Conditions: Chlamydial Infection
Keywords: Azithromycin Chlamydia Correctional Facilities Symptoms Urethral Urogenital Youth
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 100
Healthy volunteers: no

Brief summary:
The proposed study is a single center (with multiple long-term YCFs) treatment trial of the CDC-recommended azithromycin regimen (1 gm PO once) for chlamydia in males. This study is designed primarily to determine the frequency of chlamydia treatment failure following azithromycin in males who do versus do not have urethral symptoms of urethral discharge and/or dysuria. Anticipated enrollment is 446 males, between the age of 12 to 21 years old, with subject participation duration of 28 days and study duration of 4 years. The primary objective of the study is to assess the microbiological efficacy of azithromycin in uncomplicated Chlamydia trachomatis infection in males with versus without urethral symptoms in YCFs.

Detailed description:
The proposed study is a single center (with multiple long-term YCFs) treatment trial of the CDC-recommended azithromycin regimen (1 gm PO once) for chlamydia in males residing in long-term gender-segregated YCFs. This study is designed primarily to determine the frequency of chlamydia treatment failure following azithromycin in males who do versus do not have urethral symptoms of urethral discharge and/or dysuria. Males age 12 to 21 years in good health (based on vital signs and provider's clinical evaluation documented in medical records) who are residing in long-term gender-segregated (not co-ed) YCFs (usual stay \> 3 weeks) and who are identified as chlamydia-infected comprise the study population. The anticipated enrollment is 446 males with subject participation duration of 28 days and study duration of 4 years. The primary objective of the study is to assess the microbiological efficacy of azithromycin in uncomplicated Chlamydia trachomatis infection in males with versus without urethral symptoms in YCFs; in essence, this study will assess the frequency of chlamydia treatment failure to azithromycin at the Day 28 follow-up visit (Visit 2) in males with urethral symptoms compared to males without urethral symptoms. The secondary objective is to evaluate the association of laboratory findings (enrollment chlamydia load and OmpA genotype) and other participant characteristics (demographics, sexual behaviors, etc.) to chlamydia treatment failure in males after azithromycin treatment.

Arms:
arm 1: Azithromycin 1 gm PO single dose given as directly observed

Interventions: intervention 1: Azithromycin
Intervention descriptions: intervention 1: Azithromycin 1 gm PO single dose given as directly observed

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
1 
Treatment Failure and Associated Predictors Following  
Azithromycin Treatment  
for Urogenital Chlamydial Infection in Males in 
Youth Correctional Facilities 
 
DMID Protocol Number: 16-0002 
DMID Funding Mechanism: 2722013000121 
 
Principal Investigator: William M. Geisler, MD, MPH 
 
DMID Clinical Project Manager: Barbara Hahn, RN, BSN 
  
 
 
 
 
Draft or Version Number: Version 3.0 
 
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) and the 
applicable regulatory requirements:   
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
NIH Clinical Terms of Award 
• 
Completion of Human Subjects Protection Training 
• 
California laws and regulations 
 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Principal Investigator: William M. Geisler, MD, MPH 
Signed: 
 
Date: 
 
 
Name: William M. Geisler, MD, MPH 
Title: Professor of Medicine, UAB 
 
 
 
Site Investigator: Raymond Perry, MD, MSHS 
Signed: 
 
Date: 
 
 
Name: Raymond Perry, MD, MSHS 
Title: Los Angeles County Department of Health 
Services 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 .................................................................................................................................... Page 
Statement of Compliance ............................................................................................................ 2 
Signature Page ........................................................................................................................... 3 
Table of Contents ........................................................................................................................ 4 
List of Abbreviations .................................................................................................................... 7 
Protocol Summary ...................................................................................................................... 9 
1 
Key Roles ......................................................................................................................... 11 
2 
Background Information and Scientific Rationale.............................................................. 14 
2.1 
Background Information ........................................................................................ 14 
2.2 
Rationale .............................................................................................................. 15 
2.3 
Potential Risks and Benefits ................................................................................. 16 
2.3.1 
Potential Risks .......................................................................................... 16 
2.3.2 
Known Potential Benefits........................................................................... 17 
3 
Objectives ........................................................................................................................ 18 
3.1 
Study Objectives ................................................................................................... 18 
3.2 
Study Outcome Measures .................................................................................... 18 
3.2.1 
Primary Outcome Measures ...................................................................... 18 
3.2.2 
Secondary Outcome Measures ................................................................. 19 
4 
Study Design .................................................................................................................... 20 
5 
Study Enrollment and Withdrawal ..................................................................................... 22 
5.1 
Subject Inclusion Criteria ...................................................................................... 22 
5.2 
Subject Exclusion Criteria ..................................................................................... 22 
5.3 
Withdrawal Procedures ......................................................................................... 23 
5.3.1 
Reasons for Withdrawal ............................................................................ 23 
5.3.2 
Handling of Withdrawals ............................................................................ 24 
5.3.3 
Termination of Study ................................................................................. 24 
6 
Study Intervention/Investigational Product ........................................................................ 25 
6.1 
Study Product Description .................................................................................... 25 
6.1.1 
Acquisition ................................................................................................. 25 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 25 
6.1.3 
Product Storage and Stability .................................................................... 25 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 25 
6.3 
Modification of Study Intervention/Investigational Product for a Subject ................ 26 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 26 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 26 
6.6 
Concomitant Medications/Treatments ................................................................... 27 
7 
Study Schedule ................................................................................................................ 28 
7.1 
Screening ............................................................................................................. 28 
7.2 
Enrollment (Visit 1) ............................................................................................... 28 
7.3 
Follow-up Visit (Visit 2) ......................................................................................... 29 
8 
Study Procedures/Evaluations .......................................................................................... 31 


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8.1 
Clinical Evaluations ............................................................................................... 31 
8.2 
Laboratory Evaluations ......................................................................................... 31 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 31 
8.2.2 
Special Assays or Procedures ................................................................... 32 
8.2.3 
Specimen Preparation, Handling, Storage and Shipment .......................... 32 
9 
Assessment of Safety ....................................................................................................... 33 
9.1 
Specification of Safety Parameters ....................................................................... 33 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 33 
9.2.1 
Adverse Events ......................................................................................... 33 
9.2.2 
Serious Adverse Events ............................................................................ 35 
9.2.3 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ........................................................ 35 
9.3 
Reporting Procedures ........................................................................................... 35 
9.3.1 
Serious Adverse Events ............................................................................ 36 
9.3.2 
Regulatory Reporting for Studies Not Conducted Under 
DMID-Sponsored IND ............................................................................... 37 
9.3.3 
Other Adverse Events ............................................................................... 37 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 38 
9.5 
Halting Rules ........................................................................................................ 38 
9.6 
Safety Oversight ................................................................................................... 38 
10 
Clinical Monitoring ............................................................................................................ 40 
10.1 
Site Monitoring Plan .............................................................................................. 40 
11 
Statistical Considerations ................................................................................................. 41 
11.1 
Study Hypotheses ................................................................................................. 41 
11.2 
Sample Size Considerations ................................................................................. 41 
11.3 
Planned Interim Analyses (if applicable) ............................................................... 41 
11.3.1 Safety Review ........................................................................................... 41 
11.4 
Analysis Population .............................................................................................. 42 
11.5 
Final Analysis Plan ............................................................................................... 42 
12 
Source Documents and Access to Source Data/Documents ............................................ 44 
13 
Quality Control and Quality Assurance ............................................................................. 45 
14 
Ethics/Protection of Human Subjects ................................................................................ 46 
14.1 
Ethical Standard ................................................................................................... 46 
14.2 
Institutional Review Board .................................................................................... 46 
14.3 
Informed Consent Process ................................................................................... 46 
14.3.1 Informed Consent Process (in Case of a Minor) ........................................ 47 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 47 
14.5 
Subject Confidentiality .......................................................................................... 47 
14.6 
Study Discontinuation ........................................................................................... 48 
15 
Data Handling and Record Keeping ................................................................................. 49 
15.1 
Data Management Responsibilities ....................................................................... 49 
15.2 
Data Capture Methods .......................................................................................... 49 
15.3 
Types of Data ....................................................................................................... 50 


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15.4 
Timing/Reports ..................................................................................................... 50 
15.5 
Study Records Retention ...................................................................................... 51 
15.6 
Protocol Deviations ............................................................................................... 51 
16 
Publication Policy ............................................................................................................. 52 
17 
Literature References ....................................................................................................... 53 
Supplements/Appendices ......................................................................................................... 55 
Appendix A: Schedule of Events ............................................................................................... 55 
Appendix B: Toxicology Tables ................................................................................................. 56 
 
 


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LIST OF ABBREVIATIONS 
AC2 
Aptima Combo 2® Assay 
AE 
Adverse Event/Adverse Experience 
BID 
Twice a day 
CDC 
Centers for Disease Control and Prevention 
CDM 
Center for Data Management 
CI 
Confidence Interval 
CFR 
Code of Federal Regulations 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support  
CT 
Chlamydia Trachomatis 
DHHS 
Department of Health and Human Services 
DM plan 
Data Management Plan 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
GC 
Neisseria Gonorrhoeae 
GCP 
Good Clinical Practice 
gm 
Gram 
HIV  
Human Immunodeficiency Virus 
IC 
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC  
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
LA 
Los Angeles 
LACDPH 
Los Angeles County Department of Public Health 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
NAAT 
Nucleic Acid Amplification Test 
NGU 
Nongonococcal Urethritis 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OmpA 
Major Outer Membrane Protein 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PI 
Principal Investigator 


