Clinical trial NCT03632109
Conditions: Pharyngeal Gonococcal Infection
Keywords: gonorrhea pharynx treatment gentamicin
Sponsor: University of Washington
Start date: 2018-09-17; Completion date: 2019-03-12
Enrollment: 13 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 gentamicin 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 gentamicin is 91% efficacious for genital NG, its efficacy at the pharynx may be less since streptomycin, another aminoglycoside previously used to treat gonorrhea, was not effective for pharyngeal NG. It is unknown if streptomycin's poor efficacy is indicative of limitations of aminoglycosides as a class. We plan to enroll 60 men who have sex with men in a demonstration study to be conducted at the Seattle \& King County STD Clinic to test the efficacy of 360 mg of gentamicin given intramuscularly for pharyngeal gonorrhea. Secondary objectives include determining the ideal pharmacodynamic criterion (comparing in vitro minimal inhibitory concentrations (MIC) of NG to peak gentamicin serum levels), estimating resistance induction among treatment failures, and assessing the tolerability of 360 mg of IM gentamicin.

Objectives

The proposed study aims to evaluate the efficacy of a single intramuscular (IM) dose of gentamicin in the treatment of pharyngeal gonorrhea. Secondary objectives include documenting the efficacy stratified by minimal inhibitory concentration (MIC) compared with the gentamicin peak level in order to estimate a pharmacodynamic criterion. We will also attempt to determine whether gentamicin monotherapy induces antimicrobial resistance among treatment failures. Lastly, we will evaluate the tolerability of 360 mg of IM gentamicin, stratified by subject weight (i.e. weight based dosing). The specific aims are:

1. Determine the proportion of persons whose pharyngeal gonococcal infections are cured with a single dose of 360mg gentamicin intramuscularly alone.
2. Evaluate the renal safety and tolerability of 360mg IM of gentamicin.
3. Document mean peak gentamicin levels following 360mg IM of gentamicin stratified by weight.
4. Estimate the best pharmacodynamics criterion (i.e. peak/MIC ratio) for pharyngeal gonorrhea treated with gentamicin using individual and mean peak gentamicin levels and NG isolate MIC.
5. Among treatment failures, conduct exploratory analyses comparing pre- and post-treatment MIC for evidence of induced resistance.

Detailed description:

Arms: arm 1: Men who have sex with men (MSM) with pharyngeal gonorrhea will be treated with 360mg intramuscular gentamicin x 1.
Interventions: intervention 1: gentamicin 360mg IM
Intervention descriptions: intervention 1: 360mg IM of gentamicin

Protocol documents:
Prot_SAP_000.pdf: 
Gentamicin for Pharyngeal Gonorrhea – A Demonstration Study 
Study Protocol 
Version 1.2 
January 4, 2018 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 gentamicin 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 
gentamicin is 91% efficacious for genital NG, its efficacy at the pharynx may be less since 
streptomycin, another aminoglycoside previously used to treat gonorrhea, was not effective for 
pharyngeal NG.  It is unknown if streptomycin’s poor efficacy is indicative of limitations of 
aminoglycosides as a class.  We plan to enroll 60 men who have sex with men in a 
demonstration study to be conducted at the Seattle & King County STD Clinic to test the 
efficacy of 360 mg of gentamicin given intramuscularly for pharyngeal gonorrhea.  Secondary 
objectives include determining the ideal pharmacodynamic criterion (comparing in vitro minimal 
inhibitory concentrations (MIC) of NG to peak gentamicin serum levels), estimating resistance 
induction among treatment failures, and assessing the tolerability of 360 mg of IM gentamicin. 
Objectives 
The proposed study aims to evaluate the efficacy of a single intramuscular (IM) dose of 
gentamicin in the treatment of pharyngeal gonorrhea. Secondary objectives include 
documenting the efficacy stratified by minimal inhibitory concentration (MIC) compared with the 
gentamicin peak level in order to estimate a pharmacodynamic criterion.  We will also attempt 
to determine whether gentamicin monotherapy induces antimicrobial resistance among 
treatment failures.  Lastly, we will evaluate the tolerability of 360 mg of IM gentamicin, stratified 
by subject weight (i.e. weight based dosing). The specific aims are: 
1) Determine the proportion of persons whose pharyngeal gonococcal infections are cured 
with a single dose of 360mg gentamicin intramuscularly alone. 
2) Evaluate the renal safety and tolerability of 360mg IM of gentamicin. 
3) Document mean peak gentamicin levels following 360mg IM of gentamicin stratified by 
weight. 
4) Estimate the best pharmacodynamics criterion (i.e. peak/MIC ratio) for pharyngeal 
gonorrhea treated with gentamicin using individual and mean peak gentamicin levels 
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 who are not yet treated 


