Clinical trial NCT03395288
Conditions: Urinary Tract Infections
Keywords: UTI recurrent UTI
Sponsor: Washington University School of Medicine
Start date: 2018-03-22; Completion date: 2020-04-25
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study designed to evaluate the efficacy of a nutraceutical as a non-antibiotic treatment to prevent recurrent urinary tract infections in women that have completed menopause and are on vaginal estrogen therapy. An additional group of women with recurrent urinary tract infections that have completed menopause but are not using vaginal estrogen therapy will be followed while taking the nutraceutical. The study length is ninety days from the date that the study participant will be instructed is day 1.

Detailed description:
The objective of this study is to determine the efficacy of a nutraceutical as a non-antibiotic prophylaxis for postmenopausal women on vaginal estrogen therapy (VET) with a history of symptomatic, culture-proven recurrent urinary tract infection (rUTI) by means of a randomized, controlled trial. Recurrent urinary tract infections have a significant impact on patient health, quality of life, and finances (personal and societal).

The most common uropathogen for both acute and recurrent UTIs is Escherichia coli.

Historically, patients with rUTI have been placed on long-term prophylactic antibiotics to prevent recurrence. Long term antibiotic use can lead to antibiotic resistance, collateral damage to normal flora, and organ damage, such as pulmonary and hepatic toxicity with long-term nitrofurantoin use. There is an increasing prevalence of antibiotic resistance of uropathogenic E. coli and other uropathogens. Antibiotic resistance and its consequences have resulted in a need for non-antibiotic prophylaxis regimens.

A growing body of literature supports the use of vaginal estrogen therapy as a first-line non-antibiotic UTI prevention strategy in postmenopausal women. While VET has been shown to significantly reduce the risk of rUTIs, some women continue to have rUTIs. Other non-antibiotic strategies have been utilized including D-mannose, a nutraceutical. Three prior studies examined D-mannose as an isolated therapy with promising results, but in our experience, a multimodal approach has often been needed. Therefore, additional studies, such as this proposed research, are needed to determine the potential additive effect of a nutraceutical as a non-antibiotic prophylaxis for postmenopausal women using vaginal estrogen therapy.

Arms: arm 1: Participants in this arm will dissolve one (1) level teaspoon of the nutraceutical powder (D-mannose) in at least 200 ml of water one time a day, approximately every 24 hours. (200 ml of water = 6.7 fluid ounces). Duration of study drug is 90 days. arm 2: Participants in this arm will not use any additional intervention. arm 3: Participants in this arm will either take a total of 1000 mg D-mannose in capsule form every 12 hours OR they will dissolve one (1) level teaspoon of the nutraceutical powder (D-mannose) in at least 200 ml of water one time a day, approximately every 24 hours. (200 ml of water = 6.7 fluid ounces). Duration of study drug is 90 days. Participants in this arm of the study have different home medications prior to study enrollment than participants in the RCT treatment arm.
Interventions: intervention 1: D-Mannose
Intervention descriptions: intervention 1: A total of 2 g D-mannose daily

Protocol documents:
ICF_008.pdf: 
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IRB ID #: 201711120 
APPROVAL DATE: 11/13/20 
RELEASED DATE: 11/13/20 
EXPIRATION DATE: 11/12/21 
06/04/2020 
INFORMED CONSENT DOCUMENT – RCT ARM 
Project Title: 
Randomized, controlled trial to determine the efficacy of a nutraceutical versus 
control as non-antibiotic prophylaxis for recurrent urinary tract infection in postmenopausal 
women using vaginal estrogen therapy 
Principal Investigator: 
Jerry Lowder 
Research Team Contact: 
Jerry Lowder, M.D., M.Sc., 314-747-1402 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 

You should read and understand the information in this document including the procedures,
risks and potential benefits.

If you have questions about anything in this form, you should ask the research team for more
information before you agree to participate.

You may also wish to talk to your family or friends about your participation in this study.

Do not agree to participate in this study unless the research team has answered your
questions and you decide that you want to be part of this study.
WHAT IS THE PURPOSE OF THIS STUDY? 
This is a research study.  We invite you to participate in this research study because you are a 
postmenopausal woman with recurrent urinary tract infections.  Recurrent urinary tract infection (rUTI) 
means you have had multiple recent infections in your urinary tract: at least two infections in the last six 
months or at least three infections in the last twelve months. Since you are using either vaginal estrogen 
cream, tablet, or ring (meaning you are using vaginal estrogen therapy) you are invited to participate in 
the randomized clinical trial (RCT) portion of this study.  
The purpose of this research study is to evaluate a nutraceutical as a non-antibiotic treatment to prevent 
rUTI in women that have completed menopause.  In this study, the nutraceutical is a specific dietary 
supplement that is available at health food stores and without a prescription. Previous small studies have 
looked at this same nutraceutical to prevent rUTI, but none of these studies evaluated the nutraceutical 
in patients that were using vaginal estrogen therapy. Many times when women with rUTI are treated a 
combination of treatments may be considered, which is why this study is being performed to look at the 
nutraceutical as a non-antibiotic treatment in women like yourself who are on vaginal estrogen.  
The nutraceutical is considered investigational, which means that it has not been approved by the U.S. 
Food and Drug Administration.  
WHAT WILL HAPPEN DURING THIS STUDY? 


 
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You will be randomly assigned to receive one of the two study treatments; either you will be given the 
nutraceutical to take in addition to the vaginal estrogen (cream, tablet, or ring) that you are already 
taking or you will continue with only using the vaginal estrogen (cream, tablet, or ring). This means that 
the study treatment you will receive will be determined purely by chance, like flipping a coin. You will 
have a 50% chance of receiving either of the study treatments.  
 
The study team will know the specific name of the nutraceutical that is being studied, but patients in the 
study will not be informed of the specific name of the nutraceutical until after the study is completed. 
This is done because we want to get unbiased information from participants in the study. 
 
If you are assigned to receive the nutraceutical, you will take it once daily as a powder that is dissolved 
in water that you will drink. 
 
If you decide to participate in this study, the following health information will be gathered as part of the 
study: your UTI history, medical and surgical history, pregnancy history, social history, medication 
history, race, and menopausal status; history of pelvic pain; history of prior pelvic floor physical 
therapy; presence of vaginal discharge; symptoms you experience if you get a UTI during the study; side 
effects experienced in the study; urinalysis or urine culture results collected during the study. Routine 
clinical information from today’s office visit including your height, weight, physical exam findings, and 
urine culture may also be included. 
 
This study is 90 (ninety) days long from the date that we tell you is day 1 (one). Most likely study day 1 
will be 5 (five) days after you enroll in the study. You have to wait this period of time before study day 
1 to make sure that the urine culture that was sent as part of your normal office visit is negative.  If your 
urine culture was not negative, the research team will recommend you having your UTI treated with 
antibiotics like you normally would be whether if you were in the study or not. After you finish the 
antibiotics you would to have another urine culture test. After that urine culture is negative, then you 
will be told the day for your study day 1 (one).   
 
There will not be any additional office visits just for research purposes. All research will be conducted 
during normal clinic follow up appointments for patients with rUTI or by contact with you by text 
message, mail, or phone between your appointments. 
 
If you decide to participate in the study today, you will be asked to complete study related questions 
before leaving your appointment. You are free to skip any questions you would prefer not to answer. 
 
During your 90 (ninety) days in the study, you will be asked to fill out a study diary at the end of each 7 
(seven) day period. If you agree to receive text messages as part of this study, you will receive a text 
message reminding you to fill out your study diary every 7 (seven) days until study day 90 (ninety) 
when your study participation is complete. The same text message will ask you to reply ‘yes’ or ‘no’ to 
whether you have had any new symptoms from the study medications in the past week. A ‘yes’ response 
will prompt a phone call from a member of the study team. If you do not wish to receive text messages 
as part of this study you will receive a phone call no more than once a week reminding you to fill out 
your study diary. 
You will also receive a phone call from a member of the research team approximately 6 (six) weeks into 
the study. The purpose of this phone call is to check if you have any questions about your medications, 


 
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how often you are taking your medication, and if you have been treated for a urinary tract infection by 
anyone outside of our office during the study period.  
 
After you complete your 90 (ninety) days in the study, you will return to the office for a 3 (three) month 
follow up appointment. A three month follow up appointment is normal for all patients with rUTI being 
cared for at the Washington University Physicians Women’s Center for Bladder and Pelvic Health. You 
should bring your completed study diary to this appointment. If you are in the treatment arm taking the 
nutraceutical, you should bring any remaining study medication with you to this appointment. You will 
be asked to answer questionnaires related to the study while at your appointment. You are free to skip 
any questions you would prefer not to answer. 
 
If at any point you forget to complete any of the questionnaires in the office or if you forget to bring 
your study diary with you to your follow up appointment, we may ask you to complete these forms over 
the phone or have them mailed to you for completion and return to a member of the research team. If 
you stop the study early we may ask that you complete an exit survey or follow up questionnaire either 
over the phone, via mail, or at your next appointment. 
 
If you develop UTI like symptoms during the study you will be instructed to call the office just like you 
would if you were not in the study. This means that if you are having burning or painful urination, 
increased urinary frequency, and/or increased urinary urgency, you should call the office to leave a 
message for one of the nurses.  If you are having nausea, vomiting, chills, and/or one-sided pain near the 
bottom of your rib cage on your back in addition to burning or painful urination, increased urinary 
frequency, and/or increased urinary urgency then you should call the office to speak with one of the 
nurses during the day or the after-hours emergency number for the office if it is at night or on the 
weekend. An order for a urine culture will be sent to a lab of your choice so a urine sample can be 
cultured to see if there are any bacteria growing in your urine.   
 
If you have a urinary tract infection diagnosed by a urine culture that grows bacteria during the study 
period, you will be treated with an antibiotic like you normally would be whether if you were in the 
study or not. Even if you have a positive urine culture you will continue in the study for 90 days, unless 
you decide you want to withdraw from the study. 
 
Will you save my samples or research data to use in future research studies?  
As part of this study, we are obtaining data from you. We would like to use these data for studies going 
on right now as well as studies that are conducted in the future.  These studies may provide additional 
information that will be helpful in understanding recurrent urinary tract infections, or other diseases or 
conditions, including research to develop investigational tests, treatments, drugs or devices that are not 
yet approved by the U.S. Food and Drug Administration.  It is unlikely that what we learn from these 
studies will have a direct benefit to you.  There are no plans to provide financial compensation to you 
should this occur.  By allowing us to use your data you give up any property rights you may have in the 
data. 
 
We will share your data with other researchers. They may be doing research in areas similar to this 
research or in other unrelated areas.  These researchers may be at Washington University, at other 
research centers and institutions, or industry sponsors of research.  We may also share your research data 
with large data repositories (a repository is a database of information) for broad sharing with the 


 
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RELEASED DATE: 11/13/20 
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research community.  If your individual research data is placed in one of these repositories, only 
qualified researchers, who have received prior approval from individuals that monitor the use of the 
data, will be able to look at your information.   
 
If you change your mind and do not want us to store and use your data for future research, you should 
contact the research team member identified at the top of this document. The data will no longer be used 
for research purposes. However, if some research with your data has already been completed, the 
information from that research may still be used. Also, if the data has been shared with other researchers 
it might not be possible to withdraw the data to the extent it has been shared. 
 
Please place your initials in the blank next to Yes or No for each of the questions below: 
 
My data may be stored and used for future research as described above. 
 
_____ Yes          _____ No 
Initials                    Initials 
 
My data may be shared with other researchers and used by these researchers for the future 
research as described above. 
 