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PO 
By mouth 
PS 
Protocol Specialist 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAS 
Statistical Analysis Software 
SC 
Study Coordinator 
SI 
Site Investigator 
SOP 
Standard Operating Procedure 
STD 
Sexually Transmitted Disease 
STI 
Sexually Transmitted Infection 
STI CTG 
Sexually Transmitted Infection Clinical Trials Group 
UAB 
University of Alabama at Birmingham 
US 
United States 
USC 
University of Southern California 
WHO 
World Health Organization 
YCF 
Youth Correctional Facility 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY  
Title: 
Evaluation of Treatment Failure and Associated Predictors Following 
Azithromycin Treatment for Urogenital Chlamydial Infection in Males in 
Youth Correctional Facilities (YCFs) 
Phase: 
Not applicable 
Population: 
Up to 446 males ages 12-21 in good health identified as chlamydia-infected 
through screening who are residing in long-term gender-segregated YCFs in 
Los Angeles County. 
Number of Sites: 
1 site which is comprised of the Los Angeles County Department of Public 
Health and 15 YCFs located within Los Angeles County: Los Padrinos 
Juvenile Hall; Central Juvenile Hall; Barry J. Nidorf Juvenile Hall; Dorothy 
Kirby Center; Camp Afflerbaugh; Camp David Gonzales; Camp Joseph 
Paige; Camp Glenn Rockey; Camp Gregory Jarvis; Camp Ronald McNair; 
Camp Ellison Onizuka; Camp Judith Resnik; Camp Francis J. Scobee; 
Camp Michael Smith; and Camp Kilpatrick 
Study Duration: 
4 years 
Subject Participation 
Duration: 
28 days 
Description of Agent 
or Intervention: 
Azithromycin (1 gm PO single dose) for the treatment of urogenital 
chlamydia 
Objectives: 
Primary:  
Assess the microbiological efficacy of azithromycin in uncomplicated 
Chlamydia trachomatis infection in males with versus without urethral 
symptoms in YCFs; in essence, this study will assess the frequency of 
chlamydia treatment failure to azithromycin at the Day 28 follow-up visit 
(Visit 2) in males with urethral symptoms compared to males without 
urethral symptoms.  
Secondary:  
Evaluate the association of laboratory findings (enrollment chlamydia load 
and OmpA genotype) and other participant characteristics (demographics, 
sexual behaviors, etc.) to chlamydia treatment failure in males after 
azithromycin treatment. 
Estimated Time to 
Complete Enrollment: 
3.3 years 


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Description of Study Design: 
 
 
Prior to  
Enrollment 
 
 
 
 
 
Visit 1 
(Enrollment,  
 Day 1) 
 
 
 
 
 
 
 
 
Visit 2 
(Day 28 After  
Therapy, Visit 
Window Day  
25 – 35) 
 
 
 
 
 
 
Urine specimens are routinely collected in males at juvenile hall reception centers and 
tested with Aptima Combo 2® Assay (AC2) to diagnose CT and GC infection. If CT infection 
present (w/o GC co-infection) and male juvenile is likely to remain in custody longer than 28 
days, then refer for offer of study enrollment. 
Enroll up to 446 or until at least 357 evaluable males are obtained. Screen subjects by 
enrollment criteria. Obtain informed consent (IC), subject demographic info and medical 
history. Collect first-catch urine for repeat AC2. Determine CT OmpA genotype and CT load 
if indicated.  
Assessment of Final Study Outcome 
Measures 
Collect first-catch urine for AC2. Assess for adverse events (AEs). Assess clinical and 
laboratory parameters.  Determine CT OmpA genotype and CT load if indicated. 
Treat subject with azithromycin 1 gm PO single dose. 


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1 
KEY ROLES 
For questions regarding this protocol, contact: Barbara Hahn (Clinical Project Manager) at 240-
627-3267 
Individuals: 
DMID Clinical Project Manager   
Barbara Hahn, RN, BSN 
STD Branch, DMID, NIAID, NIH 
5601 Fishers Lane, Rm 8E49 
Bethesda, MD, 20892-9825 
(for FedEx, UPS, DHL use Rockville, MD, 20852) 
Phone: 240-627-3267 
bhahn@niaid.nih.gov 
 
Principal Investigator 
William M. Geisler, MD, MPH 
University of Alabama at Birmingham 
Zeigler Research Building 242 
703 19th St South 
Birmingham, AL 35294-0007 
Phone: (205) 934-4376 
Fax: (205) 975-7764 
E-mail: wgeisler@uabmc.edu 
 
DMID Medical Monitor 
Soju Chang, MD, MPH  
DMID/NIAID/NIH 
5601 Fishers Lane, Rm 7E59 
Bethesda, MD 20892-9825 
Phone: (240) 292-4178 
Email: changsoju@niaid.nih.gov 
 
Site Investigator 
Raymond C.W. Perry, MD, MSHS 
Los Angeles County Department of Health Services 
1925 Daly Street, 1st floor 
Los Angeles, CA 90031 
Office Phone: (323) 897-6300 
Fax: (323) 226-5746 
Email: rperry@dhs.lacounty.gov 
 
 
 


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Site Sub-Investigator 
David Oh, MD 
Medical Director, Juvenile Court Health Services 
1925 Daly St., 1st floor 
Los Angeles, CA 90031 
Office Phone: (323) 226 – 8723 
Fax: (323) 226-5746 
Email: doh@dhs.lacounty.gov 
 
Protocol Specialist 
Anne Rinaldi 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC  27701 
Phone: (919) 544-7040, x 11497 
Fax: (919) 544-7261 
E-mail: arinaldi@fhi360.org 
 
Protocol Data Manager 
Lalitha Venkatasubramanian  
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: (919) 544-7040, x 11338 
Fax: (919) 544-7261 
E-mail: lvenkat@fhi360.org 
 
Protocol Statistician  
 
Jeannette Y. Lee, PhD 
Professor, Department of Biostatistics 
University of Arkansas for Medical Sciences 
4301 West Markham Street, #781 
Little Rock, Arkansas 72205 
Phone: (501) 526-6712 
Fax: (501) 526-6729 
E-mail: jylee@uams.edu 
Institutions: 
Los Angeles County Department of Public Health 
Institutional Review Board 
J. Walton Senterfitt, PhD, Chairman  
 
 
 
313 N. Figueroa Street, Room 227 
Los Angeles, CA 90012 
Phone: (213) 250-8639 
Fax: (213) 481-9853 
E-mail: jsenterfitt@ph.lacounty.gov 


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University of Alabama Institutional Review Board for 
Human Use 
University of Alabama at Birmingham 
470 Administration Building 
1530 3rd Avenue South 
Birmingham, AL 35294-0104 
Phone: (205) 934-3789 
Fax: (205) 934-1301 
William Geisler Chlamydia Laboratory 
University of Alabama at Birmingham 
703 19th St South, 242 Zeigler Research Building  
Birmingham, AL 35294-0007 
Phone: (205) 934-4376  
Fax: (205) 975-7764  
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Chlamydia trachomatis infection (chlamydia) is a public health concern. The World Health 
Organization (WHO) estimates there are >105 million new cases of chlamydia annually.1 In the 
U.S. alone, approximately 3 million new cases of chlamydia are reported yearly, and the costs 
associated with their management and complications exceed $2 billion.2 Chlamydia can spread 
to the upper urogenital tract, which can cause significant morbidity. Chlamydia is a leading 
preventable cause of infertility worldwide. Inflammation associated with urogenital chlamydia 
can also increase the risk of acquisition and transmission of human immunodeficiency virus 
(HIV). In many populations, the majority of chlamydia-infected individuals are asymptomatic,3 
and unless the infection is detected through chlamydial testing (screening), their infection may 
be missed and transmitted to others or lead to complications. Chlamydia testing can now be 
performed on non-invasively collected specimens (e.g., urine) using sensitive and specific 
nucleic acid amplification tests (NAATs), which should facilitate screening in nontraditional 
clinical settings (e.g., correctional facilities).  
The Centers of Disease Control and Prevention (CDC) recommends either azithromycin 1 gram 
(gm) by mouth (PO) once or doxycycline 100 milligrams (mg) PO twice daily (BID) for 7 days as 
co-equal therapies for uncomplicated chlamydia.4 This recommendation is supported by a meta-
analysis by Lau et al. of 12 randomized clinical trials of azithromycin versus doxycycline for 
urogenital chlamydial infections, in which microbial cure rates (based on chlamydia culture in 9 
of the 12 trials) were 97% and 98%, respectively, and after pooling the data, the efficacy 
difference for microbial cure between the 2 drugs was not statistically significant.5 However, 
most efficacy studies of therapy for chlamydia relied on measuring outcome (i.e., test of cure) 
using diagnostic tests with lower sensitivity than NAATs (e.g., culture), and therefore may have 
underestimated treatment failure. Other limitations of prior chlamydia treatment studies included 
inability to limit repeat sexual exposure and nonadherence with the multi-dose doxycycline 
regimen. The possibility of higher treatment failure rates was supported by: 1) high observed 
chlamydia recurrence rates 6-9 (around 20% a few months post-therapy), which may represent 
treatment failure or repeat acquisition of chlamydia; 2) an in vitro study reporting differences in 
chlamydia eradication based on whether chlamydia is in an acute or persistent state, with 
doxycycline more effective against the former and azithromycin against the latter;10 and 3) a 
study utilizing chlamydia NAATs demonstrating repeat chlamydia rates of 8% at 10-18 weeks 
following azithromycin treatment in women who denied interval sexual activity.11  
Chlamydia prevalence is high in male and female adolescents,12 especially those entering 
YCFs, where it has been reported in about 3-9% of males and 12-25% of females.13-15 Long-
term gender-segregated YCFs (usual continuous stay >4 weeks) are an ideal setting to study 
the true efficacy of chlamydia treatment because: 1) this population has a high chlamydia 
prevalence; 2) recurrent or new chlamydia can be excluded (due to the institutionalized setting 
without the ability to leave the facility unsupervised and that all participants residing in the facility 


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can be tested and treated at study initiation, minimizing exposure or re-exposure to other 
infected persons; see Section 4 for more detailed information on furloughs); and 3) 
nonadherence to chlamydia treatment can be limited as study medications can be given as 
directly observed therapy. Genotyping of the C. trachomatis major outer membrane protein 
(OmpA) is an additional tool that can be useful in confirming treatment failure. In the clinical 
setting of a gender-segregated YCF and in the absence of exposure to the original infecting 
partner, the finding of identical ompA sequences of the chlamydial strains from the screening 
visit and the repeat chlamydia-positive follow-up visit essentially confirms treatment failure (it 
would be very unlikely that the participant would be exposed to a new partner with the identical 
ompA sequence and there is expected to be no variation in the sequence of a participant’s initial 
and follow-up C. trachomatis isolate with treatment failure).  
Determining the true efficacy of chlamydia treatment regimens and whether a repeat positive 
chlamydia test post-therapy represents chlamydia treatment failure or recurrence is a public 
health priority. Considering the high rate of repeat chlamydia test positivity following therapy, the 
in vitro data suggesting differences in azithromycin versus doxycycline anti-chlamydia activity, 
and clinical data suggesting chlamydia treatment failure in women denying post-therapy sexual 
activity, we conducted a single center, phase III randomized treatment trial of CDC-
recommended azithromycin versus doxycycline regimens for chlamydia in males and females 
residing in long-term YCFs in Los Angeles County.16 Our study design was able to address 
major limitations of prior chlamydia treatment trials of azithromycin versus doxycycline. Of 567 
participants enrolled December 2009 through April 2014, 284 were randomized to azithromycin 
and 283 to doxycycline. After accounting for early discontinuation before first follow-up at Day 
28, 155 (55%) participants in each arm completed first follow-up and comprised the per protocol 
population (65% male and 35% female). The final study visit was completed May 2014. There 
were no treatment failures in the doxycycline arm. In the azithromycin arm, treatment failure 
occurred in five participants (3.2%; 95% CI: 0.4-7.4%). The observed failure rate difference in 
the treatments was 3.2%, with a 90% upper CI of 5.9%, exceeding the predetermined 5% cutoff 
for establishing azithromycin noninferiority. Treatment safety was also evaluated. 
Gastrointestinal symptoms were the most common adverse events (AEs) in each treatment 
arm, reported in <10%. No severe or serious AEs occurred, and no participants were 
discontinued due to an AE.  
The trial was not designed or powered to evaluate azithromycin efficacy in symptomatic 
chlamydia-infected males. However, in a subanalysis of 102 males receiving azithromycin, there 
was a higher frequency of treatment failure in those who reported painful urination compared 
with those who did not (2 of 20 [10.0%] vs. 2 of 82 [2.4%], P=0.172).16  
2.2 
Rationale 
The proposed study is designed to determine the frequency of chlamydia treatment failure in 
males treated with azithromycin who do versus do not have urethral symptoms. Azithromycin is 
FDA approved for use in the U.S. and remains CDC recommended for urogenital chlamydia 
treatment (irrespective of urethral symptoms).4 As discussed above, a subanalysis from the 


