Clinical trial NCT03867734
Conditions: Gonorrhea of Pharynx Gonorrhea
Keywords: aztreonam treatment study
Sponsor: University of Washington
Start date: 2019-04-05; Completion date: 2019-09-30
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The Centers for Disease Control and Prevention has identified antimicrobial-resistant (AMR) Neisseria gonorrhoeae (NG) as one of the nation's top three urgent AMR threats. Since the advent of antibiotics in the 1930s, NG has developed resistance to every first-line antibiotic. Parenteral third-generation cephalosporins are now the only class of drug with consistent efficacy against NG. New therapies are urgently needed. Although some novel antimicrobials are under development, reevaluating older drugs is another option for quickly identifying additional treatments for gonorrhea. We propose a demonstration study to test a single dose of aztreonam for the treatment of pharyngeal gonorrhea. We chose to focus on pharyngeal gonorrhea because these infections are common, play an important role in fostering gonococcal resistance, and are harder to eradicate than genital infections. Although aztreonam appears to be \>98.6% efficacious for anogenital NG, its efficacy at the pharynx may be less. Only 8 cases of pharyngeal gonorrhea have been documented to be treated with aztreonam, but of those, only 5 (62.5%) were cured. The dose used in those studies was 1g of aztreonam. Most antibiotics have a lower efficacy at the pharynx than anogenital sites, which is likely due to drug pharmacokinetics, i.e. difficulty in penetrating pharyngeal tissue. Thus, in the proposed study, we plan to treat 50 subjects with untreated pharyngeal gonorrhea with 2g IM Aztreonam.

Objectives:

The proposed study aims to evaluate the efficacy of a single 2g intramuscular (IM) dose of aztreonam in the treatment of pharyngeal gonorrhea. Secondary objectives include documenting the efficacy stratified by minimal inhibitory concentration (MIC) compared with the previously document area under the curve (AUC) in order to estimate a pharmacodynamic criterion. We will also attempt to determine whether aztreonam monotherapy induces antimicrobial resistance among treatment failures. Lastly, we will evaluate the tolerability of 2g of IM aztreonam. The specific aims are:

1. Determine the proportion of persons whose pharyngeal gonococcal infections are cured with a single dose of 2g aztreonam intramuscularly.
2. Determine the proportion of persons with urethral and/or rectal gonorrhea whose infections are cured with a single dose of 2g aztreonam IM.
3. Evaluate the tolerability of 2g IM of aztreonam .
4. Estimate the best pharmacodynamics criterion (i.e. AUC/MIC ratio) for pharyngeal gonorrhea treated with aztreonam using previously published AUC for 2g aztreonam and NG isolate MIC.
5. Among treatment failures, conduct exploratory analyses comparing pre- and post-treatment MIC for evidence of induced resistance.

Study Design: Prospective cohort

Study Population \& Inclusion Criteria:

Persons diagnosed with pharyngeal gonorrhea or gonococcal urethritis who are undergoing pharyngeal gonorrhea testing, who are not yet treated.

Intervention: 2g IM aztreonam x 1

Primary Outcome: Negative gonorrhea culture 4-7 days (+/- 1 day) after treatment

Sample Size: 50 persons

Detailed description:

Arms: arm 1: Subjects to receive 2g Aztreonam IM for the treatment of gonorrhea
Interventions: intervention 1: Aztreonam
Intervention descriptions: intervention 1: 2g IM Aztreonam

Protocol documents:
ICF_002.pdf: 
P-555 / Consent Form Template, Standard, 06/23/2017
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UNIVERSITY OF WASHINGTON
CONSENT FORM
Aztreonam for the treatment of pharyngeal gonorrhea: A demonstration study
Researchers: 
Principle Investigator: Lindley Barbee, MD MPH
Assistant Professor, Infectious Diseases, University of Washington
Office Phone:  206.744.2595
Email:  lbarbee@u.washington.edu
Co-investigator:
Matthew Golden, MD MPH
Professor, Infectious Disease, University of Washington
Phone:  206.744.6829
Email:  golden@u.washington.edu
Contact Person: 
Angela LeClair, CCRC
Phone: 206-744-0489
Email: achein@uw.edu
24-hour emergency telephone number 
HMC Community Care Line: 206-744-2500
Researchers’ statement
We are asking you to be in a research study.  The purpose of this consent form is to give you the 
information you will need to help you decide whether to be in the study or not.  Please read the 
form carefully.  You may ask questions about the purpose of the research, what we would ask 
you to do, the possible risks and benefits, your rights as a volunteer, and anything else about the 
research or this form that is not clear.  When we have answered all your questions, you can 
decide if you want to be in the study or not.  This process is called “informed consent.”  We will 
give you a copy of this form for your records.
PURPOSE OF THE STUDY
Gonorrhea is a common sexually transmitted disease that is unique in its ability to develop 
resistance to antibiotics – that is, the bacteria changes so that it cannot be killed by standard 
antibiotics.  At present there are only two recommended drugs to treat gonorrhea – ceftriaxone (a 
shot) and azithromycin (pills) – that are used together.  However, we are now seeing gonorrhea 
that cannot be treated with azithromycin, or cefixime a cousin-drug of ceftriaxone.  New drugs 
are urgently needed.  Although some new antibiotics are being studied, looking to older drugs is 
another possibility to quickly identify additional treatments for gonorrhea.  This study plans to 
test a single dose of aztreonam for the treatment of gonorrhea of the throat.  Aztreonam is an 
antibiotic that has been used since 1968, but has not been used routinely for gonorrhea treatment.  
We are focusing on gonorrhea of the throat because these infections are common, play an 
important role in the development of antibiotic resistance, and are harder to treat than gonorrhea 
of the genitals.  We plan to enroll 50 people with gonorrhea of the throat in a demonstration 
study conducted at the Seattle & King County STD Clinic to test whether a 2g shot of aztreonam 
cures gonorrhea of the throat. 
 
