepatients who froze eggs who are coming back to use them). During these 
embryotransfers the ERA is used to personalize and improve the embryotransfer success rate. The 
ERA has been shown to be consistent intime across menstrual cycles over many years. 
Knowledge of the ERAwould help patients as they would not have to go through or pay forthis 
testing at a later time.  
10. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.