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urogenital chlamydia treatment trial performed in YCFs suggested that the azithromycin 
treatment failure rate may be higher in males with urethral symptoms. Also, during the conduct 
of the trial, there were two nongonococcal urethritis (NGU) treatment trials that reported low 
azithromycin cure rates (77% and 86%) in men with symptomatic chlamydia urethritis.17,18 
Taken together, these studies and the recent subanalysis suggest that azithromycin for 
treatment of chlamydia in males with urethral symptoms deserves further study. 
Prior chlamydia treatment studies evaluating azithromycin had one or more major limitations: 1) 
not being able to exclude re-infection or new infection as an explanation for a repeat positive 
chlamydia test post-therapy; 2) not being able to ensure azithromycin is successfully re-dosed in 
those who vomit within one hour of azithromycin administration; and 3) not always confirming 
the chlamydial infection is present at the time the treatment is initiated (some infections may 
have already resolved when patients return for treatment of a positive screening chlamydia 
test). Our study addresses these limitations through: 1) use of a study population where repeat 
infection from an untreated partner is very unlikely (a gender-segregated YCF population where 
subjects are screened and treated for chlamydia upon entry into the facility); 2) repeating 
chlamydial testing at the time treatment is initiated to ensure chlamydial infection is still present; 
3) performing C. trachomatis OmpA genotyping on chlamydia strains in those with repeat 
infections to exclude new infection (and to confirm treatment failure with the same strain); and 4) 
administration of azithromycin as directly observed therapy and then re-dosing the medication if 
vomiting occurs within one hour of initial administration. In addition to evaluating the 
azithromycin treatment failure rate in males based on presence of urethral symptoms, this study 
will also investigate whether the enrollment C. trachomatis OmpA genotype and median 
organism load are associated with treatment failure.  
We hypothesize that the chlamydia treatment failure rate following azithromycin 1 gm 
administration will be significantly higher in males reporting urethral symptoms at the time of 
treatment. We also hypothesize that: 1) the enrollment OmpA genotype will not be associated 
with treatment failure, and 2) however a higher enrollment C. trachomatis organism load will be 
associated with a higher treatment failure rate. 
Because study participant accrual rates at a single Los Angeles (LA) County YCF are too small 
to permit timely answers to the pressing question of frequency of chlamydia treatment failure in 
males following azithromycin administration, we propose to enroll at multiple YCFs in the LA 
County Correctional System, as was done for the prior clinical trial, to address our hypotheses.  
Facilities may be central detention centers, camps and/or placements that are part of the LA 
County YCF system. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
Azithromycin is FDA approved and is a first line recommended antibiotic for chlamydial infection 
treatment. In addition, azithromycin has been in use for many years with an excellent safety 


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profile. The major side effects are gastrointestinal, with nausea, vomiting, abdominal cramping, 
and diarrhea possible. On rare occasions, severe hypersensitivity allergic reactions to 
azithromycin, erythromycin, macrolide and ketolide drugs have been reported. Because 
azithromycin is principally eliminated via the liver, caution is recommended when azithromycin is 
administered to patients with impaired hepatic function (reference: package insert). We do not 
foresee any psychological, social, legal, economic, or any other risks to subjects. 
2.3.2 Known Potential Benefits 
Treatment of chlamydia may prevent complications in males (e.g., epididymitis and infertility) 
and transmission to others. This study may improve our understanding of the efficacy of 
azithromycin for treatment of uncomplicated urogenital chlamydia in males based on whether 
they have urethral symptoms. It may also provide insight into other factors influencing chlamydia 
treatment success.  


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3 
OBJECTIVES 
3.1 
Study Objectives 
• 
The primary objective of this study is to: 
Assess the microbiological efficacy of azithromycin in uncomplicated Chlamydia trachomatis 
infection in males with versus without urethral symptoms in YCFs; in essence, this study will 
assess the frequency of chlamydia treatment failure to azithromycin at the Day 28 follow-up 
visit (Visit 2) in males with urethral symptoms compared to males without urethral 
symptoms. 
• 
The secondary objectives of this study is to: 
Evaluate the association of laboratory findings (enrollment chlamydia load and OmpA 
genotype) and other participant characteristics (demographics, sexual behaviors, etc.) to 
chlamydia treatment failure in males after azithromycin treatment. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
Day 28 Follow-up (Visit 2): 
Microbiological Cure:   
Aptima Combo 2® Assay (AC2) (Hologic, Inc., San Diego, CA, USA) is negative for C. 
trachomatis at the Day 28 follow-up visit (Visit 2). 
Microbiological Failure:   
AC2 is positive for C. trachomatis at the Day 28 follow-up visit (Visit 2) and C. trachomatis 
OmpA genotyping reveals the baseline chlamydial strain and the repeat positive chlamydial 
strain to have the same ompA sequence (i.e., concordant).  
If a participant has discordant ompA sequences and no evidence for mixed strain infection, they 
will be classified as a new infection and not considered a microbiological failure.  
OmpA genotyping is not successfully performed on the baseline or repeat positive chlamydial 
isolate (i.e., there is an insufficient number of ompA copies in the sample to successfully 
amplify), but the participant did not have an unsupervised furlough (i.e., a leave from the YCF) 
prior to the chlamydia testing and the participant denies sexual activity with another person in 
the interval between treatment and repeat testing.  
Unevaluable:   


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Participant did not return for chlamydia testing at the Day 28 follow-up visit (Visit 2) or could not 
be tested for any reason at the Day 28 follow-up visit (Visit 2); this includes participants who are 
withdrawn from the study due to an AE or epididymitis.  
Participant had an AC2 negative for C. trachomatis at the time treatment was initiated 
(enrollment visit).  
Participant vomits the single dose of azithromycin within one hour of administration and is not 
successfully re-dosed with azithromycin within 24 hours of the initial treatment.  
Participant did not complete therapy.  
Participant has an unsupervised furlough. 
Indeterminate Outcome: 
C. trachomatis OmpA genotyping cannot be successfully performed on the repeat chlamydial 
isolate and the participant reports sexual exposure in the interval between treatment and repeat 
testing or the participant had an unsupervised furlough prior to the chlamydia test. These 
participants will be excluded from the primary analysis.       
3.2.2 Secondary Outcome Measures 
The study will evaluate whether demographical characteristics (collected at baseline) and 
clinical parameters (collected at baseline and follow-up visits) predict treatment outcome 
(treatment success versus failure). In addition to the more extensive STD clinical parameter 
assessment that occurs at baseline, clinical parameters will be recorded for all participants at 
each follow-up visit.  
 


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4 
STUDY DESIGN 
The proposed study is a single center (with multiple long-term YCFs) treatment trial of the CDC-
recommended azithromycin regimen (1 gm PO once) for chlamydia in males residing in long-
term gender-segregated YCFs. This study is designed primarily to determine the frequency of 
chlamydia treatment failure following azithromycin in males who do versus do not have urethral 
symptoms of urethral discharge and/or dysuria.  
Males age 12-21 years in good health (based on vital signs and provider’s clinical evaluation 
documented in medical records) who are residing in long-term gender-segregated (not co-ed) 
YCFs (usual stay >3 weeks) and who are identified as chlamydia-infected comprise the study 
population. Only individuals who have a positive chlamydia screening test (i.e., any currently 
approved C. trachomatis NAAT) are enrolled, and those with negative screening tests are 
excluded. Detention facilities categorized as adult detention facilities or those with inmates older 
than age 21 are not appropriate for this protocol. Participants who have gonorrhea co-infection 
or evidence of epididymitis are excluded. Participants known to be HIV-positive will not be 
excluded as there are no data to support differences in efficacy of chlamydia treatment if co-
infected. HIV testing or knowledge of a participant’s HIV status is not required in our protocol but 
will be noted if known.  
Consenting chlamydia-positive participants at the enrollment visit (Visit 1) will be enrolled, asked 
to provide demographic data, to provide a first-catch urine sample (not a mid-stream specimen) 
for repeat chlamydia and gonorrhea testing with AC2, and then will be treated with azithromycin 
1 gm PO single dose given as directly observed. If a participant’s AC2 from the enrollment 
treatment visit returns negative for C. trachomatis, they will be removed from the study. 
Participants whose AC2 at the enrollment treatment visit is positive for C. trachomatis will then 
be asked to provide a first-catch urine sample for repeat chlamydia testing with AC2 at 28 days 
after study drug initiation (i.e., Day 28 follow-up visit,  (Visit 2)). 
Furloughs will usually be supervised by a chaperone (e.g., adult YCF staff), although there may 
be furloughs where there is a brief period without supervision. For each participant enrolled, the 
date of any furloughs will be documented, and it will also be recorded: 1) whether they were 
supervised versus having a period of time without supervision; and 2) who served as the 
supervisor. In the event that a participant temporarily leaves the YCF (furlough) and is not 
supervised by a custody staff chaperone at all times, they will be excluded from the trial. 
For the enrollment and the Day 28 follow-up visit (Visit 2), all participating YCFs will use AC2 for 
chlamydia testing. In addition, two aliquots of each enrollment and follow-up visit urine sample 
will be initially stored at 0-10° C  for OmpA genotyping and measurement of organism load at 
University of Alabama at Birmingham (UAB). All specimens will be shipped to UAB on ice 
packs.  Aliquots from urine samples that test positive for C. trachomatis will undergo OmpA 
genotyping and organism load measurement. Aliquots from urine specimens that test negative 
for C. trachomatis will be discarded upon receipt at UAB. Participants undergo an interview at 


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the enrollment and follow-up visit. Participants who test chlamydia-positive at the follow-up visit 
will be treated and followed per their clinical provider’s routine standard of care.  
Study participation is voluntary. Chlamydia-positive participants choosing not to participate in 
the study will receive treatment per their clinical provider’s routine standard of care. Participants 
who test positive for N. gonorrhoeae or have a clinical diagnosis of epididymitis at enrollment 
will be removed from the study and excluded from analysis. Because participants reside in a 
YCF, they are not allowed to receive monetary or other direct benefits at any study visit.  
The study will be monitored by a data safety monitoring board.  