     Approved 
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     UW IRB


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STUDY PROCEDURES
If you choose to take part in this study, you will be asked to complete: 
an enrollment visit (today)
a test of cure (TOC) visit (in 4-7 days)
Each of these study activities are described in more detail below. 
Enrollment Visit:  At the enrollment visit, you will meet with study personnel for about 1  hour, 
including the time it takes to review this form.  After you have reviewed and signed this form, 
the formal study procedures will begin.
Intake & Data Entry Form:
The study coordinator or clinician will ask you questions, review your clinic chart and measure 
your height and weight, and complete a basic data entry form which includes contact 
information, demographic information (include sex assigned at birth, current gender identity, 
sexual orientation, race/ethnicity), HIV status, anatomic sites of infection, height, weight, 
concurrent medications and medical history. Persons of childbearing potential will have a 
pregnancy test.
Diagnostics and Baseline Clinical Data:
The study clinician will take swabs for culture from all body parts that were or could be positive 
for gonorrhea. This will include the throat and possibly the rectum, urethra and/or cervix, per 
routine clinical care.  A throat specimen is taken by gently touching a swab to the back part of 
the throat and moving it up and down, and over the tonsils for 5-10 seconds (like a strep test). 
Rectal swabs involve inserting a small q-tip like swab in the rectum approximately 3 cm and 
twirling it around approximately five times. To obtain a urethral swab, the clinician will use a 
smaller swab and insert it approximately 0.5 – 1 cm into the urethra and twirl 1-2 times.  For 
women  cervical specimen collection requires a pelvic exam with speculum. Once the cervix 
visualized the clinician inserts the swab into the opening approximately 1 cm and spins it about 5 
times. 
Treatment:
Once all swabs have been taken, the study clinician will give you 2g aztreonam as two4mL shots 
into your bottom, one in each buttock.  S/he will record the time of injection.  
Counseling and Follow-up Plan:
The study clinician and/or coordinator will help you set up a follow-up appointment in the next 
4-7 days to return to ensure that your infection was cured.  S/he will also counsel you about 
avoiding sexual activity until after your next visit.  Sexual activity includes performing oral sex, 
deep kissing, and oral-anal sex.
Test of Cure Visit (TOC): You will return to the PHSKC STD Clinic to meet with the study 
clinician 4-7 days (+/- 1 day) after the enrollment visit.  This visit should last about 30 minutes.  
The study coordinator will call you the day prior to the visit as a reminder.  At the TOC visit:
Diagnostics:
The study clinician will swab your throat, and any other anatomic sites that were infected at 
enrollment (e.g. urethra, rectum) again to obtain a culture for gonorrhea.  If the culture is positive 
 
     Approved 
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     UW IRB


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for gonorrhea, meaning that the medication did not cure you of the infection, study personnel 
will call you to return for the standard of care treatment – Ceftriaxone 250mg as a shot plus 
Azithromycin 1g orally once.
Behavior and Symptom screen:
The study clinician will ask you questions about any symptoms you may have had since your 
treatment to see how well aztreonem is tolerated. The form will also ask about sexual activity, 
including kissing, in the time period between treatment and TOC visit.
OTHER STUDY PROCEDURES
Access to Medical Records:  As part of this study, we are requesting your permission to access 
your medical records.  We will collect information about when you originally tested for 
gonorrhea, and other infections, and the results of the cultures conducted as part of this study, 
including information about antibiotic resistance
RISKS, STRESS, OR DISCOMFORT
There is a risk that someone could find out personal information about you, including your HIV 
status, which could lead to psychological stress and discomfort.  We will do everything possible 
to diminish this risk by using only a unique study ID on all of your data elements.
As with all drugs, there are potential for allergic reactions and side effects.  Documented side 
effects of aztreonam include decreases in your blood counts, elevations liver function tests, skin 
rash, diarrhea, nausea, and vomiting;  these side effects occur in <2% of cases.  We will ask you 
about possible side effects at your TOC visit, and you can call us if you think you might be 
experiencing a side effect.  A University of Washington medical facility can treat you, but the 
costs of the treatment may be billed to you or your health insurance just like other medical costs.
If you have any side effects or injury, such as increased stress, from participating in this study, 
you should call Dr. Lindley Barbee at 206-744-2595 or Dr. Matthew Golden at 206-744-6829. 
ALTERNATIVES TO TAKING PART IN THIS STUDY
Choosing to participate or not participate in the study will not affect your care at the Public 
Health – Seattle & King County STD clinic and/or Harborview Medical Center.  If you choose to 
not participate in this study, we will treat your for your infection as a clinic patient.
BENEFITS OF THE STUDY
One direct benefit of participating in the study is treatment for gonorrhea.  Additionally, the 
knowledge gained from this study will benefit society by helping us determine whether 
aztreonem is a possible new treatment for gonorrhea.
CONFIDENTIALITY OF RESEARCH INFORMATION
We have a Certificate of Confidentiality from the federal National Institutes of Health. This 
helps us protect your privacy. The Certificate means that we do not have to give out identifying 
 