Exclusion criteria: 
Age less than 16 years  
Receipt of antibiotics in ≤30 days 
Known allergy to any aminoglycoside  
History of renal disease (including diagnosis of solitary kidney, chronic renal 
insufficiency, renal cell carcinoma etc),  
Use of concurrent nephrotoxic drugs or muscle relaxants  
History of diabetes 
History of hearing loss or tinnitus  
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:   360mg IM gentamicin x 1 
Primary Outcome:  Negative gonorrhea culture 4-7 days (+/- 1 day) after treatment 
Sample Size:  
60 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) 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.   
We will conduct an interim analysis after we have primary outcome results for 25 subjects. If 
the cure rate is ≤44% (99% CI 17% – 74%; i.e. 12 persons of 25 persons with a positive 
culture on treatment date fail treatment), we will stop the study.  We will also monitor for renal 
toxicity at the interim analysis.  We plan to obtain pre-treatment and post-treatment Creatinine.  
Increases >40% will be considered significant.  If more than 20% of the study population has a 
>40% increase in serum Creatinine, we will halt the study. We chose 20% because if 20% of 
subjects experience renal toxicity it is unlikely to be due to chance (95% CI 7 – 40%). 
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 individual peak gentamicin 
level in order to estimate the ideal pharmacodynamic (PD) criterion (Obj. 2). For persons who 
fail treatment we will also compare the pre- and post-treatment genatmicin MIC to estimate 
whether single dose gentamicin therapy can “induce” resistance (Obj. 3) 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 gentamicin. Lastly, we will report the number and proportion of subjects 
who report side effects. 
We will evaluate subject’s tolerability (Obj. 4) using a standardized symptom questionnaire 
conducted at the TOC visit.  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. 
 
 
 
 
 
 
 


 
Responsibilities 
Principle Investigator:   
Lindley A. Barbee, MD MPH 
Department of Medicine, Division of Allergy and Infectious 
Diseases, University of Washington  
 
Study Coordinator:  
Angela LeClaire 
Study Clinician: 
 
TBD 
 
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 
 
 
 
 
 
 
 


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 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 60 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) 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 Gentamicin 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 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. 


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.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Procedures 
Screening & Enrollment 
Pre-screening will occur by the PHSKC STD Clinic RN who reviews all patients charts 
to determine which services and provider(s) are warranted.  Patients with untreated 
pharyngeal gonorrhea will be referred to the study coordinator for screening.  Screening 
will occur in person by the study coordinator, study clinician or PI.  We will use a 
standardized screening eligibility form (see Appendix D) to determine patient’s eligibility.  
Since eligibility hinges on a diagnosis of untreated pharyngeal gonorrhea, for PHSKC 
STD Clinic patients, we will ask the IRB for a waiver of consent to be able to pre-screen 
charts to access the subject’s medical record to confirm diagnosis prior to approaching 
the patient.  All other eligibility criteria will be based on self-report.  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 any aminoglycoside  
 History of renal disease (including diagnosis of solitary kidney, chronic 
renal insufficiency, renal cell carcinoma etc),  
 Use of concurrent nephrotoxic drugs or muscle relaxants  
 History of diabetes 
 History of hearing loss or tinnitus  
 Concurrent infection with syphilis or chlamydia  
 Pregnancy and/or nursing (we will screen women not using highly active 
birth control, i.e. OCPs, IUD or nexplanon, who are more than 28 days 
from their last menstrual period) 
 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 
(see Appendix E) 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, 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 
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.  Endocervical specimen collection 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. Swabs for 
culture will be plated directly onto Thayer-Martin media and placed in a candle 
(CO2) jar.  Plates will be transported to the PHSKC lab daily, those that grow N. 
gonorrhoeae will be sent to the Neisseria Reference Laboratory (NRL) for 
antimicrobial susceptibility testing.  The procedures described above are all part of 
routine clinical care. 
 