_____ Yes          _____ No 
Initials                    Initials 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 180 people will take part in this study conducted by investigators at Washington 
University.  There will be 120 patients in this randomized, controlled trial portion of the study and an 
additional 60 patients in an observational arm of the study.   
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for 90 (ninety) days after your study 
day 1 is determined as described earlier under “What will happen in this study?”. In addition to today’s 
visit the only office visit will be your routine 3 month follow up visit. This visit would be expected to 
range from 30 minutes to 1 hour in length. During the study you will also be asked to fill out your 
weekly study diary and answer a text.  We estimate the total weekly time for the diary and text to be no 
more than 5 (five) minutes. We estimate that your six week follow up phone call will take approximately 
5 (five) minutes as well.  
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
Nutraceutical 
Overall the nutraceutical used in this study is thought to be generally well tolerated in people since it is 


 
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APPROVAL DATE: 11/13/20 
RELEASED DATE: 11/13/20 
EXPIRATION DATE: 11/12/21 
 
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found in many natural foods. Risks associated with the nutraceutical are believed to be mainly related to 
gastrointestinal side effects.   You may prefer to obtain treatment for UTI like symptoms from an 
emergency room or other outside provider.   
Less Likely / Less Common 
Mild 
 Nausea 
 Vomiting 
 Flatulence (gas) 
 Diarrhea (loose stool) 
 Indigestion  
 Abdominal pain 
 Bloating 
 
Rare   
Mild 
 Rash 
 Itching 
 Allergic reaction 
 
Questionnaires 
You may feel uncomfortable or be inconvenienced by filling out study related papers.   
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may or may not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because of increased 
knowledge surrounding the use of non-antibiotic prophylaxis (giving something to try to prevent the 
UTI from occurring before it occurs) for rUTI.  
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you. The historical treatment to prevent further UTIs when a patient is diagnosed with rUTI 
is a preventative antibiotic. With increasing concern about antibiotic resistance and side effects from 
antibiotics, treatment options other than preventative antibiotics are preferred by some healthcare 
providers.  Vaginal estrogen therapy, like you are currently using, has been shown to help prevent rUTI 
in women that have completed menopause. Sometimes when vaginal estrogen is not enough by itself, 
your doctor may suggest additional nutraceuticals or medications to be added in addition to using 


 
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APPROVAL DATE: 11/13/20 
RELEASED DATE: 11/13/20 
EXPIRATION DATE: 11/12/21 
 
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vaginal estrogen. These additional nutraceuticals and medications are vitamin C, cranberry, D-mannose, 
and methenamine.  There is not a current consensus on the recommended treatment order and/or best 
combination of the additional non-antibiotic treatments. If you were not in the study you could receive 
the same nutraceutical that is being studied.  However, if you decide to be in the study then we ask that 
you don’t take any additional vitamin C, cranberry, D-mannose, and methenamine as it could change 
study outcomes.  
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
As part of this study you will receive tests and procedures that are similar to what you would receive 
during routine clinical care of your condition.  Your health plan/insurance company will be billed for 
some or all of these costs, and you will be responsible for any co-pays and deductibles that are normally 
required by your health plan/insurance.  Not all insurance plans cover the costs associated with being in 
a study. Even if they do, you may be responsible for more out-of-pocket expenses, such as co-pays and 
deductibles, when there are more tests and procedures or more expensive tests and procedures involved 
in the study than if you were to receive routine clinical care outside the study.   
 
If you wish to know whether there are more tests and procedures or more expensive tests and procedures 
in the study, you should ask your study doctor.   
 
If you wish to know whether your insurance will pay, you should contact them directly, or speak with 
the study team about obtaining a financial pre-certification prior to enrolling in the study. 
 
If you are randomly assigned to receive the nutraceutical then it will be provided at no cost to you. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.   
 
WHO IS FUNDING THIS STUDY? 
 
The University and the research team are not receiving payment from other agencies, organizations, or 
companies to conduct this research study.  
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator at 
(314)747-1402 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University. If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 


 
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Other people such as those indicated below may become aware of your participation in this study and 
may inspect and copy records pertaining to this research.  Some of these records could contain 
information that personally identifies you. We will keep your participation in this research study 
confidential to the extent permitted by law.   
 Government representatives (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
 The U.S. Food and Drug Administration 
 Your primary care physician if a medical condition that needs urgent attention is discovered 
 Hospital or University representatives to complete Hospital or University responsibilities 
 Information about your participation in this study may be documented in your health care records 
and will be available to anyone with access to your health care record, including your health 
insurance company.  This information may also be released as part of a release of information 
request. 
 The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures. 
 Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
 
To help protect your confidentiality, only research team members will have access to both the paper and 
electronic data. You will be assigned a unique study ID that will be used on all forms and database 
reporting. The database that will be used is HIPPA compliant, encrypted, and password protected. 
Electronic data files will be accessible only on password protected computers. Any hard copies will be 
maintained in a locked cabinet in a locked office by a member of the research team. For text messaging, 
we will be using a short message service (SMS) that does not collect any identifying information. Urine 
samples are not stored after testing.  
 
Any report or article that we write will not include information that can directly identify you.  The 
journals that publish these reports or articles require that we share your information that was collected 
for this study with others. Sharing this information will allow others to make sure the results of this 
study are correct and help develop new ideas for research. Your information will be shared in a way that 
cannot directly identify you.  
 
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.  
 
Are there additional protections for my health information? 
 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 


 
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Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form or as permitted 
or required by law.  When possible, the research team will make sure information cannot be linked to 
you (de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
 your treatment or the care given by your health provider. 
 your insurance payment or enrollment in any health plans.   
 any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
 You authorize the use of your PHI for this research 
 This authorization does not expire. 
 You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
 To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
 You will not be allowed to continue to participate in the study. 
 
 
Can we contact you by text? 
We would like to contact you by text message for the purposes listed below. Some of these texts may 
contain health information that identifies you.  
 To remind you to complete your diary 
 To ask you if you have had any new symptoms 
Only the research team will have access to your texting communications. We will only communicate by 
text to send you the information listed above. If you have any questions or need to contact us for an 


 
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urgent or emergent situation, please contact the research team member identified at the top of this 
document. Only the immediate response you send to a text message will be seen by a research team 
member. Other text messages sent to the study number will not be read or accessible by the research 
team.  Message and Data rates may apply. You will receive a maximum of six messages a month. You 
can text STOP or contact the research team member identified at the top of the document to opt-out of 
receiving these messages.  
  
You should be aware that there are risks associated with allowing us to text you for the purposes of this 
study.   
 There is always a risk that the text message could be intercepted or sent to the wrong 
telephone number. To avoid sending messages to the wrong number, the first text we send 
you will be a test message to ensure we have the correct telephone number. 
  
Do you agree to allow us to send you a test message at the beginning of the study, reminders to complete 
your diary, and questions about new symptoms via text?   
 
_____ Yes  
_____ No 
Initials  
Initials 
 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify.   
 
What if I decide to withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
If you decide to leave the study early, we will ask you to return any unused nutraceutical to the 
Washington University Physicians Women’s Center for Bladder and Pelvic Health.  
 
Will I receive new information about the study while participating? 
 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
Can someone else end my participation in this study? 
 


 
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Under certain circumstances, the investigator might decide to end your participation in this research 
study earlier than planned.  This might happen for no reason or because in our judgment it would not be 
safe for you to continue, if you receive an antibiotic for UTI like symptoms without having bacteria 
found on urine culture, or if funding for the research study has ended.  
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Jerry Lowder, M.D. or another member of the research team at (314)747-1402. If you 
experience a research-related injury, please contact: Jerry Lowder, M.D. or another member of the 
research team at (314)747-1402. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office at 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research participant or to speak to someone other than the 
research staff, call the Human Research Protection Office at the number above. 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
 To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
 To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
 To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
 To give the research team accurate and complete information. 
 To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 


 
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Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 11/12/21. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed) 
 
 


 
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IRB ID #: 201711120 
APPROVAL DATE: 11/13/20 
RELEASED DATE: 11/13/20 
EXPIRATION DATE: 11/12/21 
 
06/04/2020 
 
INFORMED CONSENT DOCUMENT – OBSERVATIONAL ARM 
 
Project Title: 
Randomized, controlled trial to determine the efficacy of a nutraceutical versus 
control as non-antibiotic prophylaxis for recurrent urinary tract infection in postmenopausal 
women using vaginal estrogen therapy 
 
Principal Investigator: 
Jerry Lowder 
 
Research Team Contact: 
Jerry Lowder, M.D., M.Sc., 314-747-1402  
 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
 You should read and understand the information in this document including the procedures, 
risks and potential benefits.  
 If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
 You may also wish to talk to your family or friends about your participation in this study. 
 Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We invite you to participate in this research study because you are a 
postmenopausal woman with recurrent urinary tract infections.  Recurrent urinary tract infection (rUTI) 
means you have had multiple recent infections in your urinary tract: at least two infections in the last six 
months or at least three infections in the last twelve months. Since you are not using vaginal estrogen 
you are invited to participate in the observational portion of this study.  
 
The purpose of this research study is to evaluate the nutraceutical D-mannose as a non-antibiotic 
treatment to prevent rUTI in women that have completed menopause.  D-mannose is a dietary 
supplement that is available at health food stores and without a prescription. Previous small studies have 
looked at D-mannose to prevent rUTI, but none of these studies evaluated the nutraceutical in patients 
that were using vaginal estrogen therapy. Many times when women with rUTI are treated a combination 
of treatments may be considered, which is why this study is being performed to look at D-mannose as a 
non-antibiotic treatment in postmenopausal women.  Since you are not using vaginal estrogen like the 
women in the other part of our study, your information in this study will be used to compare to the 
women using vaginal estrogen that are in the other part of our study. The observation portion of this 
study is for our patients, like yourself, that we would recommend D-mannose for as part of their normal 
treatment in our office.  
  
The use of D-mannose is considered investigational, which means that it has not been approved by the 
U.S. Food and Drug Administration.  


 
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WHAT WILL HAPPEN DURING THIS STUDY? 
 
As part of the observational arm of our study, you are a patient that we would recommend D-mannose 
for as part of your normal treatment in our office. We would provide you with the necessary dose 
information to purchase D-mannose from a supplement store, just like we would if you were not in the 
study.   
 
You will take 2 grams of D-mannose per day as either a powder that is dissolved in water that you will 
drink once daily or as two capsules that you will swallow every 12 hours. The brand you will be 
required to purchase is called NOW (and you will purchase either the NOW D-mannose pure powder or 
the NOW D-mannose 500mg capsules). You will receive an instruction sheet explaining how to take the 
D-mannose. 
 
If you decide to participate in this study, the following health information will be gathered as part of the 
study: your UTI history, medical and surgical history, pregnancy history, social history, medication 
history, race, and menopausal status; history of pelvic pain; history of prior pelvic floor physical 
therapy; presence of vaginal discharge; symptoms you experience if you get a UTI during the study; side 
effects experienced in the study; urinalysis or urine culture results collected during the study. Routine 
clinical information from today’s office visit including your height, weight, physical exam findings, and 
urine culture may also be included. 
 
This study is 90 (ninety) days long from the date that we tell you is day 1 (one). Most likely study day 1 
will be 5 (five) days after you enroll in the study. You have to wait this period of time before study day 
1 to make sure that the urine culture that was sent as part of your normal office visit is negative.  If your 
urine culture was not negative, the research team will recommend you having your UTI treated with 
antibiotics like you normally would be whether if you were in the study or not. After you finish the 
antibiotics you would to have another urine culture test. After that urine culture is negative then you will 
be told the day for your study day 1 (one).   
 
There will not be any additional office visits just for research purposes. All research will be conducted 
during normal clinic follow up appointments for patients with rUTI or by contact with you by text 
message, mail, or phone between your appointments. 
 
You will receive a phone call from a member of the research team approximately 1 week after you 
enroll in the study to find out which type of D-mannose you purchased (powder of capsules) and what 
the first day was that you started taking the D-mannose. 
 
During your 90 (ninety) days in the study, you will be asked to fill out a study diary at the end of each 7 
(seven) day period. If you agree to receive text messages as part of this study, you will receive a text 
message reminding you to fill out your study diary every 7 (seven) days until study day 90 (ninety) 
when your study participation is complete. The same text message will ask you to reply ‘yes’ or ‘no’ to 
whether you have had any new symptoms from the study medications in the past week. A ‘yes’ response 
will prompt a phone call from a member of the study team. If you do not wish to receive text messages 
as part of this study you will receive a phone call no more than once a week reminding you to fill out 
your study diary. 


 
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You will also receive a phone call from a member of the research team approximately 6 (six) weeks into 
the study. The purpose of this phone call is check if you have any questions about your medications, 
how often you are taking your medication, and if you have been treated for a urinary tract infection by 
anyone outside of our office during the study period.  
 
After you complete your 90 (ninety) days in the study, you will return to the office for a 3 (three) month 
follow up appointment. A three month follow up appointment is normal for all patients with rUTI being 
cared for at the Washington University Physicians Women’s Center for Bladder and Pelvic Health. You 
should bring your completed study diary to this appointment. You will be asked to answer 
questionnaires related to the study while at your appointment. You are free to skip any questions you 
would prefer not to answer. 
 
If at any point you forget to complete any of the questionnaires in the office or if you forget to bring 
your study diary with you to your follow up appointment, we may ask you to complete these forms over 
the phone or have them mailed to you for completion and return to a member of the research team. If 
you stop the study early we may ask that you complete an exit survey or follow up questionnaire either 
over the phone, via mail, or at your next appointment. 
 
If you develop UTI-like symptoms during the study you will be instructed to call the office just like you 
would if you were not in the study. This means that if you are having burning or painful urination, 
increased urinary frequency, and/or increased urinary urgency,  then you should call the office to leave a 
message for one of the nurses.  If you are having nausea, vomiting, chills, and/or one-sided pain near the 
bottom of your rib cage on your back in addition to burning or painful urination, increased urinary 
frequency, and/or increased urinary urgency then you should call the office to speak with one of the 
nurses during the day or the after-hours emergency number for the office if it is at night or on the 
weekend. An order for a urine culture will be sent to a lab of your choice so a urine sample can be 
cultured to see if there are any bacteria growing in your urine.   
 