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Participants will be recruited and followed in long-term YCFs located in Los Angeles County. 
After participants are identified as having urogenital chlamydia through screening with a C. 
trachomatis NAAT at each YCF, they will be approached about potential participation in the 
study. The study will enroll up to 446 males until complete data are obtained on at least 357 
evaluable participants who are assessed at the Day 28 follow-up visit (Visit 2). Offer of 
enrollment will be limited to those who are in custody at the time of receipt of their initial positive 
CT test results and who have court ordered detention in youth camp or have tested positive for 
CT and are likely to remain in custody through treatment and through at least the Day 28 follow-
up visit (Visit 2). Study retention will be improved by inclusion of those subjects with an 
anticipated length of stay at a participating YCF of at least 28 days. 
As the study population is comprised of adolescents and prisoners, additional protections 
pertaining to these populations will be assured according to Institutional Review Board (IRB) 
and Office for Human Research Protections (OHRP) regulations. 
5.1 
Subject Inclusion Criteria 
Participants must meet all of the following inclusion criteria in order to be eligible to participate in 
the study:  
1. Male between the ages of 12 and 21 years 
2. Residing in a long-term gender-segregated (no co-ed) YCF 
3. Diagnosed with urogenital chlamydia as determined by a screening C. trachomatis 
NAAT  
4. Anticipated length of stay at the YCF at the time of enrollment is at least 28 days 
5. Willingness to provide written consent 
6. Willingness to comply with study procedures 
5.2 
Subject Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from study participation: 
1. Diagnosed with gonorrhea as determined by a screening Neisseria gonorrhoeae NAAT 
2. Clinical diagnosis of epididymitis based on review of medical records 
3. Known allergy to azithromycin, erythromycin, any macrolide or ketolide drug 
 


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4. History of liver problems due to use of azithromycin 
5. Having received antimicrobial therapy with activity against C. trachomatis within 21 days 
of the positive chlamydia screening NAAT or in the interval between the positive 
screening NAAT and study enrollment 
6. Any concomitant infection, which requires antimicrobial therapy with activity against C. 
trachomatis 
7. Previously enrolled in this study 
8. Unable to swallow pills 
9. Other exclusion criteria, per clinician judgment, that prohibits subject from enrolling in 
study  
5.3 
Withdrawal Procedures 
5.3.1 Reasons for Withdrawal 
Participants are free to withdraw from participating in the study at any time upon request for any 
reason.  
A study participant will be discontinued from participation in the study if: 
1. The participant requests termination of participation.   
2. Any clinical AE or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant. 
3. The participant tests positive for C. trachomatis prior to enrollment, but tests negative for 
C. trachomatis by repeat AC2 test administered at the enrollment visit after receiving 
study medication. 
4. The participant has an unsupervised furlough after receiving the study medication.  
5. The participant permanently leaves the LA County YCF system prior to completing the 
Day 28 follow-up visit (Visit 2).  
6. The participant is clinically diagnosed with epididymitis during or following enrollment. 
7. The participant received any antimicrobial therapy with activity against C. trachomatis 
other than the study medication between enrollment and the Day 28 follow-up visit (Visit 
2).    


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8. The participant is unable to swallow the study medication and there is not an acceptable 
alternative formulation (i.e. suspension). 
9. A medical condition develops, which in the judgment of the investigator requires that the 
participant be discontinued from further study participation.  
10. The participant vomits within one hour of azithromycin re-administration. 
5.3.2 Handling of Withdrawals 
If participants are discontinued from study participation due to an AE or serious adverse event 
(SAE), including development of epididymitis, then they will be given appropriate care and 
treatment under medical supervision until the condition has resolved or becomes stable. Safety 
data will be collected on any participant who is discontinued from the study because of an AE 
(as specified in Section 9.2.1), SAE or epididymitis.  
If study personnel learn that a participant is still infected upon release from the LA County YCF 
system, study personnel will refer them on for further treatment according to their clinical 
provider’s routine standard of care. Participants who are withdrawn due to permanently leaving 
the LA County YCF system before the Day 28 follow-up visit (Visit 2) but who completed their 
study medication regimen and tolerated without difficulty will not be contacted for repeat 
chlamydia testing (“test of cure” is not routine practice in participants with uncomplicated 
chlamydia who complete their treatment). Participants withdrawn due to detection of gonorrhea 
will be treated with a CDC recommended antibiotic regimen.  
5.3.3 Termination of Study  
There are no anticipated reasons for early termination of the study. This study may be 
terminated by the DMID Sexually Transmitted Infections (STI) Branch at any time. 


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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1 
Study Product Description 
6.1.1 Acquisition 
Azithromycin is FDA approved for use in the U.S. Azithromycin 500 mg tablets will be 
purchased through the University of Southern California (USC) and will only be used for 
investigational purposes.   
6.1.2 Formulation, Packaging, and Labeling 
Azithromycin will be supplied as 500 mg film-coated tablets for oral administration. They will be 
packaged and distributed in routine pharmaceutical bottles, packets, foils, or similar appropriate 
containers. Any medication that is distributed to a study participant will be provided by 
authorized site staff associated with the study. Medication will be placed into appropriate 
packaging with a label that clearly outlines the dose, dosing schedule, and number of pills to 
take.    
6.1.3 Product Storage and Stability 
Azithromycin is stable at room temperature and will be stored at 15-30° C (59-86° F).   
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
A licensed, registered Site Research Pharmacist may be delegated the responsibility of study 
product dispensation. If a Research Pharmacist is not available, a physician, nurse practitioner, 
physician assistant, registered nurse, or other authorized healthcare practitioner, who is a 
member of the clinical study staff, may be delegated to dispense the study product. These 
personnel must be licensed, trained, and must be authorized to dispense the study product 
under state and local rules and regulations.   
Azithromycin will be directly administered orally and can be taken with or without food, but may 
be tolerated better with food. Dosage and preparation will be as follows: 
• 
Azithromycin – A 1 gm single dose is directly administered to participants by authorized 
site staff associated with the study on Day 1. This dose is comprised of two 500 mg 
tablets. A single repeat dose of azithromycin will be allowed if first dose of azithromycin 
is vomited within 1 hour of ingestion.  


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6.3 
Modification of Study Intervention/Investigational Product for 
a Subject 
There will be no modifications of the study medication.   
6.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
The Site Investigator (SI) is responsible for the distribution and disposition of study product, and 
has ultimate responsibility for accountability. The SI may delegate to the site Research 
Pharmacist or designee (e.g., Study Coordinator (SC)) responsibility for study product 
accountability. This designee will be responsible for maintaining complete records and 
documentation of study product receipt, accountability, dispensation, storage conditions, and 
final disposition of the study product. All study products, whether administered or not, must be 
documented on the appropriate study product accountability record or dispensing log. 
Used and unused study product will be retained until monitored and released for disposition, as 
applicable. Upon completion or termination of the study and after the final monitoring visit, any 
remaining unused study product will either be returned or destroyed appropriately at the clinical 
site as per Sponsor requirements and instructions. 
Azithromycin study tablets will be kept in a locked, temperature-controlled storage cabinet at 
USC until transferred to participating YCFs, according to site-approved product transportation 
standard operating procedures (SOPs). The designee will maintain a master product 
accountability log, which will document the receipt of study product from the pharmacy and 
distribution to each participating YCF. Azithromycin study tablets will be stored at the YCFs in 
controlled rooms with limited and secured access only to nurses and approved staff and will be 
segregated from other clinic medication. The study product will be administered by the 
authorized site staff associated with the study. At each YCF, a product accountability log will be 
completed by authorized staff associated with the study and will document receipt of study 
product from USC, dispensation to study participants, and final disposition. The SC will be 
responsible for reconciliation between the master and YCF product accountability logs. All study 
accountability logs will include documentation of the antibiotic’s lot number, expiration date, 
manufacturer name, and storage information. 
6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
All azithromycin 1 gm regimens will be given and directly observed by authorized site staff 
associated with the study and recorded in the participants’ clinic and study chart.  


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6.6 
Concomitant Medications/Treatments 
In the event of an AE or SAE while in the study, concomitant medications (other than antacids 
co-administered with the study medication or antimicrobial therapy with activity against C. 
trachomatis) may be administered as necessary to manage the event. Participants may also 
take any concomitant medication during the study (other than antimicrobial therapy with activity 
against C. trachomatis) for other medical (e.g., asthma, etc.) or psychiatric (e.g. depression, 
etc.) conditions. If the participant vomits within one hour of azithromycin re-administration, they 
will be withdrawn from the study and will be treated per routine standard of care. 


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7 
STUDY SCHEDULE 
Schedule of study visits: 
Visit 1 – Enrollment 
Visit 2 – Day 28 after study drug initiation 
7.1 
Screening  
Male adolescents at participating long-term gender-segregated YCFs receive routine clinical 
sexually transmitted disease (STD) education and screening for chlamydia and gonorrhea by 
NAAT. Subjects whose chlamydia screening test is positive will be approached by the study site 
personnel for determination of interest in participating in the study and to ensure potential 
participants meet all inclusion and exclusion criteria.  
7.2 
Enrollment (Visit 1) 
At enrollment (Visit 1), the study personnel will confirm the participant’s positive chlamydia 
screening test and will review inclusion and exclusion criteria to confirm eligibility. 
At each YCF, study-trained personnel will conduct the IC process. 
After consent is obtained, demographic information, medical history and sexual history will be 
collected. Participants will be asked to provide a first-catch urine specimen (approximately 20-
30 ml) for repeat chlamydia and gonorrhea testing by AC2. Participants who have voided within 
the past hour will be asked to wait or return for urine collection one or more hours since the last 
void. Two aliquots of the urine sample will be stored at 0-10° C until shipped to UAB for OmpA 
genotyping and measurement of organism load. All specimens will be shipped to UAB. Aliquots 
from urine samples that test positive for C. trachomatis will undergo OmpA genotyping and 
organism load measurement. Aliquots from urine specimens that test negative for C. 
trachomatis will be discarded upon receipt at UAB.  
After urine collection is complete, azithromycin 1 gm will be administered to each participant per 
protocol. The participant will be observed taking the study medication and the date and time 
documented. Each participant who has not eaten within the previous 1-2 hours will be offered a 
small snack prior to taking any study medication dose to improve tolerability. A single repeat 
dose of azithromycin will be allowed if the first dose of azithromycin is vomited within 1 hour of 
ingestion. If the participant vomits within 1 hour of re-administration, they will be withdrawn from 
the study and will be treated per routine standard of care. 
The urine specimen aliquoted for AC2 testing will be processed as described in Section 8.2.1, 
labeled with the study number, participant number, visit number, and date and time of collection, 
and sent to the Los Angeles County Department of Public Health (LACDPH) laboratory for 