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information about you even if we are asked to by a court of law. We will use the Certificate to 
resist any demands for identifying information.  We can’t use the Certificate to withhold your 
research information if you give your written consent to give it to an insurer, employer, or other 
person. Also, you or a member of your family can share information about yourself or your part 
in this research if you wish.
There are some limits to this protection. We will voluntarily provide the information to:
a member of the federal government who needs it in order to audit or evaluate the research;
individuals at the University of Washington, the funding agency, and other groups involved 
in the research, if they need the information to make sure the research is being done 
correctly;
the federal Food and Drug Administration (FDA), if required by the FDA;
state or local authorities, if we learn of child abuse, elder abuse, or the intent to harm yourself 
or others
Most of your samples and survey responses will only be labeled with your study ID number.  We 
will store your study data separately from information that identifies you.  However, we need to 
maintain a link between your study ID and your personal information in order to conduct the 
study. The link between your identifiers and the research data will be destroyed after the records 
retention period required by state and/or federal law. All study data will be stored securely on 
password-protected computers or in locked cabinets in a locked office.  Some of the samples you 
provide (i.e. swabs for culture) are also clinical specimens and will be identified with your name 
and medical record number (MRN).  However, there will be no indication on these specimens 
that they are part of a research study.  We will obtain the results of these tests via the medical 
record.  It will be recorded in the electronic medical record that you were treated as part of a 
research study.
As gonorrhea is an infection that is required to be reported to public health authorities, please 
note that you will be contacted by PHSKC disease intervention specialist for an interview, if you 
have not been contacted already.
Government or university staff sometimes reviews studies such as this one to make sure they are 
being done safely and legally.  If a review of this study takes place, your records may be 
examined.  The reviewers will protect your privacy.  The study records will not be used to put 
you at legal risk of harm.
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. 
OTHER INFORMATION
You may refuse to participate and you are free to withdraw from this study at any time without 
penalty or loss of benefits to which you are otherwise entitled.  You will be reimbursed for your 
time with $25 for today’s visit and $50 for the TOC visit, or $75 total.  This money will be 
provided in the form of cash at the TOC visit. If you choose to not return for the TOC visit, we 
will mail you a cash card with $25 on it.
 
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FUNDING SOURCE
The study team and/or the University of Washington is receiving financial support for this 
research from the National Institutes of Health and a University of Washington Royalty 
Research Fund grant.
RESEARCH-RELATED INJURY
If you think you have been harmed from being in this research, call Dr. Lindley Barbee at 206-
744-2595 or Dr. Matthew Golden at 206.744.6829.  If neither of the Investigators are available, 
please call the 24-hour number listed at the top of this form.  For a life-threatening problem, call 
911 right away or seek help immediately. Contact the study investigators when the medical 
emergency is over or as soon as you can.
If you are injured as a result of being in this study, necessary medical treatment will be offered at 
a UW Medicine facility. The costs of the treatment may be billed to you or your health insurance 
just like other medical costs, or it may be covered by the UW’s discretionary Human Subjects 
Assistance Program (HSAP), depending on a number of factors.   If you wish to request HSAP 
coverage yourself, contact the researcher or the UW Human Subjects Division at 
hsdinfo@uw.edu or 206-543-0098. Ask the researcher if you would like information about the 
limits and conditions of the HSAP. The UW does not normally provide any other form of 
compensation for injury. However, the law may allow you to seek payment for injury-related 
expenses if they are caused by malpractice or the fault of the researchers. You do not waive any 
right to seek payment by signing this consent form. If you have no health insurance or your 
insurance refuses to pay, we will bill you.  
Printed name of study staff obtaining consent
Signature
Date
Subject’s statement
This study has been explained to me.  I volunteer to take part in this research.  I have had a 
chance to ask questions.  If I have questions later about the research, or if I have been harmed by 
participating in this study, I can contact one of the researchers listed on the first page of this 
consent form.  If I have questions about my rights as a research subject, I can call the Human 
Subjects Division at (206) 543-0098 or call collect at (206) 221-5940.  I give permission to the 
researchers to use my medical records as described in this consent form.  I will receive a copy of 
this consent form.
Printed name of subject
Signature of subject
Date
Copies to:
Researcher
Subject
 