If you have a urinary tract infection diagnosed by a urine culture that grows bacteria during the study 
period, you will be treated with an antibiotic like you normally would be whether if you were in the 
study or not. Even if you have a positive urine culture you will continue in the study for 90 days, unless 
you decide you want to withdraw from the study.  
 
Will you save my samples or research data to use in future research studies? 
 
As part of this study, we are obtaining data from you. We would like to use this and data for studies 
going on right now as well as studies that are conducted in the future.  These studies may provide 
additional information that will be helpful in understanding recurrent urinary tract infections, or other 
diseases or conditions, including research to develop investigational tests, treatments, drugs or devices 
that are not yet approved by the U.S. Food and Drug Administration.  It is unlikely that what we learn 
from these studies will have a direct benefit to you.  There are no plans to provide financial 
compensation to you should this occur.  By allowing us to use your data you give up any property rights 
you may have in the data. 
 
We will share your data with other researchers. They may be doing research in areas similar to this 


 
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APPROVAL DATE: 11/13/20 
RELEASED DATE: 11/13/20 
EXPIRATION DATE: 11/12/21 
 
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research or in other unrelated areas.  These researchers may be at Washington University, at other 
research centers and institutions, or industry sponsors of research.  We may also share your research data 
with large data repositories (a repository is a database of information) for broad sharing with the 
research community.  If your individual research data is placed in one of these repositories only 
qualified researchers, who have received prior approval from individuals that monitor the use of the 
data, will be able to look at your information.   
 
If you change your mind and do not want us to store and use your data for future research you should 
contact the research team member identified at the top of this document. The data will no longer be used 
for research purposes. However, if some research with your data has already been completed, the 
information from that research may still be used. Also, if the data has been shared with other researchers 
it might not be possible to withdraw the data to the extent it has been shared. 
 
Please place your initials in the blank next to Yes or No for each of the questions below: 
My data may be stored and used for future research as described above. 
 
_____ Yes          _____ No 
Initials                    Initials 
 
My data may be shared with other researchers and used by these researchers for the future 
research as described above. 
 
_____ Yes          _____ No 
Initials                    Initials 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 180 people will take part in this study conducted by investigators at Washington 
University.  There will be 120 patients in the randomized, controlled trial portion of the study and an 
additional 60 patients in this observational arm of the study.  
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for 90 (ninety) days after your study 
day 1 is determined as described earlier under “What will happen in this study?”. In addition to today’s 
visit the only office visit will be your routine 3 month follow up visit. This visit would be expected to 
range from 30 minutes to 1 hour in length. During the study you will also be asked to fill out your 
weekly study diary and answer a text.  We estimate the total weekly time for the diary and text to be no 
more than 5 (five) minutes. We estimate that your six week follow up phone call will take approximately 
5 (five) minutes as well.  
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  


 
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D-mannose 
Overall D-mannose is thought to be generally well tolerated in people since it is found in many natural 
foods. Risks associated with the nutraceutical are believed to be mainly related to gastrointestinal side 
effects .  You may prefer to obtain treatment for UTI like symptoms from an emergency room or other 
outside provider.   
Less Likely / Less Common 
Mild 
 Nausea 
 Vomiting 
 Flatulence (gas) 
 Diarrhea (loose stool) 
 Indigestion  
 Abdominal pain 
 Bloating 
 
Rare   
Mild 
 Rash 
 Itching 
 Allergic Reaction 
 
Questionnaires 
You may feel uncomfortable or be inconvenienced by filling out study related papers. 
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may or may not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because of increased 
knowledge surrounding the use of non-antibiotic prophylaxis (giving something to try to prevent the 
UTI from occurring before it occurs) for rUTI.  
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you. The historical treatment to prevent further UTIs when a patient is diagnosed with rUTI 
is a preventative antibiotic. With increasing concern about antibiotic resistance and side effects from 
antibiotics, treatment options other than preventative antibiotics are preferred by some healthcare 
providers.  Vaginal estrogen therapy has been shown to help prevent rUTI in women that have 


 
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completed menopause. Sometimes when vaginal estrogen can’t be used by a patient or is not enough by 
itself, your doctor may suggest additional nutraceuticals or medications to be added in addition to using 
vaginal estrogen. These additional nutraceuticals and medications are vitamin C, cranberry, D-mannose, 
and methenamine.  There is not a current consensus on the recommended treatment order and/or best 
combination of the additional non-antibiotic treatments. If you were not in the study you could still 
receive the treatment (D-mannose) that is being studied.  However, if you decide to be in the study then 
we ask that you don’t take any additional vitamin C, cranberry, D-mannose, and methenamine as it 
could change study outcomes.  
  
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
As part of this study you will receive tests and procedures that are similar to what you would receive 
during routine clinical care of your condition.  Your health plan/insurance company will be billed for 
some or all of these costs, and you will be responsible for any co-pays and deductibles that are normally 
required by your health plan/insurance.  Not all insurance plans cover the costs associated with being in 
a study. Even if they do, you may be responsible for more out-of-pocket expenses, such as co-pays and 
deductibles, when there are more tests and procedures or more expensive tests and procedures involved 
in the study than if you were to receive routine clinical care outside the study.   
 
If you wish to know whether there are more tests and procedures or more expensive tests and procedures 
in the study, you should ask your study doctor.   
 
If you wish to know whether your insurance will pay, you should contact them directly, or speak with 
the study team about obtaining a financial pre-certification prior to enrolling in the study. 
 
D-mannose is not prescription and you would be responsible for the cost and purchasing it from store 
that sells supplements. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.   
 
WHO IS FUNDING THIS STUDY? 
 
The University and the research team are not receiving payment from other agencies, organizations, or 
companies to conduct this research study.  
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator at 
(314)747-1402 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University. If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible.  


 
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HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 
Other people such as those indicated below may become aware of your participation in this study and 
may inspect and copy records pertaining to this research.  Some of these records could contain 
information that personally identifies you. We will keep your participation in this research study 
confidential to the extent permitted by law.   
 Government representatives (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
 The U.S. Food and Drug Administration 
 Your primary care physician if a medical condition that needs urgent attention is discovered 
 Hospital or University representatives to complete Hospital or University responsibilities 
 Information about your participation in this study may be documented in your health care records 
and will be available to anyone with access to your health care record, including your health 
insurance company.  This information may also be released as part of a release of information 
request. 
 The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures. 
 Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
 
To help protect your confidentiality, only research team members will have access to both the paper and 
electronic data. You will be assigned a unique study ID that will be used on all forms and database 
reporting. The database that will be used is HIPPA compliant, encrypted, and password protected. 
Electronic data files will be accessible only on password protected computers. Any hard copies will be 
maintained in a locked cabinet in a locked office by a member of the research team. For text messaging, 
we will be using a short message service (SMS) service that does not collect any identifying 
information. Urine samples are not stored after testing.  
 
Any report or article that we write will not include information that can directly identify you.  The 
journals that publish these reports or articles require that we share your information that was collected 
for this study with others. Sharing this information will allow others to make sure the results of this 
study are correct and help develop new ideas for research. Your information will be shared in a way that 
cannot directly identify you.  
 
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.  
 
Are there additional protections for my health information? 
 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 


 
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your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form or as permitted 
or required by law.  When possible, the research team will make sure information cannot be linked to 
you (de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
 your treatment or the care given by your health provider. 
 your insurance payment or enrollment in any health plans.   
 any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
 You authorize the use of your PHI for this research 
 This authorization does not expire. 
 You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
 To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
 You will not be allowed to continue to participate in the study. 
 
Can we contact you by text? 
We would like to contact you by text message for the purposes listed below. Some of these texts may 
contain health information that identifies you.  
 To remind you to complete your diary 
 To ask you if you have had any new symptoms 
  


 
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Only the research team will have access to your texting communications. We will only communicate by 
text to send you the information listed above. If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. Only the immediate response you send to a text message will be seen by a research team 
member. Other text messages sent to the study number will not be read or accessible by the research 
team. Message and Data rates may apply. You will receive a maximum of six messages a month. You 
can text STOP or contact the research team member identified at the top of the document to opt-out of 
receiving these messages.  
  
You should be aware that there are risks associated with allowing us to text you for the purposes of this 
study.   
 There is always a risk that the text message could be intercepted or sent to the wrong 
telephone number. To avoid sending messages to the wrong number, the first text we send 
you will be a test message to ensure we have the correct telephone number. 
  
Do you agree to allow us to send you a test message at the beginning of the study, reminders to complete 
your diary, and questions about new symptoms via text?   
 
_____ Yes  
_____ No 
Initials  
Initials 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify.   
 
What if I decide to withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
Will I receive new information about the study while participating? 
 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
 
Under certain circumstances, the investigator might decide to end your participation in this research 
study earlier than planned.  This might happen for no reason or because in our judgment it would not be 


 
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safe for you to continue, if you receive an antibiotic for UTI like symptoms without having bacteria 
found on urine culture, or if funding for the research study has ended.  
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Jerry Lowder, M.D. or another member of the research team at (314)747-1402. If you 
experience a research-related injury, please contact:  Jerry Lowder, M.D. or another member of the 
research team at (314)747-1402. 
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office at 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research participant or to speak to someone other than the 
research staff, call the Human Research Protection Office at the number above. 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
 To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
 To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
 To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
 To give the research team accurate and complete information. 
 To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 


 
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Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 11/12/21. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed) 
 
 

Prot_SAP_007.pdf: 
 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
1 
 
 
Randomized, controlled trial to determine the efficacy of 
nutraceutical vs control as non-antibiotic prophylaxis for 
recurrent urinary tract infection in postmenopausal women 
using vaginal estrogen therapy 
 
Principal Investigator:   
Jerry Lowder, M.D.,M.Sc.,  Division of Female Pelvic Medicine and 
Reconstructive Surgery, Department of Obstetrics and Gynecology 
Co-investigators: 
Stacy Lenger, M.D. 
Chiara Ghetti, M.D., M.Sc. 
Christine Chu, M.D. 
Melanie Meister, M.D. 
Siobhan Sutcliffe, Ph.D., ScM, MHS 
Michael Durkin, M.D. 
Version Date/Number:  
Version 1.7 
Updated 6.04.2020 
NCT03395288 


 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
2 
TABLE OF CONTENTS 
A 
INTRODUCTION .............................................................................................................................................. 4 
A1 
STUDY ABSTRACT......................................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS .................................................................................................................................. 4 
A3 
PURPOSE OF THE STUDY PROTOCOL ............................................................................................................. 5 
B 
BACKGROUND ................................................................................................................................................. 5 
B1 
PRIOR LITERATURE AND STUDIES ................................................................................................................. 5 
B2 
RATIONALE FOR THIS STUDY ........................................................................................................................ 7 
C 
STUDY OBJECTIVES ....................................................................................................................................... 7 
C1 
PRIMARY AIM ............................................................................................................................................... 7 
C2 
SECONDARY AIMS ........................................................................................................................................ 7 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES .......................................................................... 7 
D 
INVESTIGATIONAL AGENT ......................................................................................................................... 8 
D1 
PRECLINICAL DATA ...................................................................................................................................... 8 
D2 
DOSE RATIONALE AND RISK/BENEFITS ........................................................................................................ 8 
E 
STUDY DESIGN ................................................................................................................................................. 9 
E1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................................ 9 
E2 
SUBJECT SELECTION AND WITHDRAWAL ...................................................................................................... 9 
2.a 
Inclusion Criteria ..................................................................................................................................... 9 
2.b 
Exclusion Criteria .................................................................................................................................. 10 
2.c 
Ethical Considerations .......................................................................................................................... 10 
2.d 
Subject Recruitment Plans and Consent Process ................................................................................... 11 
2.e 
Randomization Method and Blinding .................................................................................................... 12 
2.f 
Risks and Benefits ...................................................................................................................................... 13 
2.g 
Early Withdrawal of Subjects ................................................................................................................ 13 
2.h 
When and How to Withdraw Subjects .................................................................................................... 13 
2.i 
Data Collection and Follow-up for Withdrawn Subjects ........................................................................... 14 
E3 
STUDY DRUG .............................................................................................................................................. 14 
3.a 
Description ............................................................................................................................................ 14 
3.b 
Treatment Regimen ................................................................................................................................ 14 
3.c 
Method for Assigning Subjects to Treatment Groups ............................................................................ 15 
3.d 
Preparation and Administration of Study Drug ..................................................................................... 15 
3.e 
Subject Compliance Monitoring ............................................................................................................ 16 
3.f 
Packaging................................................................................................................................................... 16 
3.g 
Blinding of Study Drug .......................................................................................................................... 18 
3.h 
Receiving, Storage, Dispensing and Return ........................................................................................... 18 
F 
STUDY PROCEDURES .................................................................................................................................. 19 
F1 
SCREENING FOR ELIGIBILITY ........................................................................................................................... 19 
F2 
SCHEDULE OF MEASUREMENTS ....................................................................................................................... 19 
F3 
SAFETY AND ADVERSE EVENTS ...................................................................................................................... 20 
3.a 
Safety and Compliance Monitoring ....................................................................................................... 20 
3.b 
Medical Monitoring ............................................................................................................................... 21 
i 
Investigator only ................................................................................................................................................... 21 
ii 
Institutional Data and Safety Monitoring Board ............................................................................................... 21 
3.c 
Definitions of Adverse Events ................................................................................................................ 22 
3.d 
Classification of Events ......................................................................................................................... 22 
i 
Severity .................................................................................................................................................................. 22 
ii 
Expectedness ....................................................................................................................................................... 23 
3.e 
Data Collection Procedures for Adverse Events ................................................................................... 23 