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testing. The two urine samples aliquoted for OmpA genotyping and organism load determination 
will be refrigerated at the LACDPH laboratory at 0-10° C until shipped to UAB where CT-
negative specimens will be discarded upon receipt. 
Participants will receive counseling on sexual abstinence during the study.  
7.3 
Follow-up Visit (Visit 2) 
Prior to this visit, the study site personnel will review results of the AC2 from the enrollment visit 
and confirm the test was positive for C. trachomatis. Those participants with AC2 negative for C. 
trachomatis at the enrollment visit are removed from the study and will not participate in the 
follow-up visit. Participants who remain eligible will be asked to provide a first-catch urine 
specimen (approximately 20-30 ml) for chlamydia testing by AC2 at 28 days following initiation 
of the study drug regimen. Two aliquots of the urine sample will be stored at 0-10° C until 
shipped to UAB for OmpA genotyping and measurement of organism load. All specimens will be 
shipped to UAB. Aliquots from urine samples that test positive for C. trachomatis will undergo 
OmpA genotyping and organism load measurement. Aliquots from urine specimens that test 
negative for C. trachomatis will be discarded upon receipt at UAB.  
Participants will be queried regarding any possible side effects of the study medication. 
Participants undergo a brief assessment on clinical parameters since enrollment. Per Section 
3.1, the primary objective of the study is assessment of treatment outcome at the Day 28 follow-
up visit (Visit 2). The study will enroll up to 446 males until complete data are obtained on at 
least 357 evaluable participants who are assessed at the Day 28 follow-up visit (Visit 2). 
Participants will be evaluated for the treatment outcome at Visit 2 according to the following 
definitions: 
Microbiological Cure (treatment success):   
AC2 is negative for C. trachomatis at the Day 28 follow-up visit (Visit 2). 
Microbiological Failure (treatment failure):   
• 
AC2 is positive for C. trachomatis at the Day 28 follow-up visit (Visit 2) and C. 
trachomatis OmpA genotyping reveals the baseline chlamydial strain and the repeat 
positive chlamydial strain to have the same ompA sequence (i.e., concordant).  
• 
If a participant has discordant ompA sequences and no evidence for mixed strain 
infection, they will be classified as a new infection and not considered a microbiological 
failure.  
• 
OmpA genotyping is not successfully performed on the baseline or repeat positive 
chlamydial isolate (i.e., there is an insufficient number of ompA copies in the sample to 
successfully amplify), but the participant did not have an unsupervised furlough (i.e., a 


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leave from the YCF) prior to the chlamydia testing and the participant denies sexual 
activity with another person in the interval between treatment and repeat testing.   


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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
• 
Prior to enrollment, results and date of the screening chlamydia and gonorrhea test (part of 
juvenile intake procedure) will be obtained by study site personnel. Only those with a 
positive chlamydia test and negative gonorrhea test will be approached for possible 
enrollment. 
• 
After consent is obtained, additional eligibility criteria will be determined. This includes 
assessing if participant has received antimicrobial therapy with activity against C. 
trachomatis within 21 days of positive chlamydia screening NAAT (or in the interval between 
the positive screening NAAT and study enrollment) and whether participant has epididymitis 
symptoms based on medical records. If a participant is noted to have received antimicrobial 
therapy with activity against C. trachomatis usage within 21 days of screening or has had a 
clinical diagnosis of epididymitis between screening and enrollment, then the participant is 
ineligible.  
• 
Eligible participants will be enrolled and demographic information (race, ethnicity and date of 
birth), STD history, and sexual history will be recorded onto a data collection form at the 
enrollment visit.   
• 
At the end of the enrollment visit, azithromycin 1 gm is administered to each participant and 
ingestion is directly observed and time of administration recorded.  
• 
At the enrollment visit, counseling will be given regarding the importance of sexual 
abstinence during the course of the study. 
• 
Prior to the follow-up visit, AC2 test results from the enrollment visit are reviewed to ensure 
continued eligibility. 
• 
At follow-up visit, medical history including epididymitis symptoms, sexual history including 
sexual activity, information on furloughs, defined AEs (see Section 9.2.1), and SAEs are 
recorded. Results of AC2 testing at each visit are reviewed when they become available and 
are used for classification of treatment outcomes for that visit. 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
Specimens for evaluation are first-catch urine specimens (approximately 20-30 ml) collected at 
enrollment and the follow-up visit (Visit 2) and aliquoted as follows: 


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• 
One urine specimen for AC2 testing which will be performed per the manufacturer’s 
instructionsat the LACDPH laboratory.  
• 
Two urine specimens for OmpA genotyping and measurement of organism load will be 
refrigerated at LACDPH laboratory at 0-10° C until shipped to UAB. All specimens will be 
shipped to UAB. Aliquots from urine specimens that test positive for C. trachomatis will 
undergo OmpA genotyping and measurement of organism load. Aliquots from urine 
specimens that test negative for C. trachomatis will be discarded upon receipt at UAB. 
8.2.2 Special Assays or Procedures 
C. trachomatis OmpA genotyping will be performed on urine specimens at UAB in Dr. Geisler’s 
laboratory under his direct supervision by previously reported methodology.19 CT organism load 
quantification will also be performed on stored urine specimens at Dr. Barbara Van Der Pol’s 
laboratory at UAB using real-time PCR (Cobas® 4800, Roche, Indianapolis, IN, USA). To 
estimate organism load, a C. trachomatis calibrator is run using stock C. trachomatis samples 
with known organism counts to create cycle threshold standard curves for comparison with 
clinical samples, providing reliable and reproducible results that allow for relative quantification 
on a log scale.   
8.2.3 Specimen Preparation, Handling, Storage and Shipment 
8.2.3.1 
Instructions for Specimen Preparation, Handling, and Storage 
Urine specimens should be immediately aliquoted, refrigerated and delivered to the LACDPH 
laboratory per routine courier pick-up schedule. All specimens are to be labeled with the study 
number, participant number, visit number, and date and time of collection. At the LACDPH 
laboratory, AC2 testing will be done per manufacturer’s instructions. The two specimens for 
OmpA genotyping and measurement of organism load will be refrigerated at 0-10° C until 
shipment to UAB. 
8.2.3.2 
Specimen Shipment 
Urine specimens will be shipped on ice packs Monday through Wednesday with overnight 
delivery to the following laboratory address:  
 
 
LaDraka’ Brown 
University of Alabama at Birmingham 
703 19th St South, 242 Zeigler Research Building  
Birmingham, AL 35294-0007 
(205) 996-5382 (phone) 
(205) 975-7764 (fax) 


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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
The primary safety concern of this study is gastrointestinal tolerability of the azithromycin 
regimen, which is the most common AE associated with azithromycin and was the most 
common reported by males in the prior chlamydia treatment trial conducted in the same study 
population.16 Because safety of azithromycin was one of the study objectives of the previous 
chlamydia treatment trial and because no subjects receiving azithromycin withdrew due to an 
AE or experienced an SAE,16 we will not evaluate all AEs as an objective of the current study. 
However, because gastrointestinal tolerability of azithromycin could influence our efficacy 
outcome, we will collect data on reported gastrointestinal symptoms. We will also collect data on 
any SAE. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
Gastrointestinal AEs that occur after study drug administration (Visit 1) and through the Day 28 
follow-up visit (Visit 2) will be recorded on an AE case report form (CRF). AEs which cause a 
participant to discontinue from the study after study drug administration (Visit 1) and through the 
Day 28 follow-up visit (Visit 2) will be recorded on an AE CRF. 
At the follow-up visit (Visit 2), subjects will be queried regarding the occurrence of any 
gastrointestinal side effects since enrollment visit, and any such AEs will be recorded in the 
subject’s research chart and periodically monitored by the SI.   
Adverse Event: An AE is defined as any untoward medical occurrence in a study subject 
administered a pharmaceutical product regardless of its causal relationship to the study 
treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of the study antibiotic regimens. The occurrence of an AE 
may come to the attention of study personnel during study visits and interviews of a study 
recipient presenting for medical care, or upon review by a study monitor.  
AEs related to gastrointestinal reactions, including those not meeting the criteria for SAEs, 
should be captured on the Adverse Event CRF. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis, which would 
include MD, PA, Nurse Practitioner, DO, or DDS), and time of resolution/stabilization of the 
event. AEs must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution.  


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Pre-existing gastrointestinal conditions should be noted at baseline and not reported as an AE. 
However, if it deteriorates on or before the Day 28 follow-up visit (Visit 2), it should be recorded 
as an AE. 
All AEs, as specified in Section 9.2.1, must be graded for severity and relationship to study 
product.  
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Severity of Event: The following guidelines will be used to quantify intensity: 
Gastrointestinal side effects which include nausea, vomiting, abdominal pain, and diarrhea will 
be assessed on a scale of 1 to 3 according to the toxicology table in Appendix B of this protocol.  
Other AEs will be graded using the following general criteria:  
• 
Mild: events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• 
Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe: events interrupt a subject’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
Relationship to Study Products: The SI’s or provider’s assessment of an AE's relationship to 
test article (study drug) is part of the documentation process, but it is not a factor in determining 
what is or is not reported in the study. If there is any doubt as to whether a clinical observation is 
an AE, the event should be reported. All AEs must have their relationship to study product 
assessed using the terms: related or not related. In a clinical trial, the study product must always 
be suspect. To help assess, the following guidelines are used. 
• 
Related – There is a reasonable possibility that the study product caused the AE.  
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 