The study clinician will also obtain blood to check a baseline creatinine to measure 
renal toxicity.  This blood draw will occur with the PK blood draw 30, 45, or 60 
minutes after dosing to avoid obtaining blood from the subject more than once. 
 
3. Treatment: 
Once all diagnostic procedures have been completed, the study clinician will 
administer 360 mg gentamicin IM.  The gentamicin injections will be given as 2 
injections of 4 mL each, one in each gluteus maximus.  The time of injection will be 
recorded 
 
4. Pharmacokinetics data: 
Subjects will be assigned post-injection blood draw at either 30 minutes, 45 minutes 
or 60 minutes after the gentamicin injection in a sequential fashion, meaning that 
participant #1 will have a 30 minute draw,#2 a 45 minute and #3 at 60 minute.  This 
one green top tube of blood will be tested for gentamicin concentration as part of 
Objective 2 and Creatinine.   
 
5. 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 and a blood 
draw for a follow-up creatinine.  (Specimen processing per above). 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 (see 
Appendix F) to assess for gentamicin side effects and tolerability.  The form will also 
ask about sexual activity, including kissing, in the time period between treatment and 
TOC. 
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. 
 
 
 
 
 
 
 
 
 
 


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 provide the antimicrobial susceptibility 
data for the N. gonorrhoeae isolates recovered at both enrollment and TOC visit.  The 
culture specimens are clinical specimens and full antimicrobial susceptibility testing (AST; 
this includes, beta-lactamase, penicillin, tetracycline, ciprofloxacin, cefixime, ceftriaxone, 
azithromycin and gentamicin) is done on all isolates.  However, AST is not routinely 
reported to the clinic.  Thus, in order to obtain this data, we will submit a list of names and 
MRN to Dr. Olusegun Soge, the Director of the NRL, to pull the data for us.  All personal 
health information (PHI) will be transferred electronically using secure file transfer 
technology. 
 
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; 
time of administration of gentamicin, time of gentamicin concentration blood draw; 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 (see Appendices E and F) 
UW Lab Medicine Research Testing Services: RTS will test our blood specimens for pre- 
and post- treatment Creatinine and gentamicin levels.  We will give the specimens to them 
with study id’s and dates on them, and they will provide the data via an excel file with only 
study ID and results. 
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. 
 
 


Study Confidentiality and Security 
We will use study IDs to label data items that only pertain to the study – i.e. data entry form, 
aliquots for gentamicin level and creatinine.  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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Laboratory Processing 
Gentamicin & Creatinine levels:   
Draw blood for enrollment day gentamicin level and baseline creatinine at 30, 45 or 60 
minutes (timing to be pre-determined by sequential participants; i.e. participant 1 is 
drawn at 30 minutes, 2 at 45 minutes and 3 at 60 minutes) following administration of 
gentamicin 360mg IM.  Use green top (sodium heparin) tube.  Centrifuge and aliquot ~ 
2mL into 5ml Sarstedt polypropylene tube.  These will be transferred to freezer within 4 
hours and frozen at -80 degrees celsius until transferred to UW RTS Lab in monthly 
batches.  UW RTS determines peak Genatmicin levels using Enzyme Immunoassay 
Technique and Creatinine by Spectrophotometric technique. 
N. gonorrhoeae cultures and Antimicrobial Susceptibility Testing 
All gonorrhea cultures are clinical specimens.  The PHSKC STD Clinic’s policy is to 
collect specimens for N. gonorrhoeae culture from persons with 1) a NAAT positive test 
who are not yet treated (i.e. most of our subjects); 2) persons with symptoms of 
urethritis, or cervicitis; 3) persons who are a contact to gonorrhea, at all exposed 
anatomic sites; and 4) persons who need a test of cure (TOC). TOC are done for any 
person with a cefixime, ceftriaxone or azithromycin alert value MIC, or have pharyngeal 
gonorrhea treated with a non-ceftriaxone containing regimen (i.e. study subjects). 
Clinical gonorrhea cultures are first sent to the PHSKC Laboratory for culture and 
identification, and N. gonorrhoeae isolates are then sent to the University of 
Washington’s Neisseria Reference Laboratory (NRL) for antimicrobial susceptibility 
testing (AST) for surveillance purposes.  Once a culture is identified as positive growth 
for gonorrhea, a report is made into the PHSKC STD Clinic medical record. 
The NRL first determines cefixime, ceftriaxone and azithromycin MIC by the etest 
method initially for prompt clinical action.  Then, 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), and Gentamicin (GEN). 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 gentamicin however, other institutes have used the following 
breakpoints that we will follow in this study:  Resistant is ≥32μg/ml; Intermediate 
susceptible 8-16 μg/ml, and Susceptible ≤4 μg/ml. Full AST results will be reported to 
the PI. 