 
 
 
 
 
 
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3 
F4 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT............................................................................. 23 
G 
STATISTICAL PLAN ...................................................................................................................................... 23 
G1 
SAMPLE SIZE DETERMINATION AND POWER ............................................................................................... 23 
G2 
INTERIM MONITORING AND EARLY STOPPING ............................................................................................ 23 
G3 
ANALYSIS PLAN AND STATISTICAL METHODS ............................................................................................ 24 
G4 
MISSING OUTCOME DATA .......................................................................................................................... 24 
G5 
UNBLINDING PROCEDURES ......................................................................................................................... 24 
H 
DATA HANDLING AND RECORD KEEPING ........................................................................................... 24 
H1 
CONFIDENTIALITY AND SECURITY .............................................................................................................. 24 
H2 
TRAINING .................................................................................................................................................... 25 
H3 
RECORDS RETENTION ................................................................................................................................. 25 
I 
STUDY ADMINISTRATION .......................................................................................................................... 25 
I1 
ORGANIZATION AND PARTICIPATING CENTERS ............................................................................................... 25 
I2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ............................................................................................ 25 
I3 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................................. 25 
I4 
STUDY TIMETABLE .......................................................................................................................................... 25 
J 
PUBLICATION PLAN .................................................................................................................................... 26 
K 
ATTACHMENTS ............................................................................................................................................. 26 
K1 
INFORMED CONSENT DOCUMENTS ............................................................................................................... 26 
K2 
PATIENT EDUCATION BROCHURES ............................................................................................................... 26 
K3 
QUESTIONNAIRES OR SURVEYS ................................................................................................................... 26 
L 
REFERENCES .................................................................................................................................................. 26 
 


 
 
 
 
 
 
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4 
A Introduction 
A1 Study Abstract 
The objective of this study is to determine the efficacy of D-mannose as a non-antibiotic 
prophylaxis for postmenopausal women on vaginal estrogen therapy (VET) with a history of 
symptomatic, culture-proven recurrent urinary tract infection (rUTI) by means of a randomized, 
controlled trial. Recurrent urinary tract infections have a significant impact on patient health, 
quality of life, and finances (personal and societal).  
 
The most common uropathogen for both acute and recurrent UTIs is Escherichia coli. 
 
Historically, patients with rUTI have been placed on long-term prophylactic antibiotics to prevent 
recurrence. Long term antibiotic use can lead to antibiotic resistance, collateral damage to 
normal flora, and organ damage, such as pulmonary and hepatic toxicity with long-term 
nitrofurantoin use. There is an increasing prevalence of antibiotic resistance of uropathogenic E. 
coli and other uropathogens. Antibiotic resistance and its consequences have resulted in a need 
for non-antibiotic prophylaxis regimens. 
 
A growing body of literature supports the use of vaginal estrogen therapy as a first-line non-
antibiotic UTI prevention strategy in postmenopausal women. While VET has been shown to 
significantly reduce the risk of rUTIs, some women continue to have rUTIs. Other non-antibiotic 
strategies have been utilized including D-mannose, a nutraceutical. Three prior studies 
examined D-mannose as an isolated therapy with promising results, but in our experience, a 
multimodal approach has often been needed. Therefore, additional studies, such as this 
proposed research, are needed to determine the potential additive effect of D-mannose as a 
non-antibiotic prophylaxis for postmenopausal women using vaginal estrogen therapy.  
 
We plan to calculate the cumulative incidence of symptomatic, culture-proven urinary tract 
infections in a study population of postmenopausal women using vaginal estrogen therapy and 
randomized to additional prophylactic D-mannose treatment verses vaginal estrogen therapy 
alone. We will also compare the incidence of symptomatic, culture-proven urinary tract 
infections caused by uropathogens susceptible to D-mannose between the treatment and 
control groups. In addition to the randomized, controlled trial, we will enroll and follow an 
observational arm of women who meet the same inclusion and exclusion criteria of the RCT 
except are not able or willing to use vaginal estrogen therapy. We will also describe side effects 
of D-mannose and determine the discontinuation rate of therapy due to D-mannose side effects. 
This information will be imperative in establishing a multimodal non-antibiotic treatment regimen 
for recurrent urinary tract infection in postmenopausal women.  
A2 Primary Hypothesis 
The central hypothesis of the proposed research is D-mannose will be an effective and tolerable 
prophylactic treatment that helps further reduce rUTIs, especially those caused by Escherichia 
coli, in women using VET compared to VET alone. This hypothesis was formulated based on 
the existing D-mannose (and mannosides) literature and anecdotal clinical experience. 
However, this study is needed to provide the scientific evidence for D-mannose as part of a 
multimodal rUTI non-antibiotic treatment strategy. 


 
 
 
 
 
 
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5 
A3 Purpose of the Study Protocol 
The purpose of this study protocol is to describe how the clinical trial will be conducted and to 
ensure the safety of study participants and integrity of the data collected.  
B Background 
B1 Prior Literature and Studies 
Recurrent urinary tract infections (rUTI) are a common and serious health problem for 
postmenopausal women. A woman’s lifetime probability of experiencing a urinary tract 
infection (UTI) is 60% [1]. Approximately 11% of women in the United States report having a 
physician-diagnosed UTI each year [1]. The estimated annual societal cost in the United States 
to treat UTI in all patients is between $2.4 to over $2.6 billion [2, 3]. Up to 50% of women will 
have an additional UTI within the first year of initial infection [1, 4]. In a primary care setting, 
women 55 years and older who have a UTI have been shown to have a recurrence rate of 53% 
within one year [5]. Recurrent urinary tract infections have a significant impact on patients’ 
quality of life and have a significant personal and societal financial burden. Office, urgent care, 
and emergency room visits for UTI both have a financial cost to the patient in addition to a 
negative impact on work productivity, time away from work, and personal and family 
responsibilities. The impact of rUTI is significant as well on a woman’s quality of life. In a 
retrospective 2013 study of patients with a history of UTI, 78% of participants reported that their 
history of UTI impacted their sex life and 17% reported UTIs interrupted their sex lives [6]. 
Recurrent UTIs have significant health, quality of life, and resource utilization 
implications. Treatment strategies to maximize prevention of UTI recurrences should be 
highly prioritized. 
The increasing prevalence of antibiotic resistance of uropathogenic E. coli supports the 
need for studies comparing non-antibiotic approaches to treating and preventing 
bacterial infections [7]. The efficacy of antibiotics to prevent rUTI in non-pregnant women was 
well established by a Cochrane review [8]. Currently, the American Congress of Obstetricians 
and Gynecologists (ACOG) recommends once daily treatment with one of a variety of antibiotics 
(nitrofurantoin, norfloxacin, ciprofloxacin, trimethoprim, trimethoprim-sulfamethoxazole, or 
another agent) for 6-12 months to decrease the recurrent risk of UTI by 95% [1]. While 
antibiotics are effective, they have significant side effects and the risk of antibiotic resistance. 
Vaginal and oral candidiasis and gastrointestinal upset are common among patients taking 
antibiotics. In one study, 27.2% of women taking nitrofurantoin for rUTI prophylaxis experienced 
side effects such as diarrhea, nausea, headache, skin rash, and vaginal burning [9]. In addition, 
some patients can experience dangerous allergic reactions such as severe anaphylaxis. Use of 
long-term antibiotic prophylaxis not only results in antibiotic resistance to the particular 
prophylactic agent, it can lead to higher rates of resistance to other antibiotics as well. In a 2012 
study, trimethoprim-sulfamethoxazole prophylaxis resulted in increased resistance to 
trimethoprim-sulfamethoxazole, amoxicillin, and fluoroquinolones among E. coli isolated from 
commensal fecal flora and among uropathogenic E. coli [10]. Due to concern for antibiotic 
resistance with long-term antibiotic use, there is a critical need to find non-antibiotic 
regimens that are safe and effective at preventing rUTI. 
Past studies evaluating alternatives to antibiotic therapy, such as cranberry and vitamin 
C, for rUTI have been met with mixed results. Cranberry juice and tablets have been studied 
by many different researchers with mixed results. The most recent Cochrane review on 
cranberry products and UTI in 2012 concluded cranberry products did not significantly reduce 
symptomatic UTI occurrence in women with recurrent UTI [11]. This is a different conclusion 


 
 
 
 
 
 
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6 
than the 2008 Cochrane review on the same subject after two additional trials were added to the 
analysis. Similarly, ascorbic acid (vitamin C) is often recommended after in vitro studies 
suggested it had a bacteriostatic urinary effect with acidification of the urine [5]. Clinical 
evidence to support these in vitro studies is lacking based on few trials with contradictory results 
[4]. Vaginal estrogen has been well established to help decrease the rate of rUTI in 
postmenopausal women but recurrences still occur [5, 12]. The results of these studies leave 
providers with a need for other alternatives to antibiotic therapy that are evidence-based. 
D-mannose shows promise as an alternative to antibiotic therapy. D-mannose is a sugar 
normally present in human metabolism. There are in vitro and in vivo studies to support the use 
of D-mannose to prevent UTI. D-mannose works as a FimH antagonist by saturating the tip of 
Type 1 fimbria of enteric bacteria to prevent adhesion to D-mannose moieties present on 
urothelial cells. E. coli is the most common enteric uropathogen and has evolved a Type 1 
fimbria with high specificity to D-mannose [4, 5, 9, 13]. Type 1 fimbriae have been documented 
on certain Enterobacteriaceae family members including Escherichia coli, Klebsiella 
pneumoniae, Shigella flexneri, Salmonella typhimurium, Serratia marcescens, and Enterobacter 
cloacae [14]. In vitro studies have demonstrated the effectiveness of D-mannose on 
uropathogenic E. coli. Only one clinical study of sixty women using D-mannose from 22 to 54 
years old has documented the number of urine cultures from various uropathogens [15]. No 
clinical study has documented the frequency and resistance patterns of recurrent UTI in 
postmenopausal women on D-mannose. Obtaining and tracking this information would 
help better inform clinicians regarding the overall efficacy of D-mannose. To date, there 
have been three studies published on D-mannose for rUTI prevention. In a 3-arm RCT 
comparing D-mannose as a single therapy, antibiotic prophylaxis with nitrofurantoin, and no 
prophylaxis for rUTI prevention, D-mannose was found to have the lowest recurrence rate 
(14.6%) [9]. This study evaluated 308 women >18 years old with acute and recurrent UTI and 
found a 14.6% recurrent UTI rate in subjects on D-mannose versus 20.4% in subjects on 
nitrofurantoin and 60% in subjects who did not receive prophylaxis. While there was not a 
statistical difference between reduction in recurrence rates between D-mannose and 
nitrofurantoin groups, there was a dramatic reduction between subjects receiving D-mannose 
versus those not receiving prophylaxis. Porru et al published a randomized cross-over trial 
assessing D-mannose versus trimethoprim/sulfamethoxazole in 60 participants between the 
ages of 22-54 years old, with an average age of 42 years old [15]. This study also demonstrated 
a benefit of D-mannose over antibiotics within the age range of their cohort. In the third 
published study, a pilot study was performed to evaluate D-mannose in combination with 
sodium bicarbonate, sorbitol, and silicon dioxide as a prevention strategy in comparison to an 
untreated group [16]. The overall UTI recurrence incidence was 4.5% in the D-mannose group 
versus 33.3% in the untreated group. Although these small trials have demonstrated promising 
benefits, additional studies of D-mannose as part of a multimodal non-antibiotic treatment 
strategy are needed to confirm these findings before D-mannose can be routinely 
adopted in practice.  
Ideal non-antibiotic methods to prevent recurrent UTI should be better tolerated than 
long-term antibiotic prophylaxis.  In one of the previously mentioned RCTs of D-mannose as 
an isolated therapy, patients taking D-mannose prophylaxis had a significantly lower risk of side 
effects than patients on nitrofurantoin prophylaxis (RR 0.276, 95% CI 0.132-0.574, p<0.0001) 
[9]. Another study found the frequency of mannose adverse effects was dose dependent, with 
doses >0.2 g mannose/kg body weight causing gastrointestinal disturbances and bloating in 
nearly half the participants [17]. Only 10% of study participants experienced similar symptoms at 
0.15 g mannose/kg body weight. Further studies are needed to assess the side effects and 
subsequent discontinuation rates of D-mannose before it can be recommended as a 


 
 
 
 
 
 