     Approved 
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     UW IRB

Prot_SAP_000.pdf: 
1 
 
Aztreonam for Pharyngeal Gonorrhea – A Demonstration Study 
Study Protocol 
Version 1.3 
April 26, 2019 
I. 
Purpose/Executive Summary 
II. 
Responsibilities 
III. 
Recruitment & Retention of Subject 
IV. 
Study procedures 
V. 
Data Sources and Data Management 
VI. 
Study Confidentiality and Security 
VII. 
Laboratory Processing 
VIII. 
Resolving & reporting Protocol Deviations, AEs and Unanticipated problems 
IX. 
Data Analysis 
X. 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Executive Summary 
The Centers for Disease Control and Prevention has identified antimicrobial-resistant (AMR) 
Neisseria gonorrhoeae (NG) as one of the nation’s top three urgent AMR threats.  Since the 
advent of antibiotics in the 1930s, NG has developed resistance to every first-line antibiotic. 
Parenteral third-generation cephalosporins are now the only class of drug with consistent 
efficacy against NG.  New therapies are urgently needed.  Although some novel antimicrobials 
are under development, reevaluating older drugs is another option for quickly identifying 
additional treatments for gonorrhea.  We propose a demonstration study to test a single dose 
of aztreonam for the treatment of pharyngeal gonorrhea.  We chose to focus on pharyngeal 
gonorrhea because these infections are common, play an important role in fostering 
gonococcal resistance, and are harder to eradicate than genital infections.  Although 
aztreonam appears to be >98.6% efficacious for anogenital NG, its efficacy at the pharynx may 
be less. Only 8 cases of pharyngeal gonorrhea have been documented to be treated with 
aztreonam, but of those, only 5 (62.5%) were cured.  The dose used in those studies was 1g of 
aztreonam.  Most antibiotics have a lower efficacy at the pharynx than anogenital sites, which 
is likely due to drug pharmacokinetics, i.e. difficulty in penetrating pharyngeal tissue.  Thus, in 
the proposed study, we plan to treat 50 subjects with untreated pharyngeal gonorrhea with 2g 
IM Aztreonam.   
Objectives 
The proposed study aims to evaluate the efficacy of a single 2g intramuscular (IM) dose of 
aztreonam in the treatment of pharyngeal gonorrhea. Secondary objectives include 
documenting the efficacy stratified by minimal inhibitory concentration (MIC) compared with the 
previously document area under the curve (AUC) in order to estimate a pharmacodynamic 
criterion.  We will also attempt to determine whether aztreonam monotherapy induces 
antimicrobial resistance among treatment failures.  Lastly, we will evaluate the tolerability of 2g 
of IM aztreonam. The specific aims are: 
1) Determine the proportion of persons whose pharyngeal gonococcal infections are cured 
with a single dose of 2g aztreonam intramuscularly. 
2) Determine the proportion of persons whose urethral gonococcal infection are cure with 
a single dose of 2g aztreonam intramuscularly 
3) Evaluate the tolerability of 2g IM of aztreonam . 
4) Estimate the best pharmacodynamics criterion (i.e. AUC/MIC ratio) for pharyngeal 
gonorrhea treated with aztreonam using previously published  AUC for 2g aztreonam 
and NG isolate MIC. 
5) Among treatment failures, conduct exploratory analyses comparing pre- and post-
treatment MIC for evidence of induced resistance. 
Study Design:  Prospective cohort 
 
 


3 
 
Study Population & Inclusion Criteria:  
Persons diagnosed with pharyngeal gonorrhea or gonococcal urethritis who are 
undergoing pharyngeal gonorrhea testing, who are not yet treated. 
Exclusion criteria: 
Age less than 16 years  
Receipt of antibiotics in ≤30 days 
Known allergy to aztreonam  
History of renal disease (including diagnosis of solitary kidney, chronic renal 
insufficiency, renal cell carcinoma etc.)  
Concurrent infection with syphilis or chlamydia  
Pregnancy and/or nursing 
Unable to return for a follow-up visit 4-7 days (+/- 1 day).   
Study team’s discretion 
Intervention:   2g IM aztreonam x 1  
Primary Outcome:  Negative gonorrhea culture 4-7 days (+/- 1 day) after treatment 
Sample Size:  
50 persons 
Statistical Analysis Plan: 
The primary endpoint is the pharyngeal cure rate – that is, the proportion of subjects who 
return for TOC who clear their infections as evidenced by a negative culture 4-7 (+/-1) days 
after treatment.  Persons who test negative for NG at their enrollment visit (i.e. infection 
cleared between initial clinical screening test and enrollment or had gonococcal urethritis in the 
absence of pharyngeal gonorrhea) will be excluded from analysis. Treatment failure will be 
defined as a positive culture 4-7 (+/-1) days after treatment. The cure rate will be calculated as 
the number of cured subjects divided by the total number of subjects who received treatment 
and returned for follow-up testing in a modified an intention to treat (mITT) analysis.  We will 
also calculate the 95% CI for this proportion.   
For our second objective, we will compare the MIC of cures to treatment failures using a 
stratified approach (Table 2), and we will correlate this data with known (i.e. previously 
published) AUC for 2g aztreonam to estimate the ideal pharmacodynamic (PD) criterion (Obj. 
3). For persons who fail treatment we will also compare the pre- and post-treatment aztreonam 
MIC to estimate whether single dose aztreonam therapy can “induce” resistance (Obj. 4) as an 
exploratory analysis.  We will consider an increase in the MIC by two doubling-dilutions (i.e. 
from MIC of 2 to 8 µg/mL, or 8 to 32 µg/mL) to represent induced resistance, and we will 
calculate the proportion of isolates among those that fail treatment that demonstrate induced 
resistance following receipt of aztreonam. Lastly, we will report the number and proportion of 
subjects who report side effects (Obj 2). 