Data Safety and Monitoring Plan, Resolving & reporting Protocol Deviations, AEs and 
Unanticipated problems 
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 including efficacy and renal toxicity 
and AEs in aggregate on at a single interim analysis after 25 subjects, and at the end of the 
study.  The Medical Monitor will review serious adverse events (SAEs), hearing loss, 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: 
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, and with Creatinine monitoring. 
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.  
MANAGEMENT OF RISKS TO SUBJECTS 
Expected AEs 
Expected AEs associated with gentamicin include:   
 Pain at injection site 
 Bruising at injection site 
AE Management 
 Warm compresses as needed 
 Tylenol  as needed 


DATA ANALYSIS PLANS 
The Medical Monitor will conduct interim analyses after we have primary outcome results for 
10 and 25 subjects.  (Enrollment will pause until analyses can be conducted).  Stopping rules 
include the primary end point (i.e. pharyngeal cure rate), and adverse events.  If after 10 and 
25 subjects, the cure rate is ≤44% (99% CI 17% – 74%; i.e. 11 persons of 25 persons with a 
positive culture on treatment date fail treatment), we will stop the study.  We chose these 
numbers using the O’Brien-Fleming method of alpha spending for multiple analyses, assuming 
and alpha of 0.003 for the first analysis and a alpha of 0.049 for the final analysis.  Using the 
99% CI obtained with 11/25 treatment failures, the upper bound is less than 75%. (Our 
hypothesis is that gentamicin alone will be 80% effective for pharyngeal gonorrhea, with the 
goal to use it in combination with a second agent).   Alternatively, if at interim analysis more 
than 20% of subjects (99% CI 20% - 46%) have a greater than 40% increase in their creatinine 
from baseline, we will halt the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Data Analysis 
The proposed study aims to evaluate the efficacy of a single intramuscular (IM) dose of 360 
mg of gentamicin in the treatment of pharyngeal gonorrhea. Secondary objectives include 
evaluating the renal safety and tolerability of 360mg of gentamicin, documenting peak serum 
gentamicin levels by subject weight, and estimating the ideal pharmacodynamic criterion using 
a combination of peak gentamicin concentration levels compared to MIC and treatment 
outcomes.  In exploratory analyses, we will attempt to determine whether gentamicin-
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 360mg gentamicin intramuscularly alone. 
2) Evaluate the renal safety and tolerability of 360mg IM of gentamicin. 
3) Document mean peak gentamicin levels following 360mg IM of gentamicin stratified by 
weight. 
4) Estimate the best pharmacodynamics criterion (i.e. peak/MIC ratio) for pharyngeal 
gonorrhea treated with gentamicin using individual and mean peak gentamicin levels 
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 gentamicin  
 
Persons who test negative for NG at their enrollment visit (i.e. infection cleared between initial 
clinical screening test and enrollment) will be excluded from analysis. Treatment failure will be 
defined as a positive culture 4-7 (+/-1) days after treatment.  
For our second objective, we will obtain pre- and post-treatment serum creatinine.  An 
elevation of >40% will be considered significant.  We will evaluate subject’s tolerability (Obj. 2) 
using a standardized symptom questionnaire (see Appendix F) conducted at the TOC visit.  
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. 
Our third objective is to document the pharmacokinetics of 360mg of IM gentamicin by weight.  
We will obtain serum gentamicin levels at 30, 45 and 60minutes post dosing based on 
previous studies that estimated that IM gentamicin peaks between 30-60 minutes post-dose.  