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9.2.2 Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
• 
Death during the period of protocol defined surveillance 
• 
Life Threatening adverse event (defined as a subject at immediate risk of death at the 
time of the event) 
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization 
during the period of protocol defined surveillance  
• 
Results in a persistent or significant disability/incapacity. 
• 
Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based 
upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
9.2.3 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings 
All positive tests for gonorrhea and chlamydia will be reported within 24 hours to the appropriate 
study personnel by the LACDPH laboratory. In the event of a positive test for gonorrhea, study 
personnel will contact the subject to arrange for treatment and discontinuation from the study. 
Test results will be reported by name to the LA County health department as required by law.    
9.3 
Reporting Procedures 
All AEs specified in Section 9.2.1 including local and systemic reactions not meeting the criteria 
for “serious adverse events” will be captured on Adverse Event CRF. Information to be collected 
includes event description, time of onset, investigator assessment of severity, relationship to 
study product, and time of resolution/stabilization of the event. Adverse events must be 
documented appropriately regardless of relationship.  
As noted in Section 9.2.1, medical conditions that are present at the time the subject is 
screened should be considered as baseline and not reported as an AE.  
All Sexually Transmitted Infection Clinical Trials Group (STI CTG) protocols follow the NIAID 
guidelines for reporting of AEs. The FHI 360 Center for Data Management (CDM) will provide a 
listing of AEs to the Principal Investigator (PI) for review on a monthly basis. The CDM will 


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compile these events in a secure tabular format and forward them to the Protocol Specialist 
(PS) for posting on the study’s SharePoint site within the STI CTG. The Protocol Team has 
access to the specific study SharePoint.   
All serious adverse events will be immediately reported to the SI at each site and to the PI, Dr. 
Geisler. In addition, SAEs should be reported to all pertinent IRBs according to their AE 
reporting guidelines. The CDM, the DMID Clinical Project Manager (CPM), and the PS should 
be notified within 24 hours. 
All AEs that meet the expedited reporting requirements of NIAID are reported to DMID’s 
pharmacovigilance contractor. These events will be referred to as SAEs. DMID’s 
pharmacovigilance contractor will respond to SAEs and will disseminate reports to the DMID 
Medical Monitor, the PI, and the PS. It is the responsibility of each YCF to provide this 
information to the LA County IRB, if required. 
9.3.1 Serious Adverse Events 
All SAEs will be: 
• 
recorded on the appropriate SAE form 
• 
followed through resolution by a study physician 
• 
reviewed by a study physician 
SAEs must be documented from the first study intervention, Study Day 1 through the Day 28 
follow-up visit. 
Any AE that meets a protocol-defined serious criterion must be submitted within 24 hours of 
site awareness on an SAE form to the DMID Pharmacovigilance Group, at the following 
address:  
Medical Affairs/Pharmacovigilance 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS)  
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20814, USA 
SAE Hot Line: 1-800-537-9979 (US)  
SAE FAX Phone Number: 1-800-275-7619 (US)  
SAE Email Address: PVG@dmidcroms.com 
Questions about SAE reporting can be referred to the SAE Hotline (available 24 hours a 
day/7 days a week)  
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible.  


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The DMID medical monitor and CPM will be notified of the SAE by the DMID 
Pharmacovigilance Group. The DMID medical monitor will review and assess the SAE for 
regulatory reporting and potential impact on study subject safety and protocol conduct.  
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event to the DMID 
Pharmacovigilance Group. 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
• 
The SC will transmit copies of all SAEs (including deaths) within the timeframes 
specified above. These events will be entered into an SAE database on a protocol-
specific basis.  
• 
Tabulations of SAEs will be electronically transmitted quarterly to NIAID/DMID with 
hard copies to the PI and to the NIAID Project Officer and to the NIAID Medical 
Monitor. These tabulations will consist of cumulative summaries of SAEs by type of 
event, severity grade, and relationship to study drug therapy.   
• 
Sign-off by the NIAID Medical Monitor, PI, and NIAID Project Officer within 5 working 
days of receipt and returned to complete tracking process. 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension 
of an NIAID-funded Clinical Trial is Reported to the NIAID Program Director 
Responsible for the Contract 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the PI will convene the protocol team and SI by conference call to discuss the 
options. The STI CTG Coordinating Center will inform the NIAID Program Director when studies 
are temporarily or permanently closed. All amendments to protocols must be approved by the 
NIAID. 
9.3.2 Regulatory Reporting for Studies Not Conducted Under DMID-Sponsored 
IND 
As this study will not be conducted under an Investigational New Drug Application (IND), 
MedWatch will be used to report related AEs. DMID will be copied simultaneously when an 
alternate method of reporting is utilized. 
9.3.3 Other Adverse Events 
Not applicable. 


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9.4 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
AEs will be followed until resolution even if this extends beyond the study-reporting period. 
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.   
9.5 
Halting Rules 
Findings that will alert the PI to conduct a safety review will include the number of SAEs overall, 
the number of occurrences of a particular type of SAE, and severe AEs/reactions. If the PI and 
the NIH Medical Monitor determine that the number of SAEs and severe AEs/reactions warrants 
investigation, the PI will immediately request that enrollment be halted until such an 
investigation has been completed. The study enrollment and dosing will be halted for Data and 
Safety Monitoring Board (DSMB) review if two study subjects develop the same study product 
related SAE. 
9.6 
Safety Oversight  
DATA AND SAFETY MONITORING PLAN 
The proposed research does not include any IND or Investigational Device Exemption (IDE). All 
study procedures will be approved by IRBs at each institution, and the site will notify IRBs, 
according to their guidelines, of any AEs that could possibly be attributed to participation in the 
study.  
A DSMB will be created to review this study. The DSMB will be approved by the DMID. 
Meetings of the DSMB will be arranged, facilitated, and documented by CROMS SOCS. The 
initial responsibility of the DSMB will be to approve the initiation of this clinical trial. After this 
approval and annually during the course of the trial, the DSMB responsibilities are to: 
 
Review the research protocol, IC documents, and plans for data and safety monitoring; 
 
Evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, subject recruitment, accrual and retention, subject risk versus benefit, 
 
Performance of the trial site, and other factors that can affect study outcome; 
 
Consider factors external to the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety of 
the subjects or the ethics of the trial; 
 
Review clinical centers performance, make recommendations and assist in the 
resolution of problems reported by the PI; 


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 
Protect the safety of the study subjects; 
 
Report on the safety and progress of the trial; 
 
Review SAEs for increased frequency, although SAEs are not anticipated for this trial; 
 
Make recommendations to the sponsor, the PI, and if required, to the FDA concerning 
continuation, termination or other modifications of the trial based on the observed 
beneficial or adverse effects of the treatment under study; 
 
Ensure the confidentiality of the trial data and the results of monitoring;  
 
Assist the PI by commenting on any problems with study conduct, enrollment, and 
sample size and/or data collection. 
Members will likely include experts in STDs, clinical trials methodology, and biostatistics. 
Members will consist of persons independent of the investigators who have no financial, 
scientific, or other conflict of interest with the trial. Written documentation attesting to absence of 
conflict of interest will be required.   
The first meeting, also known as the organizational meeting, will take place before initiation of 
the study to discuss the protocol, approve the commencement of the study, and to establish the 
charter to monitor the study. The DSMB will meet annually. A final DSMB meeting will take 
place at the close-out of the study. An ad hoc emergency meeting of the DSMB can be called at 
any time by any party should question of subject safety arise. The PI and the SI and/or other 
study team members will be present (via conference call) at each meeting. A simple majority will 
be considered a quorum for DSMB meeting and voting purposes. The DSMB will advise DMID 
of its findings. 


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10 
CLINICAL MONITORING 
10.1 
Site Monitoring Plan 
DMID, the sponsoring agency, or its designee will conduct site-monitoring visits as detailed in 
the clinical monitoring plan and in accordance with DMID policies. Site monitoring is conducted 
to ensure that the human subject protections, study and laboratory procedures, study 
intervention administration, and data collection processes are of high quality and meet sponsor, 
ICH/GCP guidelines and applicable regulations; and that the study is conducted in accordance 
with the protocol, protocol-specific manual of procedures and applicable sponsor SOPs. 
Monitoring visits will include, but are not limited to, inspection of study facilities, review of 
regulatory files, accountability records, CRFs, informed consent forms (ICFs), printouts of 
medical and laboratory reports from the electronic medical records (EMR) system, and protocol 
and GCP compliance. Site monitors will have access to the study site, study personnel, and all 
study documentation according to the DMID-approved site monitoring plan. Study monitors will 
meet with SIs to discuss any problems and actions to be taken and document visit findings and 
discussions. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID. Following a monitoring visit the monitors will disseminate a 
report to the study site, the PI, CDM, CPM, and the PS.   
 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 
Study Hypotheses 
The primary objective of this study is to determine whether there is a significant difference in the 
urogenital chlamydia treatment failure rate in males treated with azithromycin 1 gm who do 
versus do not have urethral symptoms. We hypothesize that the chlamydia treatment failure rate 
will be significantly higher in males with urethral symptoms compared with no symptoms at the 
time of azithromycin treatment. The primary endpoint, treatment failure, will be evaluated at the 
Day 28 follow-up visit (Visit 2). As a secondary endpoint, treatment failure will be evaluated 
based on treatment outcome assessed at the Day 28 follow-up visit (Visit 2) and all non-study 
visits. Secondary objectives of the study are to determine whether the enrollment OmpA 
genotype and the enrollment C. trachomatis organism load are associated with treatment 
failure.  
We hypothesize that OmpA genotype will not be associated with treatment failure, however 
there will be a significantly higher median C. trachomatis organism load in those with treatment 
failure compared to the median load in those without treatment failure.  
11.2 
Sample Size Considerations 
The primary outcome measure is chlamydia treatment failure, and the primary endpoint is 
occurrence of treatment failure at the Day 28 follow-up visit (Visit 2, see Section 3.2.1). The 
sample size calculation is based on data extrapolated from the recent analysis of the NIAID 
sponsored trial since the study would be extended in the same clinical setting and with similar 
clinical procedures. Of the factors that may influence the azithromycin treatment rate, presence 
of urethral symptoms is the primary one of interest based on preliminary findings from the initial 
RCT and findings from the two recent NGU studies. 17,18 Assumptions are that 20% of enrolled 
chlamydia-infected males will have urethral symptoms and azithromycin treatment failures will 
occur in 10% of symptomatic men vs. 2% of asymptomatic men. To detect a significant 
difference at the one-sided 0.05 significance level with power of 0.80 will require a sample size 
of 357 evaluable males, approximately 72 symptomatic and 285 asymptomatic males. 
Assuming 20% of males enrolled will be unevaluable for azithromycin treatment failure (either 
due to leaving the YCF before the Day 28 test-of-cure follow-up visit (Visit 2) or due to having a 
negative enrollment CT test), a total of 446 males will need to be enrolled. In accordance with 
ICH Statistical Guidelines, a one-sided significance level is used for testing. 
11.3 
Planned Interim Analyses (if applicable) 
11.3.1 Safety Review 
The DSMB will receive an annual safety report, prepared by the study statistician with input from 
the PI, with each scheduled DSMB meeting. Because AEs are expected to be uncommon and 


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mostly of mild severity, we have not identified any specific safety criteria for stopping the study 
due to adverse events. Indeed, possible minor side effect of treatment will be monitored as one 
of the study outcomes. However, the DSMB will be independent of study investigators and will 
be able to make recommendations based on the data it receives. In addition, the DSMB will 
receive immediate notification of any SAE that could be related to the study. The DSMB will 
decide whether to halt enrollment.   
The null hypothesis is that the treatment failure rate at the Day 28 follow-up visit (Visit 2) is 10% 
for males with urethral symptoms (discharge and/or dysuria) versus 2% for males without 
urethral symptoms. After half of the study participants have Day 28 follow-up visit (Visit 2) 
outcome data available, an interim analysis will be performed.  
The DSMB will receive an independent presentation of interim results, prepared by the study 
statistician. In preparation for each annual DSMB meeting, we will prepare summary reports of 
recruitment (by site), known outcome events, and any adverse events (including medication 
side effects). In addition, one interim analysis of the primary efficacy outcomes will occur when 
half of subjects have Day 28 follow-up visit (Visit 2) outcome data available using the Lan-
DeMets spending function with an O’Brien-Fleming boundary for the values of the boundaries 
and the associated operating characteristics) to maintain the overall significance level of 0.05 for 
the primary outcome analysis, and to assess the significance of the interim results that emerge 
during the trial. The purpose of the interim analysis is to determine whether a difference in 
efficacy between symptomatic and asymptomatic participants can be established early before 
all participants are enrolled and complete follow-up. 
 