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7 
standard treatment. This study would provide the necessary information to address 
these knowledge gaps.  
B2 Rationale for this Study 
Currently, the mainstay of prophylactic treatment for rUTI is long term antibiotic therapy. 
Increased antibiotic use has led to increased antibiotic resistance. Long term use of antibiotics 
is associated with serious side effects, collateral damage to normal flora, and antibiotic 
resistance. At the time of literature review, there were three published studies examining D-
mannose alone to prevent rUTI. The two randomized, controlled trials evaluated D-mannose as 
an isolated therapy, and in one of the randomized, controlled trials, the average patient age was 
42 years old, with the oldest enrolled patient being 54 years old. The study populations reported 
on so far may be very different than the postmenopausal cohort in the proposed study. 
Postmenopausal women are at the highest cumulative risk for rUTIs.  In the third study, D-
mannose was combined with sodium bicarbonate, sorbitol, and silicone dioxide (none of these 
have been shown to reduce the risk of UTI/rUTI). In clinical practice, a multimodal approach to 
rUTI prevention is typically utilized when non-antibiotic agents are not; D-mannose is not 
typically used alone. Vaginal estrogen therapy (VET) is considered by many as a standard first 
line prevention for rUTI in postmenopausal women when there is not a contraindication. Our 
study would help determine the potential additive effect of D-mannose as adjunct therapy with 
VET. This study seeks to further our knowledge towards precision rUTI prevention and the goal 
of using non-antibiotic regimens as the mainstay of prophylactic treatment for rUTI.  
C Study Objectives 
C1 Primary Aim 
To compare the cumulative incidence of symptomatic, culture-proven urinary tract infections in 
postmenopausal women with a history of rUTI on vaginal estrogen therapy randomized to 
receive prophylactic D-mannose versus women using vaginal estrogen therapy alone (control). 
C2 Secondary Aims 
There are multiple secondary aims of this study: 
 
To compare the incidence of symptomatic, culture-proven urinary tract infections caused 
by all uropathogens potentially susceptible to D-mannose therapy in women receiving D-
mannose and the control group.  We will also compare these findings to the incidence of 
symptomatic, culture-proven urinary tract infections caused by uropathogens susceptible 
to D-mannose therapy in the absence of vaginal estrogen therapy (observational arm).  
 
To describe the side effects of D-mannose and determine the incidence of 
discontinuation of therapy due to side effects. 
 
To compare the cumulative incidence of symptomatic, culture-proven urinary tract 
infections between women receiving prophylactic D-mannose treatment alongside 
vaginal estrogen therapy verses women receiving prophylactic D-mannose treatment 
whom are not on vaginal estrogen therapy (observational arm). 
 
To gain information to use in designing future rUTI studies. 
C3 Rationale for the Selection of Outcome Measures 
The proposed RCT examining D-mannose efficacy in postmenopausal women with a history of 
rUTI on vaginal estrogen therapy is innovative. To date, no study has examined D-mannose in 
the context of use with other therapies. The primary and secondary outcomes of this study are 


 
 
 
 
 
 
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8 
expected to add greatly to the understanding of non-antibiotic regimens as the mainstay of 
prophylactic treatment for rUTI in postmenopausal women. In addition to the randomized, 
controlled trial, the observational arm of the study will help track and verify outcomes in 
participants with rUTI who either have a contraindication to vaginal estrogen use or chose to not 
use vaginal estrogen therapy. Use of other agents (cranberry extract, Vitamin C, etc.) will be 
recorded and controlled for. 
D Investigational Agent  
D1 Preclinical Data 
Our study will evaluate the impact of D-mannose in patients already using or willing to start VET 
for the prevention of rUTI. Since use of VET as an accepted and proven strategy to reduce rUTI 
in postmenopausal women is part of the inclusion criteria for the RCT portion of this study, D-
mannose is the only “study drug” being evaluated in this study. Vaginal estrogen therapy (VET) 
has been well established to help decrease the rate of rUTI in postmenopausal women [5, 12]. 
VET provides hormone in a low dose to local vaginal tissue with minimal systemic absorption 
[18]. Studies have shown that low dose VET, as used with rUTI therapy, does not cause 
sustained serum estrogen levels outside the normal menopausal range [18]. For these reasons, 
as a non-antibiotic treatment, vaginal estrogen should be included as a standard treatment in 
any study analyzing rate of recurrent UTI in postmenopausal women without contraindications. 
The prior small trials evaluating D-mannose did not include VET in all patients as a standard of 
care.  
The female pelvic medicine and reconstructive surgery (FPMRS) division has a strong 
track record of recruiting patients into clinical research and into studies for rUTI. In the eight 
weeks prior to submission of this research protocol, our division has seen an average of four 
new and/or referral patients for rUTI per week. This number does not include preexisting 
patients with a new diagnosis of rUTI. In the previous rUTI studies in our division, patients with 
rUTI have been very willing to participate in research for rUTI therapy, with very few declining 
participation. Taking into consideration exclusion criteria the feasible enrollment is estimated to 
be ten patients a month in this study, achieving enrollment of one hundred twenty study patients 
in the randomized, controlled trial within twelve months of initiating study enrollment.  
D2 Dose Rationale and Risk/Benefits  
The RCT treatment arm of this study will use 2 grams of D-mannose powder dissolved in water 
once daily.  The observational arm of this study will use either the same 2 grams of D-mannose 
powder daily as used in the RCT treatment arm or two 500 mg D-mannose capsules every 12 
hours (for a total of 2 grams every day). 
The prior studies previously mentioned evaluating D-mannose each used a different 
dose. The first RCT used 2 grams of D-mannose dissolved in 200 ml water [9]. In the other 
RCT, participants were started on D-mannose 1 gram three times daily for two weeks (as 
treatment for acute urinary tract infection) followed by 1 gram twice daily [15].   
To date the FPMRS division clinical practice has been to recommend either two 500 mg 
capsules of D-mannose twice daily or 2 grams (1 teaspoon of powder) dissolved in water once 
daily. The powdered D-mannose will be used for the randomized, controlled trial as pure D-
mannose can be dissolved in water and administered without the additional additives required to 
encapsulate D-mannose.  Using the powdered D-mannose limits the possible additional side 
effects due to additives.  For the observational arm, the powdered D-mannose will be strongly 
recommended, but patients will be allowed to purchase either the powder or capsules and 
formulation will be tracked.  


 
 
 
 
 
 
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9 
Alton et al found the frequency of mannose adverse effects is dose dependent, with only 
10% of their study subjects experiencing gastrointestinal disturbances and bloating at 0.15 g 
mannose/kg body weight [17]. Using the numbers from Alton’s study, if a study participant 
weighs 100 pounds then the participant would have a 10% chance of experiencing 
gastrointestinal side effects if a mannose dose of 6.8 grams were used, which is a much larger 
dose than the 2 grams per day in this study protocol. This same study also found that 
regardless of the mannose dose used in their study (which ranged from 0.1-0.25 g mannose/kg 
body weight), participants’ blood glucose levels were stable and within the normal physiologic 
range. This study protocol uses a smaller dose of D-mannose that Alton’s study: for a 100 
pound study participant, the 2 grams/day total dose would equal 0.044 g D-mannose/kg body 
weight.  In order to exceed the maximum D-manose dose in Alton’s study (where the blood 
glucose level was still not affected), a participant in our study would have to weigh less than 18 
pounds, which is considerably less than the weight of a post menopausal woman.  
E Study Design  
E1 Overview or Design Summary 
In the RCT portion of the study, we will enroll 120 postmenopausal female patients with rUTI 
(either new patients or existing patients with a new diagnosis of rUTI) as defined by  2 culture-
proven UTI episodes in the last six months or  3 culture-proven UTI episodes in the last twelve 
months. Each subject must have at minimum a documented culture-proven UTI with a D-
mannose susceptible microbe. Subjects will be randomized to vaginal estrogen therapy (VET) 
plus D-mannose versus VET alone and will be followed for 90 days. All RCT participants will 
have a minimum four-week run-in period with VET prior to study day 1. Subjects previously on 
VET will not require a run-in period as long as the four-week minimum on VET has been met. 
According to the North American Menopause Society, the effect of vaginal estrogen therapy is 
rapid and can generally be observed within four weeks of treatment onset with cream, ring, or 
tablet forms of vaginal estrogen therapy [19]. Subjects randomized to treatment with D-mannose 
will receive their D-mannose as part of the study so that D-mannose treatment is controlled for 
the use of pure D-mannose powder. A study period of 90 days was determined as an adequate 
study period as prior publications have demonstrated that UTI recurrence most commonly 
occurs within two months [9, 20, 21].   
In the observation arm of the study, we will enroll 60 postmenopausal women with rUTI 
(either new patients or existing patients with a new diagnosis of rUTI) as defined by  2 culture-
proven UTI episodes in the last six months or  3 culture-proven UTI episodes in the last twelve 
months. Each study participant must have at minimum a documented culture-proven UTI with a 
D-mannose susceptible microbe. These patients must meet all of the same inclusion and 
exclusion criteria as the randomized, controlled trial subjects with the exception of not using 
VET due to a contraindication or preference not to use VET. Participants in this arm of the study 
will be followed for three months after starting D-mannose. For the observational arm, the 
powdered D-mannose will be strongly recommended, but patients will be allowed to purchase 
either the powder or capsules and formulation will be tracked.   
E2 Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
For the RCT arms of the study, the following inclusion criteria will apply: 
a. Postmenopausal women with recurrent UTI  
i. 
Recurrent UTI defined as:  


 
 
 
 
 
 
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10
1. ≥ 2 symptomatic, culture-proven UTI in 6 months OR 
2. ≥ 3 symptomatic, culture-proven UTI in 12 months 
ii. 
Postmenopausal defined as no menses for at least 12 months or surgical 
menopause 
b. At least one documented prior uropathogen susceptible to D-mannose  
c. Using VET for a minimum of two weeks at enrollment (with plan for four weeks prior to 
study day 1) 
 
Inclusion criteria for the Observational arm of the study are the same with the exception of item 
‘c.’ above (using VET ) as participants will not be on vaginal estrogen therapy. 
2.b 
Exclusion Criteria  
For the RCT arms of the study, the exclusion criteria are as follows: 
a. Not postmenopausal 
b. Currently on daily antibiotic UTI prophylaxis 
i. 
If this is the only exclusion criteria met, a woman could be cleared for inclusion in 
study/enrollment after a 2 week washout period occurs prior to inclusion in the 
study (RCT or Observational arm) 
c. Complicated UTIs 
i. 
known renal tract anomaly  
ii. 
inability to empty bladder due to neurologic causes  
iii. 
performs self-catheterization or has an indwelling catheter  
d. Patients with incomplete bladder emptying (defined as PVR > 150 cc when minimal 
voided volume is >150 cc) 
e. Known contraindication to VET unless approved by patient’s oncologist, oncologic 
surgeon, or primary care physician 
i. 
History of or current endometrial cancer without approval of patient, patient’s 
oncologist, oncologic surgeon, or primary care physician to use vaginal estrogen 
after counseling 
ii. 
History of estrogen sensitive breast cancer without approval of patient, patient’s 
oncologist, oncologic surgeon, or primary care physician to use vaginal estrogen 
after counseling 
f. History of interstitial cystitis/painful bladder syndrome 
g. Urothelial cancer 
h. Non-English speaking 
i. 
Enrolled in other clinical trials for UTIs 
j. 
Currently using D-mannose or Methenamine for UTI prevention 
Exclusion criteria for the Observational arm of the study are the same with the exception of item 
‘e.’ above (known contraindication to VET) as participants will not be on vaginal estrogen 
therapy. 
2.c 
Ethical Considerations  
Inclusion of Women and Minorities 
The patient sample for this study is limited to women as rUTI is most common in 
postmenopausal women. Men with UTI are by definition complicated and would not meet the 
inclusion criteria. In addition, men do not go through menopause and do not have a vagina and 
would thus not be treated with VET. All four locations of the Washington University Physicians 


 
 
 
 
 
 