We will stratify the results by time post-dose, as well as by subject weight in kilograms 
(categorized). 
In order to estimate the ideal PK/PD criterion, we will compare the MIC of cures to treatment 
failures using a stratified approach (Table 2), and we will correlate this data with individual 
peak gentamicin level in order to estimate the ideal pharmacodynamic (PD) criterion (Obj. 4). 
As these results are ratios and may have a skewed distribution, we will log transform them and 
calculate a geometric mean. We anticipate that the vast majority of isolates will have a 
gentamicin MIC ≤8 µg/mL, and that most subjects’ peak concentration will be between 16-27 
µg/mL giving a ratio of 2-4. Variations in subjects’ weight or the gentamicin MICs might alter 
those predictions. Assuming an 80% cure rate (n=40), and a mean ratio of 3, with a standard 
deviation of 1, we anticipate a 95% CI of the peak/MIC ratio of 2.7 – 3.3, suggesting that our 
sample size is adequate to calculate this ratio.  
 
For persons who fail treatment we will also compare the pre- and post-treatment genatmicin 
MIC to estimate whether single dose gentamicin 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 gentamicin. 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 
GENTAMICIN MIC 
(µg/mL) 
Cure 
(N=XX) 
Treatment 
Failures 
(N=XX) 
Gentamicin Serum Level  
(Mean, Range) 
Peak/MIC Ratio 
(Mean, Range) 
≤1 
 
 
 
 
2 
 
 
 
 
4 
 
 
 
 
8 
 
 
 
 
16 
 
 
 
 
32 
 
 
 
 
≥64 
 
 
 
 
 
As a means to preserve funding and ensure safety, we will conduct interim analyses after we 
have primary outcome results for 10 and 25 subjects.  (Enrollment will pause until analyses 
can be conducted).  Stopping rules include the primary end point (i.e. pharyngeal cure rate), 
and adverse events.  If after 25 subjects, the cure rate is ≤44% (99% CI 17% – 74%; i.e. 11 
persons of 25 persons with a positive culture on treatment date fail treatment), we will stop the 
study.  We chose these numbers using the O’Brien-Fleming method of alpha spending for 
multiple analyses, assuming and alpha of 0.003 for the first analysis and an alpha of 0.049 for 
the final analysis.  Using the 99% CI obtained with 11/25 treatment failures, the upper bound is 
less than 75%.   Alternatively, if at interim analysis 32% or more of subjects (99% CI 9.4% - 
63%) have a greater than 40% increase in their creatinine from baseline, we will halt the study. 
 


Appendices 
A.  Clinician Information and Referral Script 
B.  Study Info Card 
C.  Appointment Reminder Card 
D. Screening Eligibility Form 
 
E. Enrollment visit data entry form 
F.  TOC visit data entry form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


APPENDIX A 
Clinician Informational and Referral Script for The Gent Study 
RN or Clinician:  You have gonorrhea in your throat.  We are conducting a study about a new 
medication for pharyngeal gonorrhea.  Are you interested in learning more? 
Patient: No 
End of discussion 
OR 
Patient:  Yes.  What does it entail? 
RN or Clinician:  Great.  I can just give you an overview, but instead of our usual treatment, 
you will get a different injection called gentamicin.  Then you’ll have to come back in about a 
week for a visit to make sure that you cleared the infection.  You will earn up to $XXX for 
participation.  If you are still interested, I will call the study coordinator to come get you started. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


APPENDIX B 
 
 
 
 
 


APPENDIX C 
 
 
 
 
 


APPENDIX D 
Eligibility Screening Form 
 
From Pre-screening Chart Review:   
Pharyngeal Gonorrhea Positive?  Y or N 
  
 
 
Date of Pharyngeal gonorrhea test:  ________ 
  
 
 
Chlamydial infection?  Y or N  (If yes, patient not eligible) 
  
 
 
Syphilis infection?    Y or N   (If yes, patient not elgibile) 
 
Researcher: Is it alright with you if I ask you some questions in order to assess your eligibility 
for the study?  Some of the questions are personal in nature. 
 