Information Rate 
Reject H0 (one-sided) 
P-value 
0.50 
Z > 2.538 
0.006 
1.00 
Z > 1.662 
0.05 
11.4 
Analysis Population 
The primary analysis population for treatment failure will be the per protocol population, which is 
comprised of subjects who complete therapy and whose failure status can be established at the 
Day 28 follow-up visit (Visit 2). See Section 3.2.1 for definitions of evaluable subjects for the per 
protocol population.  
11.5 
Final Analysis Plan 
For each of the two groups of males (those with versus without urethral symptoms), the binomial 
proportion and its 95% confidence interval will be used to estimate the failure rate. The Mantel-
Haenszel-Cochran test will be used to compare the two groups across YCFs with respect to 
failure rate. To evaluate racial and ethnic group variation with respect to failure rate, a logistic 


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regression analysis will be performed with failure rate as the outcome variable, and with 
symptom status (symptomatic, asymptomatic), race and ethnicity included as covariates. While 
the primary analysis will use the combined urethral symptom variable (discharge and/or 
dysuria), secondary analyses with each urethral symptom will also be performed. 
An ordinal scale will be used to quantify the intensity of each AE (0-None, 1-Mild, 2-Moderate, 
and 3-Severe). The incidence and severity level of AEs will be summarized for all subjects for 
each visit.  
To assess the association between clinical/laboratory parameters and chlamydia treatment 
failure, including OmpA genotype and C. trachomatis organism load, univariate analyses of 
each factor against treatment failure will be conducted using Fisher’s exact test for dichotomous 
factors and the Wilcoxon rank sum test for continuous variables. Those which are statistically 
significant at the 0.10 level will be incorporated into a logistic regression model. Since the 
underlying treatment failure rate is expected to be 0.04 (approximately 13 of 357 evaluable 
subjects), it may be difficult to identify characteristics that are associated with failure rate.   


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and research records for this study, in compliance 
with ICH E6 GCP, Section 4.9 and regulatory and site institutional requirements for the 
protection of confidentiality of subjects. Only the named investigator(s) and research personnel 
assigned to the project will have access to the records. As part of participating in a DMID-
sponsored study, the site will permit authorized representatives of DMID, and the FDA to 
examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.  
All facilities of Los Angeles County Juvenile Probation are included in a “closed” system. EMRs 
can be accessed from all facilities within the system and are available when minors are 
transferred to a different facility. All medical records are stored electronically in a secure 
database. Only authorized staff have access to individual medical records of minors. Medical 
records for persons in the study will be marked indicating they are participating in a study.   
Study specific lab results and certified copies obtained from medical records should not contain 
personal identifying information. All study participants will receive a unique participant number 
that will be recorded on all paper forms. Paper CRFs, consent forms, contact information 
sheets, and other paper data collection instruments will be stored in a locked file cabinet located 
in a secure location at the study site. In addition, all CRFs will be entered into the primary data 
entry and management system at FHI 360 CDM. Only approved site study staff, monitors, the 
FDA and auditors will access these files.   
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the participating site is 
responsible for conducting routine quality assurance (QA) and quality control (QC) activities to 
internally monitor study progress and protocol compliance. The study site will provide direct 
access to all trial related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
FHI 360 CDM, the data-coordinating center for this STI CTG study, will implement quality 
control procedures beginning with the data entry system. All data collected for the trial will be 
thoroughly checked for accuracy, completeness, and adherence to this protocol and GCP. 
Specifically, CDM staff review, double data verification, the DMNet web portal quality control 
tools, and SAS programs check study data and CRFs for errors in procedure and data entry, 
missing and out of range data, and consistency within and across forms. All discrepant data will 
be queried and all discrepancies will be sent to the site for resolution on a regularly scheduled 
basis. Further detail on data quality control can be found in Section 15 of this protocol. 
All staff participating in the study will have received appropriate training in ethical issues 
involving human subject protection and good clinical practice, as required by NIH and their local 
institutions. Training documentation will be kept current and will be maintained on site. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Ethical Standard 
This study will be conducted in full conformity with the Declaration of Helsinki, with the 
International Conference for Harmonization Good Clinical Practice (ICH-GCP) regulations and 
guidelines, or with the Office of Human Research Protection guidelines involving prisoners in 
Research, whichever affords the greater protection to the subject. 
The investigator will also ensure that this study is conducted in full conformity with the principles 
set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997).   
14.2 
Institutional Review Board 
Prior to the enrollment of participants into this trial, the approved protocol and ICF will be 
reviewed and approved by the appropriate ethics review committee or IRB. The responsible 
official for the IRB will sign the IRB letter of approval prior to the start of the trial and a copy will 
be provided to DMID. Any amendments to the protocol or consent materials will also be 
approved by the IRB before they are implemented.  
All participating institutions hold a current U. S. Federal-Wide Assurance issued by OHRP. The 
IRB Federal Wide Assurance number will be provided to DMID.   
Each participating YCF shall comply with all requirements for approval or notification of research 
to be conducted. Research conducted in Los Angeles County shall comply with the legal authority 
that governs the conduct of research within the YCF as specified by the Superior Court, Juvenile 
Division, Chapter 7, available at 
http://www.lacourt.org/courtrules/ui/index.aspx?ch=Chap7&ct=TR&tab=2. As required, upon final 
local IRB approval, a petition to the Superior Court, Juvenile Division must also be submitted and 
approved.   
14.3 
Informed Consent Process 
A written and signed ICF will be obtained from each participant prior to enrollment. The 
participant will be asked to read the consent or may request to have the consent read to him. 
Upon reviewing the consent with the participant, the site study staff will explain the research 
study and answer any questions that may arise. The participants will have the opportunity to 
discuss the study prior to agreeing to participate. The participants will sign the ICF prior to any 
procedures being done specifically for the study.  


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The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the signed ICF will be offered to the participants. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. Decisions regarding a participant’s stay at the 
YCFs will not be adversely affected if a participant declines to participate in this study.   
14.3.1 Informed Consent Process (in Case of a Minor) 
Due to the nature of this research, IRB approval will be sought to enroll minors aged 12 to 17 
years old with a waiver of parental consent. California statute grants minors, ages 12 years or 
older, the right to consent to the diagnosis and treatment of any suspected sexual transmitted 
disease without parental notification or specific parental consent as specified under Family 
Code 6926 (a) [http://law.onecle.com/california/family/6926.html]. Hence, to require parental 
consent to participate in this research study would result in the unintended consequence of a 
violation of the confidentiality protections currently guaranteed to minors under existing laws.  
Since azithromycin is considered a currently accepted first line treatment for chlamydia, as 
recommended in the CDC treatment guidelines, we are requesting that a waiver of parental 
consent to participate in research be granted. Azithromycin is the treatment currently being 
routinely used in this setting for chlamydia treatment (primarily due to the single dose treatment 
option). This study population, which has high chlamydia rates and a study setting which makes 
re-infection unlikely for a sufficiently long time period after treatment to assess treatment 
efficacy, provides a unique opportunity to address an important medical and public health matter 
that would otherwise not be possible to study.     
14.4 
Exclusion of Women, Minorities, and Children (Special 
Populations) 
Per Section 2.1 and 2.2 discussion, only males are enrolled in this study. The demographic and 
ethnic distribution of the study population will be generally reflective of the distribution of STDs 
within the county of each gender-segregated YCF. No male will be excluded based on their 
demographic or ethnic status. The study will include children, adolescents, and adults ages 12 
to 21, which is also an age group with the highest rates of chlamydia. 
14.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. In the event that a participant reports sexual assault, sexual abuse, or non-
consensual sex during the course of data collection, staff will follow standard reporting 
procedures within the juvenile correctional system. No information concerning the study or the 


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data will be released to any unauthorized third party, without prior written approval of the 
sponsor.  
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the Investigator for the participants in this study, 
including printouts of relevant source documentation from the site’s EMR system. The clinical 
study site will permit access to such records. 
Additional precautions will be taken to ensure subject confidentiality, including keeping contact 
information separate from data, using secure computer systems with upgraded virus software, 
keeping study files in locked cabinets, and confirming the identify of persons who are contacted 
over the telephone. 
14.6 
Study Discontinuation 
In the event that the study is discontinued, participants will be notified. Participants will be given 
appropriate care and treatment for chlamydia under medical supervision until the condition has 
resolved or becomes stable.  