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11
Women’s Center for Bladder and Pelvic Health are located in the St. Louis Metropolitan area, 
which is the 20th largest metropolitan statistical area in the nation [22]. As of 2015, of the 2.8 
million people in the St Louis Metropolitan Area, approximately 510,000 individuals identify as 
Black and an additional 81,000 identify as Hispanic [22]. The main office location for the 
Women’s Center for Bladder and Pelvic Health is located in St. Louis City where approximately 
50% of residents are Black or African American [23]. Six percent of the citizens of the St. Louis 
Missouri and Illinois Metropolitan area are non-English language speakers, which is 
considerably lower than the national average of 21.5% [22].  For this reason, even though this 
study is limited to English speaking patients, we do not anticipate this will negatively impacting 
the racial/ethnic minority representation in our study.  
Inclusion of Children 
We will not include children younger than 18 years old in our study. Our criteria require 
postmenopausal status for inclusion into this study.  
2.d 
Subject Recruitment Plans and Consent Process 
All new or newly diagnosed women with rUTIs receiving care at the Washington University 
Physicians Women’s Center for Bladder and Pelvic Health who meet screening criteria will be 
approached. Existing rUTI patients that are not currently using D-mannose may also be 
approached. Enrollment may occur at any of the practice’s four outpatient locations 
(Washington University Physicians’ offices at: Center for Outpatient Health, Missouri Baptist 
Medical Center Women’s Wellness Center, Center for Advanced Medicine - South County, and 
Barnes Jewish West County Medical Building). This study will involve only adult, 
postmenopausal women as rUTI predominantly affect this population. Recurrent UTI in men 
would be considered complicated and would not be addressed with a prophylactic treatment like 
d-mannose. In addition, men do not go through menopause and do not have a vagina and 
would thus not be treated with VET. Women meeting study criteria will be approached by a 
member of the research team for consent at the conclusion of the clinical visit during which the 
patient is screened eligible for the study. Women who meet RCT eligibility criteria except for a 
minimum of four weeks of VET use but are being started on VET for clinical indications will 
followup in approximately four weeks for a routine follow up clinical visit. These patients will be 
offered enrollment in the study at that time if they have been using VET for a couple weeks even 
if they aren’t at the four week mark yet. However, their study day one cannot occur until they 
have been using VET for four weeks.  
Eligible women interested in the study will have the study explained to them, the consent 
reviewed, and questions reviewed in a confidential manner in a private room. If the potential 
research participant would like to take the consent home with them to review before their next 
office appointment that will be allowed.  
The following methods may be used to inform the public about our research study: letter 
and/or email to local and/or referring providers, Twitter, study flyers, news story or segment. 
Inclusion in this list does not guarantee that the method will be used, but instead allows for the 
method to be used. All of the methods would require a potential research participant to be 
referred to the office for care of their rUTI. A “Dear Doctor” letter and/or email to local and/or 
referring providers can be sent to referring providers to inform them of ongoing recurrent UTI 
research at the Washington University Physicians Women’s Center for Bladder and Pelvic 
Health. Twitter posts will be limited to IRB-approved tweets and images. The Twitter posts will 
be able to link to the Washington University Physicians Women’s Center for Bladder and Pelvic 
Health website (at urogyn.wustl.edu) to find out more about the Washington University 
Physicians Women’s Center for Bladder and Pelvic Health. A study flyer would provide the 
Washington University Physicians Women’s Center for Bladder and Pelvic Health name and 
phone number with information describing rUTI and that our research team is trying to 


 
 
 
 
 
 
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12
determine the beneft of non-antibiotic treatments to prevent recurrent urinary tract infections in 
menopausal women. These flyers could be distributed to local and/or referring providers with 
the “Dear Doctor” letter to display in their waiting room or offices. The flyer could also be 
displayed in break rooms at Barnes Jewish Hospital, Center for Outpatient Health, Center for 
Advanced Medicine, St. Louis Children’s Hospital, and St. Louis College of Pharmacy. The 
research team would like the opportunity to work with the Washington University School of 
Medicine Medical Public Affairs office to spread word about this study via a local television or 
radio as part of a news story or segment. The principal investigator would work with the Medical 
Public Affairs office to contact specific local reporters and pitch the story to them. There will not 
be an official news release. If any current subjects would like to share their experiences in the 
trial with the media for a news story or segment then all HIPAA protocol will be complied with. 
Subjects would be made aware that their care and participation in the trial would not be affected 
by their voluntary decision to share their experience, and that they do not have to share their 
story if they do not wish to. 
2.e 
Randomization Method and Blinding 
For the randomized, controlled trial portion of the study: 
Allocation concealment will be in place to ensure the individual enrolling the subject into the 
study has no a priori knowledge of group assignment. Block randomization will occur with 
randomly mixed block sizes of 2, 4, and 6.  The allocator will hide block size from the executer 
in order to prevent the executor from predicting the next assignment. Randomization will be 
carried out by having a piece of paper that has the phrase “Intervention (Nutraceutical + VET)” 
or “Control (VET only)” placed inside an envelope.  The outside of the envelopes will be labeled 
with the sequence number.  After a patient has been enrolled into the study and consented, the 
next sequence numbered envelope on the stack will be opened to determine the study group 
that the subject will enter.  
 
For the observational portion of the study, no randomization or blinding will occur.   
 
The diagram below outlines randomization details: 
 


 
 
 
 
 
 
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13
2.f 
Risks and Benefits 
D-mannose is a nutraceutical sold over the counter solely for the prevention of UTI. It falls under 
the category of dietary supplements regulated by FDA under the Dietary Supplement Health 
and Education Act of 1994 (DSHEA) [24]. This is a different set of regulations than the 
regulations used for conventional food and drug products [24]. Risks associated with D-
mannose use are believed to be mainly related to gastrointestinal side effects (bloating, loose 
stool, and diarrhea). Other possible side effects can include but are not limited to 
hypersensitivity or allergic reactions (acute skin or pulmonary changes).  These side effects 
would be the same for subjects enrolled in this study as for patients not enrolled in this study 
that we recommend D-mannose prophylaxis to on a daily basis.  Other potential risks of the 
study include participants may feel uncomfortable or be inconvenienced by filling out study 
related papers. They may prefer to obtain treatment for UTI-like symptoms from an urgent care 
or other outside provider.  However, all rUTI patients in our office (no matter if enrolled in the 
study or not) are instructed to call our office when they experience UTI-like symptoms since our 
clinical practice is to obtain (when possible) urine cultures prior to initiating treatment and to 
have our patients followed primarily through our office for their urinary tract infections.  
A potential benefit is the decreased incidence of rUTI among patients randomized to D-
mannose in the randomized, controlled trial portion of the study or patients in the observational 
arm of the study. Otherwise, benefits for the participant are no different than if they were 
recommended D-mannose as part of their routine clinical care as a patient without being 
enrolled in the study. There is a global benefit of increased knowledge surrounding the utility of 
non-antibiotic prophylaxis for rUTI.  
2.g 
Early Withdrawal of Subjects  
At the time of consent, participants will be informed that their participation in this research is 
voluntary and that they may discontinue participation without penalty at any time.  
2.h 
When and How to Withdraw Subjects  
Withdrawal of subject as the result of subject decision: 
 
A subject enrolled in the study may decide to withdraw from the research at any time by 
notifying the principle investigator and/or another member of the research team by 
calling the office at 314-747-1402 and letting the office staff know she needs to speak to 
the principle investigator and/or member of the research team. The investigator speaking 
with the subject will clarify whether the subject wishes to withdraw from all components 
of the trial or only from a particular component of the trial. If the latter is desired, then 
follow-up data collection activities, for which the subject perviously gave consent may 
continue.   
 
If a subject withdraws from the study then a member of the research team will ask the 
subject if she is willing to complete an study exit survey and/or the information that would 
have been gathered at the originally planned 3 month follow up appointment. This exit 
survey and 3 month follow up visit information may be obtained by appointment, by 
phone, or by mail. 
 
Withdrawal of subject as the result of investigator decision: 
 
If an investigator terminates a subject’s participation in the trial, the investigator should 
explain to the subject the reasons for this action and, as appropriate, other treatment 
options. 
 
If subjects were to have a serious adverse reaction to the medication, the investigator 
would recommend discontinuation of medication. 


 
 
 
 
 
 
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14
 
An investigator may terminate a subject’s participation in the study to protect a 
participant from excessive risk or risk with demonstrated lack of benefits or to maintain 
integrity of the data (for instance if a participant is not following study procedures or may 
be deliberately providing false information).  
 
If a subject is treated for an acute UTI during the 90 day study period without having an 
urine culture performed then data will be assessed both as if she did and did not have an 
acute UTI. She does not need to be withdrawn from the study as of the date of treatment 
of subjective UTI.. Antibiotics used for reasons other than UTI do not require subject 
withdrawal. Data obtained for any subject to the point of study withdrawal may be used 
in the study.  
 
If a subject is withdrawn from the study then a member of the research team will ask the 
subject if she is willing to complete an study exit survey and/or the information that would 
have been gathered at the originally planned 3 month follow up appointment. This exit 
survey and 3 month follow up visit information may be obtained by appointment, by 
phone, or by mail.  
 
Subjects lost to follow up will be presumed to not have an acute urinary tract infection 
from the time of last contact.  
2.i 
Data Collection and Follow-up for Withdrawn Subjects  
Data collected prior to participant withdrawal may be retained and used including Protected 
Personally Identifiable Information (PPII) in a manner that is consistent with the study purpose 
and procedures as noted in this protocol and supplemental documents, unless the study 
participant notifies the primary investigator that all participant information must be removed from 
the study.  All subjects that withdraw or are withdrawn from the study will be asked if they would 
be willing to complete an exit survey or the questions from the 3 month follow up visit form. The 
purpose of the exit survey would be to obtain information such as the “spot checks” that are built 
into the 3 month follow up/end of study form and to find out more information about why the 
subject decided to withdraw. This exit survey would be completed in clinic (at their next 
scheduled appt), by phone, or by mail.   
E3 Study Drug  
3.a 
Description  
D-mannose is a nutraceutical available over the counter at pharmacies, supermarkets, and 
supplement stores and for purchase online. D-mannose is a sugar normally present in human 
metabolism. It falls under the category of dietary supplements that is regulated by FDA under 
the Dietary Supplement Health and Education Act of 1994 (DSHEA) [24]. This is a different set 
of regulations than the regulations used for conventional food and drug products [24]. Studies 
have shown that D-mannose saturates FimH adhesin located at the end of type 1 fimbria of 
enteric bacteria on the epithelium of the urinary tract [5, 7, 25, 26]. 
3.b 
Treatment Regimen  
To date the FPMRS division clinical practice has been to recommend either two 500 mg 
capsules of D-mannose every 12 hours or 2 grams (1 teaspoon of power) dissolved in water 
once daily. The RCT treatment arm of this study will use 2 grams of D-mannose powder 
dissolved in water once daily.  The observational arm of this study will use either the same 2 
grams of D-mannose powder daily as used in the RCT treatment arm or two 500 mg D-
mannose capsules every 12 hours (for a total of 2 grams every day). The instructions to patients 
on their patient information handout will be as follows: 


 
 
 
 
 
 
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15
 
“Powder specific instructions: Dissolve one (1) teaspoon of the nutraceutical powder in at 
least 200 ml of water one time a day.  (200 ml of water = 6.7 fluid ounces). Please attempt to 
take doses of the nutraceutical powder dissolved in water approximately 24 (twenty-four) 
hours apart.  It is ok if you use a larger volume of water to dissolve the powder, but do not 
use any less than 200 ml of water.  You MUST drink all of the water that the powder is 
dissolved in.” 
 
“Capsule specific instructions: Take two 500 mg capsules (total of 1000 mg dose) every 12 
hours.” 
 
The powdered D-mannose will be used for the RCT as pure D-mannose can be dissolved in 
water and administered without the additional additives required to encapsulate D-mannose.  
Using the powdered D-mannose limits the possible additional side effects due to additives. For 
the Observational arm, the powdered D-mannose will be strongly recommended, but patients 
will be allowed to purchase either the powder or capsules and formulation will be tracked.  
3.c 
Method for Assigning Subjects to Treatment Groups  
If a participant is using VET and therefore eligible for the RCT portion of the study, they will be 
randomized according to the preset randomization allocation to determine if she is in the 
treatment arm of the randomized control trial (D-mannose plus vaginal estrogen therapy) or the 
control arm of the randomized controlled trial (vaginal estrogen therapy only).  
If a patient is not using VET but meets all other study requirement then she would be 
eligible only for the Observational arm of the study.   
3.d 
Preparation and Administration of Study Drug  
For the treatment arm of the RCT, the D-mannose powder will be ordered and distributed by the 
research team. The study team has selected NOW D-mannose pure powder as the D-mannose 
to be used in the RCT. The manufacturer label will be covered up/removed and a study label 
stating contents of a nutraceutical will be used to maintain patient blinding to which nutraceutical 
is being used.   
For both arms of the RCT, the VET may be renewed or prescribed by a physician on the 
research team per routine clinical care. The patient will then pick up their prescription (vaginal 
cream, ring, or tablet) from their pharmacy of choice for continued use.   
For the Observational arm of the study we will recommend the powdered D-mannose, 
but since participants will be purchasing their own D-mannose in the Observational arm they will 
be instructed to purchase either NOW D-mannose pure powder or NOW D-mannose 500 mg 
capsules. NOW will be the only brand patients are instructed to purchase, and example labels 
will be available for viewing by participants in the Observational arm to confirm they purchase 
the recommended D-mannose. We will communicate with the participants after they purchase 
their D-mannose of choice to record if powder or tablet and brand/manufacturer.  
 