☐Yes ☐No 
 
If the potential subject answers yes above, complete the following questions.  Please check 
the boxes at left to indicate the question has been asked.  Answer the question to the Right.  
Eligibility criteria are in italics following the question.  You may stop the interview if, based on a 
single question, they do not meet eligibility criteria 
 
☐  Are you 16 years old or older? Yes 
☐ Do you speak and read in English? Yes 
☐Have you taken any antibiotics (e.g. Keflex, bactrim, penicillin etc) in the past 30 days?  Y or 
N (If yes, they are not eligible) 
 
☐Are you allergic to any antibiotics?  If so, which ones? _______________ (Allergy to 
gentamicin, spectinomycin, kanamycin, netilmycin, streptomycin, amikacin or tobramycin is an 
exclusion criteria.) 
 
☐Do you have kidney disease?  Kidney diseases include renal failure (including dialysis); 
diagnosis of solitary kidney, renal cell carcinoma etc. (Report of any renal disease is cause for 
exclusion.)     
 
☐  Do you have Diabetes?  Y or N  (Patients with diabetes are not eligible). 
 
☐ Do you have a history of hearing loss or tinnitus? Y or N (Patients with these symptoms are 
ineligible). 
 
☐What medications do you take on a regular basis?  (Potentially nephrotoxic drugs such as, 
Lisinopril, lithium and muscle relaxants, are cause for exclusion. If questions about certain 
drugs, call study PI.) 
 
List Here:  


☐Are you able to return to the PHSKC STD Clinic in 4-7 days for a TOC visit?  (Yes) 
Study personnel: 
☐In your estimation is the potential subject able to comply with the study procedures? Yes 
Study personnel conducting screening:  ___________________________ 
 If female-bodied patient, do urine pregnancy test.  Record result here:  Positive  Negative 
Ineligible if pregnant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
APPENDIX E 
Study ID:____ 
The Gent Study – Enrollment Data Entry Form  
Date:  _______________  
Age:  _____  
Race/ethnicity:  ______________ 
Current Gender:  [ ] Male  [ ] Female  [ ] Trans MTF  [ ] Trans FTM  [ ] NB/GQ 
Sex Assigned at Birth:  [ ] Male  [ ] Female 
Gender of Sex Partners: [ ] Male  [ ] Female  [ ] Trans MTF  [ ] Trans FTM  [ ] NB/GQ 
HIV Status: [ ] Positive  
[ ] Negative      Number of oral sex partners <2 months: __ 
Date of last oral sex exposure:   ____________ 
Anatomic Sites of Gonorrhea Infection and Date and Test Type: 
 
Pharynx:   
Test Date: ______    
NAAT [ ] Yes [ ] No  Culture [ ] Yes  [ ] No 
 
 
 
 
 
 
 
NAAT Type: __________________ 
 
Rectum:   
Test Date: ______    
NAAT [ ] Yes [ ] No  Culture [ ] Yes  [ ] No 
 
 
 
 
 
 
 
NAAT Type: __________________ 
   
Urethra:   
Test Date: ______    
NAAT [ ] Yes [ ] No  Culture [ ] Yes  [ ] No 
 
 
 
 
 
 
 
NAAT Type: __________________ 
Cervix/Vagina:  Test Date: ______   
NAAT [ ] Yes [ ] No  Culture [ ] Yes  [ ] No 
 
 
 
 
 
 
 
NAAT Type: __________________ 
Height:  __________ cm 
 
Weight:  _________ kg 
Medical History:  
___________________________________________________________________ 
__________________________________________________________________________ 
Current Medications (and doses):________________________________________________ 


___________________________________________________________________________ 
Date & Time of Administration of Gentamicin: _____________________________ 
Date & Time of Blood Draw for Gent PK and Cr:  __________________________ 
Immediate reactions (if any):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
APPENDIX F 
Study ID:  ______ 
The Gent Study – TOC Visit Data Entry Form  
TOC Visit Date:   ________   
 