4 
 
We will evaluate subject’s tolerability (Obj. 2) using a standardized symptom questionnaire 
conducted at the enrollment visit (for questions related to injection) and the TOC visit.  The 
TOC visit symptoms questioned will include, but not be limited to, rash, tinnitus, decreased 
hearing, nausea, vomiting, diarrhea, headaches, and decreased appetite.  There will also be a 
section for free response. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


5 
 
Responsibilities 
Principle Investigator:   
Lindley A. Barbee, MD MPH 
Department of Medicine, Division of Allergy and Infectious 
Diseases, University of Washington  
 
Co-Investigator: 
 
Matthew R. Golden, MD, MPH 
Department of Medicine, Division of Allergy and Infectious 
Diseases, University of Washington  
 
Study Clinician: 
 
Jennifer Morgan, ARNP 
 
 
 
 
STD Clinic, PHSKC  
 
Study Coordinator:  
Angela LeClair, CCRC 
STD Clinic, PHSKC 
 
Medical Monitor: 
 
Ann Collier, MD 
  
 
 
Professor of Medicine, Division of Allergy and Infectious Diseases 
University of Washington 
Director, UW AIDS Clinical Trials Unit 
Associate Director, Center for AIDS Research 
University of Washington and Fred Hutch 
 
 
Study Communication: 
Harborview Medical Center – STD clinic 
 
 
 
 
325 9th Ave, Box 359777 
 
 
 
 
Seattle, WA 98104 
 
 
 
 
Phone:  (206) 744.2595 
 
 
 
 
Fax:  (206) 744.4151 
 
 
 
 
Email:  lbarbee@u.washington.edu 
 
 
Study Site: 
 
 
Public Health – Seattle & King County 
 
 
 
 
STD Clinic 
 
 
 
 
908 Jefferson St, 11th Floor 
 
 
 
 
Seattle, WA 98104 
 
 
 
 
Phone:  (206) 744.3590 
 
 
 
 
 


6 
 
Recruitment and Retention of Subjects 
Patients who screen positive for pharyngeal gonorrhea, with or without concomitant GC at 
other anatomic sites, and have not yet received treatment for this infection or other antibiotics 
in the past 30 days are eligible for this study.  We will also include men with GC urethritis (per 
gram stain) who will undergo pharyngeal GC screening the same day.  We will not exclude 
based on gender or HIV status. Recruitment will primarily occur at PHSKC STD Clinic, 
however, we will also encourage high-diagnosing partner clinics to refer eligible patients as 
well.  We plan to enroll 50 persons with untreated pharyngeal gonorrhea for this study. 
Recruitment at PHSKC STD Clinic: 
 
We will employ several strategies to recruit at PHSKC STD Clinic. 
1) Patients who screen positive for pharyngeal gonorrhea and are called with their test 
results to return for treatment will be told on the phone that they may be eligible for a 
treatment study.  (PHSKC STD Clinic providers (ie. ARNP, PA and/or RN) routinely call 
patients with positive tests results, thus these clinical staff will tell patients about their 
eligibility for the study, however, PHSKC STD Clinic providers will not conduct formal 
study eligibility screening nor will they elaborate about study procedures (see script,  
Appendix A).) If patients indicate interest, the PHSKC provider will make an 
appointment for the patient with the study coordinator (for more information about the 
study, eligibility screening and enrollment procedures) and study clinician (for testing 
and treatment procedures) at their earliest convenience, ideally the next day.   
2) Male patients with gonococcal urethritis (as defined as urethral discharge and gram-
negative diplococci on gram stain) who are to have pharyngeal testing that day, will also 
be invited to participate.  PHSKC STD Clinic clinicians will be asked to refer these 
patients to study clinician. 
3) Some patient may not receive a phone call with test results prior to coming in for 
treatment (i.e. they see results electronically on MyChart [patient portal] or they were 
not informed of the study via a test results phone call, or were referred by an outside 
clinic to the PHSKC STD Clinic for treatment as their provider does not stock the 
recommended therapy in their office).  Patients who arrive at the PHSKC STD Clinic for 
treatment of pharyngeal gonorrhea and have not yet been informed about the study will 
be told by the triage RN or their clinician that they may be eligible and inquire about 
their interest.  If they indicate any interest in the study, they will be referred to the study 
coordinator and/or study clinician at that time. 
Recruitment outside of PHSKC STD Clinic: 
We will advertise the Aztreonam Study with high diagnosing providers in the community.  
Through a large CDC surveillance grant, SURRG, we already have a relationship with 
many of these providers: Madison Clinic, Dr. Shalit’s office, and Capitol Hill Medical 


7 
 
Group.  We will inform providers in these clinics about the study and provide study info 
cards (see Appendix B).  When they diagnose a patient with untreated pharyngeal 
gonorrhea, they will inform the patient that they may be eligible for this study, and if the 
patient is interested, either the provider or patient can call the study coordinator to set 
up an appointment. 
Recruitment at Madison Clinic: 
Madison Clinic patients diagnosed with pharyngeal gonorrhea, in the absence of 
chlamydia and syphilis, will be contacted about their test results by the Madison Clinic 
nurse.  Patients will be informed about the need for treatment and their potential 
eligibility in a research study.  The Madison clinic nurse will refer interested patients to 
the study coordinator to schedule an appointment. 
Retention of subjects: 
This study consists of two study visits.  Once enrolled, subjects need to return 4-7 days 
(+/- 1day) for a test of cure (TOC) visit.  At their enrollment visit, the subject will set up a 
TOC visit with either the study coordinator or study clinician, hand them an appointment 
reminder card (see Appendix C).  Less than 24 hours prior to the appointment, the study 
coordinator will call the patient with an appointment reminder call. If the subject does not 
show up for their appointment, the study coordinator will call them that day to set up 
another TOC visit appointment.   
 