Medication (D-mannose, VET) will be self-administered by the patient. For patients using 
VET they will continue to use their VET as previously prescribed prior to enrollment in this study. 
On study day 1, if the patient is in an arm using D-mannose they will begin self administering D-
mannose according to the instructions on the patient information handout. These instructions 
are as follows: 
 
“Powder specific instructions: Dissolve one (1) teaspoon of the nutraceutical powder in at 
least 200 ml of water one time a day.  (200 ml of water = 6.7 fluid ounces). Please attempt to 
take doses of the nutraceutical powder dissolved in water approximately 24 (twenty-four) 
hours apart.  It is ok if you use a larger volume of water to dissolve the powder, but do not 
use any less than 200 ml of water.  You MUST drink all of the water that the powder is 
dissolved in.” 


 
 
 
 
 
 
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16
 
“Capsule specific instructions: Take two 500 mg capsules (total of 1000 mg dose) every 12 
hours.” 
3.e 
Subject Compliance Monitoring  
All participants will be asked to complete a simple weekly study diary. The 90 days of the study 
will be divided into 12 full weeks and 1 partial week for a total of 13 weeks of the diary. In the 
diary, one of the questions asked for each week of the study is number of doses missed each 
week. This study will use a text message service through the REDCap (Research Electronic 
Data Capture) database. During the 90 day study period, all study participants in both the RCT 
and Observational arms will receive text message reminders to complete their study diary for 
the week on study days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 90. This same text 
message will ask patients if any new symptoms were experienced in the past week and request 
a “Yes” or “No” response via text message. Study participant responses will automatically be 
entered in the REDCap (Research Electronic Data Capture) database for this study. If the study 
participant sends a “Yes” response by text message a member of the research team will contact 
the patient to follow up for more information about the symptoms. If they declined text 
messaging when enrolling in the study, the study participant will receive periodic phone calls 
with reminders to complete their study diary. The subject will be instructed to bring their study 
diary to each appointment. 
 
Six weeks into the study, each study participant will receive a phone call from a member 
of the research team. During this phone call questions referencing compliance with completing 
the study diary, taking study medications as prescribed, if they have been treated for a UTI by 
anyone outside of our office during the study period, side effects noted, and if they have any 
questions to be answered will all be addressed.  
All participants will be seen by a physician and research staff after 3 months in the study 
(when they have completed their 90 days in the study). At this visit, participants will be asked to 
bring their study diary and any unused D-mannose to their appointment (including empty bottles 
if more than one bottle was provided to a patient in order for a patient to have a 90 day supply of 
D-mannose). A 3 month follow up survey and exit survey will be given to the participant to fill out 
at the 3 month follow up appointment. Depending on participant convenience, this 3 month 
follow up survey can be completed at their appointment, by phone, or by mail. The survey will 
include questions on medication adherence. The study team will review the chart for any 
adverse events or UTIs not previously reported.  Participants will fill out a questionnaire at this 
appointment to confirm the same.  If a participant does not show for their 3 month follow up 
appointment then a member of the research team will attempt to contact the participant to 
reschedule this appointment. If a participant does not bring their study drug to their 3 month 
follow up, or if the participant is lost to follow up, then a reasonable attempt will be made to 
contact the patient and ask her to bring the study drug to the office. If a participant is lost to 
follow up then a reasonable attempt will be made to see if the participant is willing to complete a 
3 month follow up survey and/or exit survey over the phone or by mail. If the participant does 
not complete all 90 days of the study, or if they forget to bring their study diary to their 3 month 
follow up appointment, then she will be offered the alternative of mailing or faxing her study 
diary to the office. If a participant completed the study early then she will be asked if she is 
willing to complete the 3 month follow up appointment information and exit survey at their next 
office visit, by phone, or by mail. 
3.f 
Packaging  
D-mannose is the only study drug and will be in its original container from the manufacturer. The 
study team has selected NOW D-mannose pure powder as the D-mannose to be used in the 


 
 
 
 
 
 
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17
RCT. The patient label for the treatment arm of the randomized, controlled portion of the study 
will be updated to maintain blinding of the patient to which nutraceutical is being studied.  
 
Planned label for the treatment arm of the randomized, controlled trial is as follows: 
 
 
 
Participants in the Observational arm will be instructed to purchase either NOW D-mannose 
pure powder or NOW D-mannose 500 mg capsules.  
 
The following are examples of the D-mannose labels from NOW. NOW does not have a 
separate instruction for use from the label.  
 
 
example 3 ounce powder label size: 2 3/4” x 7 3/8”  
Study Name: Nutraceutical efficacy in rUTI 
IRB Number: XXXXX 
Principal Investigator: Jerry Lowder, MD, M.Sc. 
 
 
Office Phone: (314)747-1402 
 
Participant Name: XXXX XXXXX 
 
Dose and Frequency: Dissolve one (1) level teaspoon of the nutraceutical powder in at 
least 200 ml of water one time a day.  (200 ml of water = 6.7 fluid ounces). Please attempt 
to take doses of the nutraceutical powder dissolved in water approximately 24 (twenty-four) 
hours apart. You may use a larger volume of water to dissolve the powder, but do not use 
any less than 200 ml of water.  You MUST drink all of the water that the powder is 
dissolved in. 
 
Caution: New Drug – Limited by United States law to investigational use. 
 


 
 
 
 
 
 
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18
 
example 6 ounce powder label size: 3 1/2 ” x 9” 
 
example capsule label size: 3 1/2” x 9”  
3.g 
Blinding of Study Drug  
For the treatment arm of the RCT, the D-mannose powder will be ordered and distributed by the 
research team. The manufacturer label will be covered up/removed and a study label stating 
contents of a nutraceutical will be used to maintain patient blinding to which nutraceutical is 
being used. The research team will not be blinded to the study drug. There are no placebos 
being used in this study.  
3.h 
Receiving, Storage, Dispensing and Return  
After receiving the purchased D-mannose, it will be stored in a secure area for each of the four 
outpatient locations for the Washington University Physicians Women’s Center for Bladder and 
Pelvic Health and in a secure area in the academic offices for the Washington University 
Division of Female Pelvic Medicine and Reconstructive Surgery. D-mannose should be stored in 
a cool place where the container is kept dry and tightly closed. It should be stored away from 
extreme heat.  
The only medication that will be dispensed to study participants during the course of this 
study will be D-mannose to patients in the treatment arm of the RCT. Once a subject is 
randomized to the treatment arm, they will receive D-mannose in its original packaging but 


 
 
 
 
 
 
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19
relabeled as Nutraceutical to maintain patient blinding to which nutraceutical is being tested in 
the smallest quantity available to meet the amount required for a 90 day supply. For example, 
many manufacturers only distribute powder D-mannose in 42 day or 80 day supply bottles. In 
this situation, one 80 day and one 42 day bottle of D-mannose will be given to the patient in 
order to meet the 90 day required supply for the study. The medication that is not used will be 
brought to the patient’s 3 month follow up appointment to be weighed.  
F Study Procedures  
F1 Screening for Eligibility 
Prior to a new patient appointment, all patients referred for or with a chief complaint of frequent 
or recurrent urinary tract infections will be prescreened by a member of the research team. 
Items from the patient’s chart or clinical records that may be used to identify potential 
participants for recruitment include: name, date of birth, date of appointment, reason for 
appointment, history of UTI, medication history, menopausal status, if patient has a known renal 
tract anomaly, neurogenic bladder, performs self-catheterization of has indwelling catheter, 
history of incomplete bladder emptying, history of contraindication to vaginal estrogen therapy 
including but not limited to current endometrial cancer or breast cancer without approval of 
patient's oncologist, surgical oncologist, or primary care physician, history of interstitial 
cystitis/painful bladder syndrome, history of urothelial cancer, and primary language spoken.  
For patients that are existing patients of FPMRS division but with a new diagnosis of 
rUTI, the member of the research team that diagnoses the patient with rUTI will notify the 
members of the research team performing screening that the existing patient will be coming to 
the office for a new diagnosis of rUTI. Prior to the patient’s appointment, she will be 
prescreened by a member of the research team. If the patient appears eligible from screening 
then any missing information will be obtained during routine clinical care during the patient’s 
appointment to complete the screening process. If a patient is an existing patient of the FPMRS 
division with rUTI and not already using D-mannose, then they may be screened when they 
attend a routine clinical appointment with a member of the research team.  
If a patient is noted to be eligible during an office visit (i.e. the new diagnosis of recurrent 
urinary tract infection was made during an appointment) and therefore the patient was not 
prescreened prior to the appointment, then a member of the research team will be notified as 
soon as possible to complete the screening process to see if a patient is eligible for study 
participation.  
F2 Schedule of Measurements 
During the clinical visit where the participant is enrolled, she will be asked to complete a 
form with study-related questions. A urine specimen or other labs may be ordered as part of 
routine clinical practice at this visit. No additional specimens will be collected for this study 
except for those clinically indicated. 
If a participant is in the Observational arm, then they will receive a phone call 
approximately one week after study enrollment to confirm if D-mannose powder or capsules 
were purchased. They will also be asked what brand was purchased and confirm they were able 
to start the D-mannose on the planned study day 1. If there are delays in the participant’s 
purchasing and receiving of their D-mannose then the date of study day 1 will be adjusted 
accordingly. 
Participants will be expected to complete a weekly paper study diary. All participants that 
agree to receive text messages will receive a weekly text message reminder to complete their 
weekly study diary. Text messages will be sent at a standardized time on study days 7, 14, 21, 


 
 
 
 
 
 
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20
28, 35, 42, 49, 56, 63, 70, 77, 84, and 90. This same text message will ask patients if any new 
symptoms were experienced in the past week and request a “Yes” or “No” response via text 
message. Study participant responses will automatically be entered in the REDCap (Research 
Electronic Data Capture) database for this study. If the study participant sends a “Yes” response 
by text message a member of the research team will contact the patient to follow up for more 
information about the symptoms. If they declined text messaging when enrolling in the study, 
the study participant will receive periodic phone calls with reminders to complete their study 
diary. The subject will bring their study diary to each appointment. 
 
Six weeks into the study, each study participant will receive a phone call from a member 
of the research team. During this phone call questions referencing compliance with completing 
the study diary, taking study medications as prescribed, if they have been treated for a UTI by 
anyone outside of our office during the study period, side effects noted, and if they have any 
questions to be answered will all be addressed. 
 
In addition to the clinical visit in which the patient was enrolled, there will be a routine 
clinical 3 month follow up visit scheduled where the 3 month follow up form for the subject’s arm 
of the study will be completed. A 3 month follow up visit is standard protocol in our office for all 
rUTI patients that are started on a new medication. No additional specimens will be collected 
other than those indicated for routine clinical care at this appointment. If a participant missed a 
scheduled follow-up clinical visit, we will attempt to reach the participant by phone and 
reschedule their visit as soon as possible.  
If any of the measures planned for 3 month follow up are not completed by the participant 
at this appointment, then it can alternatively be completed by phone or by mail, depending on 
participant convenience. If the participant does not complete all 90 days of the study, or if they 
forget to bring their study diary to their 3 month follow up appointment, then she will be offered 
the alternative of mailing or faxing her study diary to the office. If a participant completes the 
study early due to culture proven UTI then she will be asked to complete the 3 month follow up 
appointment information at their next office visit, by phone, or by mail. 
If a participant does not bring their study drug to their 3 month follow up, or if the 
participant is lost to follow up, then a reasonable attempt will be made to contact the patient and 
ask her to bring the study drug to the office. If a participant is lost to follow up then a reasonable 
attempt will be made to see if the participant is willing to complete a 3 month follow up survey 
and/or exit survey over the phone or by mail. If the participant does not complete all 90 days of 
the study, or if they forget to bring their study diary to their 3 month follow up appointment, then 
she will be offered the alternative of mailing or faxing her study diary to the office. If a participant 
ended the study early then she will be asked if she is willing to complete the 3 month follow up 
appointment information and exit survey at their next office visit, by phone, or by mail. 
F3 Safety and Adverse Events  
3.a 
Safety and Compliance Monitoring 
All women will be asked to complete a simple weekly study diary. The 90 days of the study will 
be divided into 12 full weeks and 1 partial week for a total of 13 weeks of the diary. In the diary, 
one of the questions asked for each week of the study is number of doses missed each week. 
This study will use a text message service through the REDCap (Research Electronic Data 
Capture) database. If agreed to by the participant, during the 90 day study period, a text 
message will be received by the participant as a reminder to complete their study diary for the 
week on study days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 90. This same text 
message will ask patients if any new symptoms were experienced in the past week and request 
a “Yes” or “No” response via text message. Study participant responses will automatically be 
entered in the REDCap (Research Electronic Data Capture) database for this study. If the study 


 
 
 
 
 
 
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21
participant sends a “Yes” response by text message a member of the research team will contact 
the patient to follow up for more information about the symptoms. If they declined text 
messaging when enrolling in the study, the study participant will receive periodic phone calls 
with reminders to complete their study diary. The subject will be instructed to bring their study 
diary to each appointment. 
 