Days since Tx:  ___________________ 
Symptoms since Tx: 
Y or N Headache (if yes, characterize):____________________________________________ 
Y or N Vision Changes (if yes, characterize):________________________________________ 
Y or N Changes in Hearing (if yes, characterize):___________________________________ 
Y or N Tinnitus (if yes, characterize):_____________________________________________ 
Y or N Urinary Symptoms (if yes, characterize):_____________________________________ 
Y or N Nausea or Vomiting (if yes, characterize):____________________________________ 
Y or N Diarrhea (if yes, characterize):_____________________________________________ 
Y or N Constipation (if yes, characterize):_________________________________________ 
Y or N Rash (if yes, characterize):________________________________________________ 
Y or N Other (if yes, characterize):________________________________________________ 
Sexual Activity Since Treatment: 
1) Have you been intimate with any partners since treatment?  Y or N   
(Intimacy includes kissing, oral-anal sex, oral-penile sex, anal-penile sex, penile-vaginal 
sex) 
 
2) Were any of your partners since treatment the same as someone you were intimate with 
in the 2 months prior to your pharyngeal gonorrhea diagnosis?  Y or N 
If Yes to #1 above, ask the following questions: 
3) How many days did you deep kiss a partner since treatment?  _________ 
4) How many partners did you deep kiss since treatment?  ___________ 
5) How many times did you perform oral sex on a penis since treatment?  ____________ 


6) How many male-bodied persons did you give oral sex to since treatment?  _________ 
7) How many times did you rim a partner since treatment?  _____________ 
8) How many partners did you rim since treatment?  ____________ 
9) How many times did you top (i.e. insertive anal intercourse) a partner since treatment? 
_____ 
10) How many partners did you top since treatment?  ________ 
11) How many times did you bottom (i.e. have receptive anal intercourse) for a partner 
since treatment?  ____ 
12) For how many partners did you bottom since treatment?  _____ 
13) How many times did you have vaginal sex with a partner since treatment? _____ 
14) How many partners did you have vaginal sex with since treatment?  _____ 
TOC Testing Conducted and Results: 
 
Pharynx:   
NAAT  Result [ ] Positive [ ] Negative 
Culture Done [ ] Yes  [ ] No 
 
 
 
Culture Results [ ] Positive  [ ] Negative 
 
 
 
AST results (in mcg/mL):  PCN: ____ 
TET: ____ 
CIP: ____ 
 
CFX: ____ 
CTX: ____  AZM: ___ 
GENT: ____ 
 
Rectum:   
NAAT  Result [ ] Positive [ ] Negative 
Culture Done [ ] Yes  [ ] No 
 
 
 
Culture Results [ ] Positive  [ ] Negative   
 
 
 
AST results (in mcg/mL):  PCN: ____ 
TET: ____ 
CIP: ____ 
 
CFX: ____ 
CTX: ____  AZM: ___ 
GENT: ____ 
   
Urethra:   
NAAT  Result [ ] Positive [ ] Negative 
Culture Done [ ] Yes  [ ] No 
 
 
 
Culture Results [ ] Positive  [ ] Negative   
 
 
 
AST results (in mcg/mL):  PCN: ____ 
TET: ____ 
CIP: ____ 
 
CFX: ____ 
CTX: ____  AZM: ___ 
GENT: ____ 
Cervix: 
NAAT  Result [ ] Positive [ ] Negative 
Culture Done [ ] Yes  [ ] No 


 
 
 
Culture Results [ ] Positive  [ ] Negative 
 
 
 
 
AST results (in mcg/mL):  PCN: ____ 
TET: ____ 
CIP: ____ 
 
CFX: ____ 
CTX: ____  AZM: ___ 
GENT: ____ 
Repeat Treatment needed?  Y or N 
Date of Repeat Treatment:  _________ 
Repeat treatment given:  [ ] Ceftriaxone 250mg IM  + Azithromycin 1g PO 
 
 
 
        [ ] Ceftriaxone 250mg IM + Doxycycline 100mg PO BID 
 
 
 
        [ ] Other:  _____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
APPENDIX G 
Identifying Data (to be maintained separately from study data) 
Name:  _____________________________________ 
Date of birth: _______________________________________ 
PHSKC STD Clinic MRN: ____________________________________________ 
Cell Phone Number:  ________________________________________ 
Email:  _____________________________________________ 
Address:  __________________________________________