 
 
 
 
 
 
 
 
 
 


8 
 
Study Procedures 
Screening & Enrollment 
Pre-screening will occur by the PHSKC STD Clinic MA/RR who reviews all abnormal 
laboratories.  Patients with untreated pharyngeal gonorrhea will be call the patient to inform 
them of their infection, let them know they need to come back for treatment and inform that 
they may be eligible for a study, and ask if they’d like to hear more.  Interested potential study 
subjects will verbally consent to an eligibility screen over the phone and then will schedule and 
appointment with the study clinician.  Alternatively, subjects who arrive at the clinic for 
treatment of pharyngeal gonorrhea or gonococcal urethritis will be identified by clinical staff as 
potentially eligible based on their chart.  These patients will be referred to the study clinician 
who will offer the study in person and proceed with the other study procedures (eligibility 
screening, consent).  We will use a standardized screening eligibility form (see Appendix D) to 
determine patient’s eligibility.  Patient will be excluded if they meet any of the following criteria:  
• Age less than 16 years  
• Receipt of antibiotics in ≤30 days 
• Known allergy to aztreonam 
• History of renal disease (including diagnosis of solitary kidney, chronic 
renal insufficiency, renal cell carcinoma etc),  
• Known concurrent infection with syphilis or chlamydia  
• Pregnancy and/or nursing  
• Unable to return for a follow-up visit 4-7 days (+/- 1 day).   
• Study team’s discretion 
 
 
Once it has been determined that the patient is eligible for and interested in the study, the 
study team member will go through the informed consent with the patient in detail.  After the 
subject has signed the informed consent, formal study procedures will begin. 
1. Intake & Data Entry Form: 
The study coordinator or clinician will fill out the first section of the data entry form  
which includes subject contact information, demographic information (include sex 
assigned at birth, current gender identity, sexual orientation, race/ethnicity), HIV 
status, anatomic sites of infection (or screening if presenting with gonococcal 
urethritis), height, weight, concurrent medications and medical history. 
 
2. Diagnostics and Baseline Clinical Data: 
The study clinician will obtain specimens for culture from all anatomic sites that were 
screen positive for gonorrhea. This will include the pharynx (by inclusion criteria) and 
possibly the rectum, urethra and endocervix, per routine clinical care.  A pharyngeal 
specimen is taken by gently touching a swab to the posterior aspect of the throat 
and moving it up and down, and over the tonsils for 5-10 seconds. Rectal swabs 


9 
 
involved inserting a small q-tip like swab in the rectum approximately 3 cm and 
twirling it around approximately five times. To obtain a urethral swabs, clinician use a 
smaller swab and insert it approximately 0.5 – 1 cm into the urethra and twirl 1-2 
times. Women who are able to get pregnant will have a pregnancy test.  If not 
pregnant, women who screen positive for vaginal gonorrhea will have endocervical 
specimen collected which requires a pelvic exam with speculum. Once the cervical 
os is visualized the clinician inserts the swab into the cervical os approximately 1 cm 
and spins it about 5 times for an adequate sample. All swabs for culture will be 
plated directly onto Thayer-Martin media and placed in a candle (CO2) jar.  Plates 
will be transported to the Neisseria Reference Laboratory (NRL) for culture and 
antimicrobial susceptibility testing within < 24 hours.  The procedures described 
above are all part of routine clinical care. 
 
3. Treatment: 
Once all diagnostic procedures have been completed, the study clinician will 
administer 2g aztreonam IM.  The aztreonam injections will be given as 2 injections 
of 4 mL each, one in each gluteus maximus.  (Reconstitute Aztreonam with 6mL of 
sterile water) 
 
4. Counseling: 
The study clinician will counsel the subject to avoid sexual activity, and most 
specifically performing oral sex, deep kissing, and oral-anal sex until they return for 
the TOC visit. 
Test of Cure Visit 
Subjects will return to the PHSKC STD Clinic to meet with the study clinician 4-7 days 
(+/- 1 day) after their enrollment visit.  The study coordinator will call the subject the day 
prior to the visit as a reminder.  At the TOC visit: 
1. Diagnostics: 
The study clinician will obtain a pharyngeal culture for N. gonorrhoeae.  If the culture 
is positive for N. gonorrhoeae, the subject will be called to return for standard of care 
treatment – Ceftriaxone 250mg IM plus Azithromycin 1g orally once. 
 
2. Behavior and Symptom screen: 
The study clinician will administer a standardized symptom screening form to assess 
for aztreonam side effects and tolerability.  The form will also ask about sexual 
activity, including kissing, in the time period between treatment and TOC. 
 


10 
 
Retention Plan 
The study coordinator will attempt to schedule the TOC visit at 4 days after the 
enrollment visit so that if the subject fails to show to that visit, there are still opportunities 
to reschedule the TOC visit.  Additionally, although the subject will be compensated for 
their time in the study, the will not receive compensation until they return for the TOC 
visit.  This is an incentive for them to keep their follow-up visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


11 
 
Data Sources and Data Management 
PHSKC STD Clinic Medical Record:  We will use gonorrhea test results that occurred 
prior to enrollment visit from the STD clinic medical record for inclusion criteria. This data 
will be extracted by chart review during the enrollment visit using subject name and DOB as 
identifiers.  The information will then be entered using a subject ID in the study database.  
We will also use demographic and sexual behavior data from the medical record. 
Neisseria Reference Laboratory:  The NRL will conduct and provide culture results and 
the antimicrobial susceptibility data for the N. gonorrhoeae isolates recovered at both 
enrollment and TOC visits.  Dr. Soge will inform the study team of positive cultures via 
email using only the study ID, and will also provide an official paper result. Full antimicrobial 
susceptibility testing (AST) includes beta-lactamase, penicillin, tetracycline, ciprofloxacin, 
cefixime, ceftriaxone, azithromycin, gentamicin and aztreonam.  Dr.  Soge will provide AST 
Results for both enrollment and treatment failure isolates using an excel spreadsheet listing 
Study ID, date of collection, anatomic site, and whether the isolates was collected at 
enrollment or TOC visit.   
 