Six weeks into the study, each study participant will receive a phone call from a member 
of the research team.  During this phone call questions referencing compliance with completing 
the study diary, taking study medications as prescribed, if they have been treated for a UTI by 
anyone outside of our office during the study period, side effects noted, and if they have any 
questions to be answered will all be addressed.  
All subjects will be seen by a physician and research staff after 3 months in the study 
(when they have completed their 90 days in the study). At this visit, subjects will bring their 
study diary and any unused D-mannose to their appointment (including empty bottles if more 
than one bottle was provided to a patient in order for a patient to have a 90 day supply of D-
mannose). A survey will be given to the patient to fill out at the 3 month follow up appointment. 
The survey will include questions on medication adherence. The study team will review the 
chart for any adverse events or UTIs not previously reported. Patients will fill out a questionnaire 
at this appointment to confirm the same.  If a subject does not show for their 3 month follow up 
appointment then a member of the research team will attempt to contact the patient to 
reschedule this appointment. If any of the measures planned for 3 month follow up are not 
completed by the participant at this appointment, or if a participant does not show and does not 
reschedule this appointment, then it can alternatively be completed by phone or by mail, 
depending on participant convenience. If the participant does not complete all 90 days of the 
study, or if they forget to bring their study diary to their 3 month follow up appointment, then she 
will be offered the alternative of mailing or faxing her study diary to the office. If a participant 
completes the study early then she will be asked if she is willing to complete the 3 month follow 
up appointment information and exit survey at their next office visit, by phone, or by mail. 
For confidentiality, only research team members will have access to the study 
information and the information entered into the database. Subjects will be assigned a unique 
study ID that will be used on all case report forms and database reporting. The database that 
will be used is REDCap which is HIPPA (Health Insurance Portability and Accountability Act of 
1996) compliant, encrypted, and password protected. Any hard copies will be maintained in a 
locked cabinet in a locked office by a member of the research team. Data collection will occur 
on participants’ private devices (and sent to a locked phone) and/or on paper and placed in a 
locked cabinet in a locked office by a member of the research team. For text messaging, we will 
be using a SMS service that does not collect protected health information (PHI).   
3.b 
Medical Monitoring  
i 
Investigator only 
Data will be collected via the weekly text message, possible phone call to follow up on text 
message response, the six week follow up phone call, and the three month follow up office visit 
with regard to any side effects experienced during the study period.  All of this data will be 
reviewed weekly.  
ii 
Institutional Data and Safety Monitoring Board 
After the first ten participants have completed the study, review of adverse events experienced 
by the first ten participants will be compiled and assessed. The data and compiled information 
will be made available to an institutional data and safety monitoring board (DSMB) for 


 
 
 
 
 
 
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22
independent analysis. A similar sequence of events will occur after half of the participants in the 
study have completed the study and again at completion of all participants in the study. 
 
The DSMB will include an individual with expertise and experience with conducting randomized 
controlled trials in the field of obstetrics and gynecology, an individual with expertise in urology 
and experience with recurrent UTI, and a biostatistician.   
3.c 
Definitions of Adverse Events 
Adverse events will include medication side effects including gastrointestinal upset symptoms 
such as nausea, vomiting, flatulence, diarrhea, dyspepsia, and abdominal pain. Other 
medication side effects may include rash or itching.  
3.d 
Classification of Events 
i 
Severity 
All expected adverse events are of mild severity. 
 
For this study, the following standard adverse event (AE) definitions are used: 
 
Adverse event: Any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure. 
 
Serious Adverse Event (SAE):  Any AE related to the study drug that results in any of the 
following circumstances:  death, life-threatening, event requiring inpatient hospitalization or 
prolongation of existing hospitalization, persistent or significant disability/incapacity 
 
AEs are graded according to the following scale: 
 
Mild: An experience that is transient and requires no special treatment or intervention.  The 
experience does not generally interfere with usual daily activities.   
 
Moderate: An experience that is alleviated with simple therapeutic treatments. The 
experience impacts usual daily activities.   
 
Severe: An experience that require therapeutic intervention. The experience interrupts usual 
daily activities. If hospitalization (or prolongation of hospitalization) is required for treatment 
of something related to the study drug, it becomes a SAE.  
 
The study uses the follow AE attribution scale: 
 
Not related: The AE is clearly not related to the study procedure (i.e., another cause of the 
event is most plausible and/or a clinically plausible temporal sequence is inconsistent with 
the onset of the event). 
 
Possibly related: An event that follows a reasonable temporal sequence from the initation of 
study procedures, but that could readily have been produced by a number of other factors. 
 
Related: The AE is clearly related to the study procedures.  


 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
23
ii 
Expectedness 
Less common: gastrointestinal upset symptoms (such as nausea, vomiting, flatulence, diarrhea, 
constipation, dyspepsia, and abdominal pain) 
 
Rare: Rash or itching with medication. 
3.e 
Data Collection Procedures for Adverse Events 
Adverse events will be noted in each subject’s file. Their text message response to the weekly 
question about new symptoms related to study medication will be reviewed in a timely fashion.  
If symptoms were noted by text message response, then a follow up phone call to the patient 
will be made. 
F4 Study Outcome Measurements and Ascertainment 
Outcomes will be measured by a weekly study diary with follow up as indicated and by the 
patient notifying the office if UTI like symptoms are experienced. Control checks to make sure a 
UTI was not missed are built into a six week follow up phone call and the three month follow up 
appointment.  
G Statistical Plan  
G1  Sample Size Determination and Power 
We based our sample size estimate on assumptions for our primary aim, as this is the most 
important aim for providing information to support future recommendations and studies aimed at 
individualized patient care. The first published study on D-mannose was a RCT that showed 
14.6% of rUTI patients develop another UTI while on treatment [9]. To be conservative in our 
sample size calculations, we assume 20% of patient on D-mannose will develop a UTI during 
the three-month treatment period. Very few studies have stated the percent of rUTI patients that 
develop another UTI while on vaginal estrogen therapy [27-29]. Due to the range of the 
published values, an average of these numbers was taken to arrive at an assumption that 45% 
of patients on only vaginal estrogen therapy will develop another UTI during the treatment 
period. We also accounted for a 10% dropout rate during the study period. Using these numbers 
to determine sample size, we calculated 60 patients would be needed per RCT arm for a total of 
120 patients in the RCT. We recognize that our power for secondary aims is lower; however, we 
included these to begin to explore these other areas that are fundamental for understanding the 
underlying mechanism of D-mannose and how it works with rUTI. We have decided to also 
enroll 60 patients in the Observational arm of the study. 
G2  Interim Monitoring and Early Stopping 
In late 2019/early 2020 an interim analysis will be performed on the study data with all data to 
date serving as a “pilot” of the study. This will allow for interim analysis of safety and efficacy of 
the nutraceutical. The Haybittle-Peto rule will be followed for early stopping. Due to a slower 
recruitment rate than expected, an additional feasibility manuscript has been planned to inform 
the scientific community of these aspects of the trial. We would like to include a preliminary 
estimate of effect size and variability from interim analysis. The interim analysis rule is being 
used to avoid inflating type 1 error, but we expect to finish the trial as originally planned 
irrespective of the preliminary estimate, so no bias in study conduct should be introduced. The 
investigators will remain blinded to participants’ assignment. 


 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
24
G3  Analysis Plan and Statistical Methods 
We are studying D-mannose in postmenopausal women with a history of rUTI on VET. We will 
plan for an intent to treat analysis with an additional per protocol analysis likely.  
For our primary outcome of the RCT, we will calculate the cumulative incidence of 
symptomatic culture-proven UTIs. If we have loss to follow-up, we will use the Kaplan-Meier 
method to calculate the cumulative incidence by arm (i.e., 1.0 - survival). We will compare the 
cumulative incidence between arms by chi-squared tests, Fisher's exact tests, or log-rank tests, 
as appropriate. Although women will be randomized into the two arms, we will compare their 
distributions of potential confounding variables by calculating group-specific means and 
proportions, as appropriate. If these differ by an appreciable degree, we will calculate adjusted 
associations, using logistic or Cox proportional hazards regression, as appropriate.  
We will calculate the incidence of side effects and discontinuation as the number of 
women in the D-mannose +VET arm who experience these events during follow-up divided by 
the number of women in the D-mannose +VET arm. 95% confidence limits will be calculated by 
normal approximation or the Clopper-Pearson exact method, as appropriate.   
G4  Missing Outcome Data 
Missing data and patterns will be assessed monthly by the data manager.  Remedial measures, 
including retraining of staff, will be used as needed to minimize missing data.   
 
We plan for an intent to treat analysis. In doing this, study participants that are lost to followup 
will be presumed to not have an acute urinary tract infection from the time of last contact with 
the study participant. 
 
We will additionally have a per protocol analysis. 
G5  Unblinding Procedures  
Every attempt will be made to ensure that the patients enrolled in the RCT under the knowledge 
that a nutraceutical is being studied will continue to be blinded to which nutraceutical is being 
studied. If a patient is in the treatment arm of the RCT, and they are unblinded then this will be 
documented and reported to the research team for recording purposes.  
 
H Data Handling and Record Keeping  
H1 Confidentiality and Security 
Confidential and informed consent will occur in a private counseling room. Every precaution will 
be taken to ensure data confidentiality. Only research team members will have access to both 
the paper and electronic data. Subjects will be assigned a unique study ID that will be used on 
all case report forms and database reporting. The database that will be used is REDCap which 
is HIPPA compliant, encrypted, and password protected. Electronic data files will be accessible 
only on password protected computers. Any hard copies will be maintained in a locked cabinet 
in a locked office by a member of the research team. Data collection will occur on participants’ 
private devices (and sent to a locked phone) and/or on paper and placed in a locked cabinet in 
a locked office by a member of the research team. For text messaging, we will be using a SMS 
service that does not collect PHI. There will be strict adherence to data management protocols. 


 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
25
H2 Training  
All members of the research team will be educated on the study protocol at a division meeting 
or meeting set up for training purposes.  All members of the research team will be able to ask 
questions at this education session and after the education session to ensure they are 
comfortable with all aspects of the study protocol. Members of the research staff that will be 
using REDCap (Research Electronic Data Capture) will be trained on how to use this database. 
H3 Records Retention 
Subjects will be assigned a unique study ID that will be used on all case report forms and 
database reporting. 
 
Any hard copies will be maintained in a locked cabinet in a locked office by a member of the 
research team.   
 
Weekly study diary reminder response will be collected via text message. Data will be stored in 
REDCap which is HIPPA compliant, encrypted, and password protected. Work will only be done 
on password protected computers. Only members of the research team will have study 
information access. 
I Study Administration 
I1 
Organization and Participating Centers 
The location of this study will be the four outpatient office locations of the Division of Female 
Pelvic Medicine and Reconstructive Surgery in the Department of Obstetrics and Gynecology at 
Washington University in St. Louis School of Medicine.   
I2 
Funding Source and Conflicts of Interest 
Funding for this project will be supplied by the division of Female Pelvic Medicine and 
Reconstructive Surgery.  This is a division of the Department of Obstetrics and Gynecology in 
the Washington University in St. Louis School of Medicine.  
I3 
Subject Stipends or Payments  
Subjects will not be reimbursed for their participation in this research study. Patients in the 
treatment arm of the RCT portion of the study will received their D-mannose as part of the 
study.   
I4 
 Study Timetable 
Study Measure (mo = months) 
[Month 0 = January 2018] 
0-4 
mo 
4-8 
mo 
8-12 
mo 
12-16 
mo 
16-20 
mo 
20-24 
mo 
Patient enrollment 
 
 
 
 
 
 
3 mo of D-mannose treatment vs control 
treatment with patient follow up and re-
examination 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
Manuscript preparation and submission 
 
 
 
 
 
 
 


 
 
 
 
 
 
_____________________________________________________________________________________________ 
 
26
J Publication Plan  
 
We plan use the data from this study to write a manuscript for publication in a respected peer-
reviewed journal in a timely fashion. Journal choice will be dependent on study findings, but will 
likely be relating to the fields of female pelvic medicine and reconstructive surgery, gynecology, 
or urology.  
K  Attachments  
K1 Informed consent documents 
The following documents are attached in the myIRB application: 
 
Informed consent – RTC arm 
 
Informed consent – Observational arm 
K2  Patient education brochures 
 
Participant instructions – RCT arm 
 
Participant instructions – Observational arm 
K3  Questionnaires or surveys 
The following documents are attached in the myIRB application:  
 
Nutraceutical efficacy in rUTI screening log 
 
Enrollment visit form – complete with participant 
 
Study Diary – RCT Arm 
 
Study Diary – Observational Arm 
 
Follow up call for Yes text response form 
 
1 week confirmation of D-mannose in Observational Arm 
 
6 week follow up phone call – RCT Arm 
 
6 week follow up phone call – Observational Arm  
 
3 month followup appointment form – RCT Arm 
 
3 month followup appointment form – Observational Arm 
 
Exit survey (completed less than 90 days of study) 
 
Exit survey (completed 90 days of study) 
 
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28
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