Data Entry Form:  The study coordinator and study clinician will record key data points on 
a paper data entry form which will be transcribed into electronic data entry form in RedCap.  
Data to be collected will come from both the STD Clinic medical record and patient 
interview.   Data points will include: date of visit, gender identity, sex assigned at birth, age, 
race, height, weight, site of infections pre-enrollment and type of test used to diagnosis; 
results of treatment visit testing (culture results at each site); date of TOC visit, symptoms 
since treatment; sexual activity since treatment (including kissing, oral-anal, oral-penile, 
anal-penile, penile-vaginal etc.); anatomic sites tested by culture and results; repeat 
treatment needed etc.  
 
 
Data Management 
We will use RedCap to collect and store all study data.  Data can be exported from RedCap 
as a Stata database, which will be used for analysis.  Upon export from RedCap, we will 
remove identifiers except for subject ID and maintain a separate database to link subject 
identifiers/contact info to subject ID. 
We will use Appointments Everywhere software for appointment scheduling and reminders, 
including text message reminders for TOC visit. 
 
 


12 
 
Study Confidentiality and Security 
We will use study IDs to label data items that only pertain to the study – i.e. data entry form, 
and culture specimens.  Specimens that are also clinical specimen, will be labeled with the 
patient’s clinic label.  Data will be obtained from the medical record and entered into the data 
entry form which will only be labeled with the Study ID.   We will maintain a separate data base 
in RedCap that links the patient study ID and PHI. RedCap is 21 CFR part 11 compliant.  We 
will destroy the link between the patient’s identifying data and study ID after the study has 
been published or by December 31, 2021, whichever is sooner. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


13 
 
Laboratory Processing 
N. gonorrhoeae cultures and Antimicrobial Susceptibility Testing 
We will send specimens for culture and identification, antimicrobial susceptibility testing (AST) 
to the Neisseria Reference Laboratory.  Gonorrhea isolates undergo AST according to the 
Clinical and Laboratory Standards Institute (CLSI) recommended agar dilution method for 
further surveillance.[13]    AST testing includes: Penicillin (PEN), Tetracycline (TET), Cefixime 
(CFM), Ceftriaxone (CRO), Ciprofloxacin (CIP), Azithromycin (AZM), Gentamicin (GEN) and 
Aztreonam (AZT). We used CLSI [15] breakpoints to interpret MICs for penicillin (≥2.0μg/ml), 
tetracycline (≥2.0μg/ml), spectinomycin (≥128.0μg/ml), and ciprofloxacin (≥1.0μg/ml),[15] and 
used GISP alert values for azithromycin (≥2.0μg/ml), cefixime (≥0.25μg/ml), and ceftriaxone 
(≥0.125μg/ml) as CLSI has not established breakpoints for these antimicrobial agents.[12]   
Neither CLSI nor CDC have published breakpoints for aztreonam. Full AST results will be 
reported to the PI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


14 
 
Data Safety and Monitoring Plan, Resolving & reporting Protocol Deviations, AEs and 
Unanticipated problems 
Aztreonam Known Side Effects: 
Aztreonam is usually a very well tolerated antibiotic in adults.  Documented side effects 
(including, neutropenia, eosinophilia, thrombocytopenia, elevated liver function tests, skin rash, 
diarrhea, nausea, and vomiting) occur in <2% of cases.  There may be pain related to the 
injection.  Given that we are only dosing aztreonam once, we anticipate side effects to be rare. 
As with all drugs, there is a risk of allergic reaction.  Type 1 allergic reaction (i.e. IgE 
mediated—anaphylaxis reactions) usually occur immediately.  We will observe subjection for 
approximately 15 minutes following injection of aztreonam.  Other types of allergic reaction 
occur later and are usually, but not always, less severe.  A study clinician will evaluate the 
patient 4-7 days following administration of the drug and will ask about interim side effects.   
DSMB OVERSIGHT RESPONSIBILITIES 
Day-to-day oversight of the trial is provided by the Principal Investigator (PI), Dr. Barbee, along 
with Dr. Golden (co-I).  Dr. Barbee assures that informed consent is obtained prior to 
performing any research procedures, that all subjects meet eligibility criteria, and that the study 
is conducted according to the IRB-approved research plan.  Drs. Barbee and Golden review all 
study data and any adverse events (AEs) real-time, and report all SAEs to the Medical Monitor 
and IRB according to the approved DSMP. 
Medical Monitor:  Monitoring for the study will be provided by a volunteer Medical Monitor, Dr. 
Ann Collier, Professor of Medicine in the Division of Allergy and Infectious Diseases, who has 
over 25 years of experience with clinical trials, but is not directly related to the study team. 
MONITORING PROCEDURES 
The Medical Monitor, Dr. Collier, will review study conduct at the end of the study.  The 
Medical Monitor will review serious adverse events (SAEs),  and serious drug allergies in real-
time.  Study data are provided to the Medical Monitor prior to the interim and final analysis.  
Data reports are prepared by the PI, Dr. Barbee. 
MONITORING REPORT 
The Medical Monitor, Dr. Collier, will provide a written report to the study team with 
recommendations for study modification, study continuation/discontinuation as relevant. The 
study team is responsible for forwarding the report to the IRB.  
COLLECTION AND REPORTING OF SAEs AND AEs 
For this study, the following standard AE definitions are used: 


15 
 
Adverse event:  Any unfavorable and unintended sign (including an abnormal laboratory 
finding), 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:  Any AE that results in any of the following outcomes: 
• 
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, & requires no special treatment or intervention.  
The experience does not generally interfere with usual daily activities.  This includes 
transient laboratory test alterations. 
Moderate:  An experience that is alleviated with simple therapeutic treatments.  The 
experience impacts usual daily activities.  Includes laboratory test alterations indicating 
injury, but without long-term risk. 
Severe:  An experience that requires therapeutic intervention.  The experience 
interrupts usual daily activities. If hospitalization (or prolongation of hospitalization) is 
required for treatment it becomes an SAE. 
The study uses the following AE attribution: 
Not related:  The AE is clearly not related to the study procedures (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 
initiation 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.   
AEs are identified at the TOC visit using the symptom screen. 
SAEs and specific procedure-associated AEs are reported to the Medical Monitor within 24 
hours.  In addition, all AEs are reported according to the University of Washington AE reporting 
guidelines.  
 


16 
 
MANAGEMENT OF RISKS TO SUBJECTS 
Expected AEs 
Expected AEs associated with aztreonam include:   
• Pain at injection site 
• Bruising at injection site 
AE Management 
• Warm compresses as needed 
• Tylenol  as needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


17 
 
DATA ANALYSIS PLANS 
The proposed study aims to evaluate the efficacy of a single intramuscular (IM) dose of 2g of 
aztreonam in the treatment of pharyngeal gonorrhea. Secondary objectives include evaluating 
the tolerability of these regimens, and estimating the ideal pharmacodynamic criterion.  In 
exploratory analyses, we will attempt to determine whether aztreonam-monotherapy induces 
antimicrobial resistance among treatment failures.   The specific aims are: 
1) Determine the proportion of persons whose pharyngeal gonococcal infections are cured 
with a single dose of 2g aztreonam intramuscularly alone,  
2) Determine the proportion of persons whose urethral gonococcal infections are cured 
with a single dose of 2g aztreonam intramuscularly alone 
3) Evaluate the tolerability of 2g IM of aztreonam. 
4) Estimate the best pharmacodynamics criterion (i.e. AUC/MIC ratio) for pharyngeal 
gonorrhea treated with aztreonam using previously documented AUC for 2g aztreonam 
and NG isolate MIC. 
5) Among treatment failures, conduct exploratory analyses comparing pre- and post-
treatment MIC for evidence of induced resistance. 
Analyses 
The primary endpoint is the pharyngeal cure rate – that is, the proportion of subjects who 
return for TOC who clear their infections as evidenced by a negative culture 4-7 (+/-1) days 
after treatment.  The cure rate will be calculated as the number of cured subjects divided by 
the total number of subjects who received treatment and returned for follow-up testing in a 
modified an intention to treat (mITT) analysis.  We will also calculate the 95% CI for this 
proportion.   
Cure rate = number of subjects with negative pharyngeal culture at TOC  
   
        number of subjects with + throat test at enrollment & received aztreonam  
 
Persons who test negative for pharyngeal NG at their enrollment visit (i.e. infection cleared 
between initial clinical screening test and enrollment or were negative) will be excluded from 
the primary analysis. Treatment failure will be defined as a positive culture 4-7 (+/-1) days after 
treatment.  
For our secondary objectives, we will evaluate subject’s tolerability (Obj. 2) using a 
standardized symptom questionnaire (see Appendix F) conducted at both the enrollment and 
the TOC visit. At enrollment, questions will focus on tolerability of the injection.  At TOC, the 
symptoms questioned will include, but not be limited to, rash, tinnitus, decreased hearing, 
nausea, vomiting, diarrhea, headaches, and decreased appetite.  There will also be a section 
for free response. 


18 
 
For persons who fail treatment we will also compare the pre- and post-treatment aztreonam 
MIC to estimate whether single dose aztreonam therapy can “induce” resistance (Obj. 5) in an 
exploratory analysis.  We will consider an increase in the MIC by two doubling-dilutions (i.e. 
from MIC of 2 to 8 µg/mL, or 8 to 32 µg/mL) to represent induced resistance, and we will 
calculate the proportion of isolates among those that fail treatment that demonstrate induced 
resistance following receipt of aztreonam. Should we see a signal for induced resistance, we 
plan to apply for additional funding to conduct whole genome sequencing to look for genetic 
determinants of resistance. 
 
Table 2:  Proposed Description of Primary Study Findings 
Aztreonam MIC 
(µg/mL) 
Cure 
(N=XX) 
Treatment 
Failures 
(N=XX) 
0.03 
 
 
0.06 
 
 
0.12 
 
 
0.25 
 
 
0.5 
 
 
1.0 
 
 
2 
 
 
>2