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15 
DATA HANDLING AND RECORD KEEPING 
The CDM at FHI 360 serves as the data coordinating center for this STI CTG study. The CDM 
will provide assistance with all aspects of data management which will be carried out in 
accordance with GCP, this protocol, and relevant FHI 360 SOPs.  
The PI will work closely with the CDM and will oversee all aspects of data management.  
15.1 
Data Management Responsibilities 
A detailed data management (DM) plan will be written prior to study initiation. It will be modified 
during the study when significant changes are made to document how data are handled in the 
study. The following is a brief summary of the plan. 
The CDM will format the CRFs based on the content development by the PI. The data manager 
will obtain final approval for the CRFs from the PI and PS. The CDM will produce, distribute, 
maintain, and implement version control for all study CRFs.  
All study participants will be assigned a unique participant identifier that will be required on all 
CRFs, study collection instruments, and files used in analysis. Instructions for assigning site and 
participant numbers will be in the DM plan.  
The CDM will design a study-specific 21 CFR Part 11 compliant clinical database. Error 
specifications will be written in consultation with the statistician to check for accuracy, 
completeness, and consistency on the CRFs. The error specifications will be run regularly and 
will produce ‘discrepancies’ that will be sent to the site electronically.  
Data will be entered and verified through double data entry. Illegible, out-of-range, or other data 
that cannot be entered will be flagged and sent to site study staff for clarification.  
The CDM will provide reports on study progress and will provide in-house and medical coding 
using the most current version of the dictionary of Medical Dictionary for Regulatory Activities 
(MedDRA), specified in the DM plan. All coding will be reviewed by the PI. 
Data freezes will be requested by the statistician for all interim and final reports. Thorough 
cleaning and closure of participant data will be performed at study close-out according to the 
DM plan. Prior to closure all participant data will be complete or accounted for.  
15.2 
Data Capture Methods 
All data will be recorded on CRFs supplied by FHI 360 CDM. Each CRF must be initialed and 
dated by the on-site study staff member who completed it. The SI, however, is responsible for 
the accuracy of data entered on the CRFs and will sign a statement on the final form for each 


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participant stating that he or she has reviewed all CRFs for that participant and certifies that all 
information on them is correct. 
The source documents including signed ICFs, laboratory reports, patient records, and the CRFs 
should be maintained in the participant’s file, and should be available for review during 
monitoring visits. 
The completed CRFs will be emailed to CDM. The original CRFs will be retained at the site in 
the participant's clinic study file. It is imperative that the original and emailed copies match in 
every detail. Therefore no changes may be made on the originals or the emailed copies after 
the CRFs have been submitted to CDM. Before the CRFs are submitted, any change to the data 
should be dated and initialed by the person making the change. Use of opaque correction fluid 
is not permitted. Changes needed after the original has been emailed must be documented with 
requests for Manual Data Discrepancies. 
All CRFs should be stored securely. File cabinets should be locked, maintained, and viewed by 
study staff only. No names or personal identifying information will be contained on the CRFs. 
Access to all CRFs will be restricted to authorized personnel. 
CRFs that have been emailed to CDM will be filed in participant file folders, ordered by 
participant number, in a file cabinet or drawer designated for the study. These CRFs are stored 
in a locked file room at CDM. 
Data will be double-entered by trained data entry staff at the CDM. All data will be stored in FHI 
360 CDM’s 21 CFR Part 11 compliant clinical database.  
Error specifications will be developed to check data for accuracy and completeness. All 
discrepancies with the error specifications will be sent to the site using an Internet-based 
system, which allows for electronic communication between site staff and CDM staff. FHI 360 
CDM staff will update the database based on the SI’s or designee’s written response. SIs or 
designees must keep copies of all discrepancies stapled to the CRFs in the participant’s study 
file.  
15.3 
Types of Data 
Data for this study includes clinical (e.g., epididymitis) and microbiological (e.g., chlamydia test 
results, OmpA genotypes, C. trachomatis organism load) outcomes, demographic (e.g., age and 
race/ethnicity) and clinical parameters (relating to sexual history taken in participants with 
treatment failure), as well as safety data for participants who have been discontinued from the 
study due to an AE or epididymitis.  
15.4 
Timing/Reports 
The CDM will generate monthly and quarterly reports that provide information on data 
submissions, data quality, and information that might be helpful in making operational decisions. 


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The contents and frequency of these reports will be based on the PI’s requests. A detailed 
description of the regular data reports will be provided in the DM plan, which will be finalized 
before the start of data collection. Ad hoc reports will also be generated as needs arise.  
FHI 360 CDM will produce data freezes for the study based on requests from the project leader, 
statistician or PS. Data will be uploaded to a secure web-portal and access to download these 
data will be granted via login and password to individuals listing in the request for a data freeze. 
15.5 
Study Records Retention 
Hard copies of all CRF emails and data discrepancy forms will be kept at FHI 360 CDM for a 
minimum of three years after study completion. Records may not be destroyed without written 
permission from NIAID/DMID. 
Study sites will maintain study records and reports, including, but not limited to, CRFs, source 
documents, ICFs, laboratory test results, and medication inventory records for 3 years after 
study completion. The investigator may transfer custody of the records to another person who 
will accept responsibility for them. Notice of transfer must be given to the sponsor preferably 
before, but no more than ten days after the transfer. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the investigator and FHI 360 CDM when these documents no longer need 
to be retained.  
15.6 
Protocol Deviations 
A protocol deviation (PD) is any noncompliance with the clinical trial protocol or GCP. The 
noncompliance may be either on the part of the subject, the investigator, or the study site staff. 
As a result of deviations, corrective actions will be developed though a plan agreed upon by the 
site and the study PI and then implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within five working days of identification of the PD, or within five working days of the scheduled 
Protocol-required activity. All deviations will be promptly reported to DMID, via DMID-designated 
contractor’s web- or fax-based system. 
All deviations from the Protocol will be addressed in study subject source documents. A 
completed copy of the DMID PD Form will be maintained in the Regulatory File, as well as in the 
subject’s study chart. PDs will be sent to the local IRB/Independent Ethics Committee (IEC) per 
their guidelines. The SI and study personnel are responsible for knowing and adhering to their 
IRB requirements. 


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16 
PUBLICATION POLICY 
Following completion of the study, the investigator is expected to publish the results of this 
research in a scientific journal. The International Committee of Medical Journal Editors (ICMJE) 
member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov20, which is sponsored by the National Library of Medicine. Other biomedical 
journals are considering adopting similar policies. It is the responsibility of DMID to register this 
trial in an acceptable registry. Any clinical trial starting enrollment after 01 July 2005 must be 
registered on or before patient enrollment.   
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from 
this policy. 
Any presentation, abstract, or manuscript will be made available by the Investigator to the STI 
CTG Manuscript Review Committee and DMID for review prior to submission or presentation. 
 
 


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17 
LITERATURE REFERENCES 
1. World Health Organization. Global incidence and prevalence of selected curable 
sexually transmitted infections – 2008. 
http://www.who.int/reproductivehealth/publications/rtis/2008_STI_estimates.pdf 
(accessed November 23, 2015). 
2. Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in 
the United States. Sex Transm Dis. 1999;26:S2-7. 
3. Farley TA, Cohen DA, Elkins W. Asymptomatic sexually transmitted diseases: the case 
for screening. Prev Med 2003;36:502–9.  
4. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment 
Guidelines 2015. MMWR Recomm Rep 2015;64:1-137  
5. Lau C, Qureshi AK. Azithromycin verus doxycyline for genital chlamydial infections. Sex 
Transm Dis. 2002;29:497-502. 
6. Xu F, Schillinger JA, Markowitz LE, et al. Repeat Chlamydia trachomatis infection in 
women: analysis through a surveillance case registry in Washington State, 1993-1998. 
Am J Epidemiol. 2000;152:1164-70. 
7. Kjaer HO, Dimcevski G, Hoff G, et al. Recurrence of urogenital Chlamydia trachomatis 
infection evaluated by mailed samples obtained at home: 24 weeks' prospective follow 
up study. Sex Transm Infect. 2000;76:169-72.  
8. Whittington WL, Kent C, Kissinger P, et al. Determinants of persistent and recurrent 
Chlamydia trachomatis infection in young women: results of a multicenter cohort study. 
Sex Transm Dis. 2001;28:117-23.  
9. Burstein GR, Snyder MH, Conley D, et al. Adolescent chlamydia testing practices and 
diagnosed infections in a large managed care organization. Sex Transm Dis. 
2001;28:477-83.  
10. Reveneau N, Crane DD, Fischer E, Caldwell HD. Bactericidal activity of first-choice 
antibiotics against gamma interferon-induced persistent infection of human epithelial 
cells by Chlamydia trachomatis. Antimicrob Agents Chemother. 2005;49:1787-93. 
11. Golden MR, Whittington WLH, Handsfield HH, et al. Impact of expedited sex partner 
treatment on recurrent or persistent gonorrhea or chlamydial infection. N Eng J Med. 
2005;352:676-85. 
12. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 
2014. Atlanta: U.S. Department of Health and Human Services; 2015. 
13. Mertz KJ, Voigt RA, Hutchins K, et al. Findings from STD screening of adolescents and 
adults entering correctional facilities. Sex Transm Dis. 2002;29:834-9. 
14. Bauer HM, Chartier M, Kessell E, et al. Chlamydia screening of youth and young adults 
in non-clinical settings throughout California. Sex Transm Dis. 2004;31:409-14. 
15. Robertson AA, Thomas CB, St. Lawrence JS, Pack R. Predictors of Infection with 
chlamydia or gonorrhea in incarcerated adolescents. Sex Transm Dis. 2005;32:115-22. 


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16. Geisler WM, Uniyal A, Lee JY, Lensing SY, Johnson S, Perry RCW, Kadrnka CM, 
Kerndt PR. Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis 
Infection. N Eng J Med. 2015;373:2512-21. 
17. Schwebke JR, Rompalo A, Taylor S, Seña AC, Martin DH, Lopez LM, Lensing S, Lee 
JY. Re-evaluating the treatment of nongonococcal urethritis: emphasizing emerging 
pathogens--a randomized clinical trial. Clin Infect Dis. 2011 Jan15;52(2):163-70. 
18. Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR, 
Hakhu NR, Thomas KK, Hughes JP, Jensen NL, Totten PA. Standard treatment 
regimens for nongonococcal urethritis have similar but declining cure rates: a 
randomized controlled trial. Clin Infect Dis. 2013 Apr;56(7):934-42. 
19. Geisler WM, Black CM, Bandea CI, Morrison SG. Chlamydia trachomatis OmpA  
genotyping as a tool for studying the natural history of genital chlamydial infection.  
Sex Transm Inf 2008;84:541-544. 
20. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351:1250-1. 
 


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SUPPLEMENTS/APPENDICES  
 
 
APPENDIX A: SCHEDULE OF EVENTS 
 
 
Procedures 
Visit 1 
(Enrollment) 
Visit 2 (Day 28) 
Written Consent  
X 
 
Assessment of Eligibility Criteria 
X 
 
Review Relevant Medical History 
X 
X 
Review Sexual History/Activity 
X 
X 
Review Demographic Information 
X 
 
Counseling on Sexual Abstinence 
During the Trial 
X 
 
Confirmation of Positive Chlamydia 
X 
 
Assessment of Clinical Parameters 
 
X 
Completion of CRFs 
X 
X 
Review of Concomitant Medications  
X 
X 
Review of Concomitant 
Immunizations 
X 
X 
Administration of Study Medication 
X 
 
Assessment of Adverse Events 
(X) 
X 
Laboratory: 
• First-Catch Urine for AC2  
• CT load determination and CT 
OmpA genotyping 
 
X 
(X) 
 
 
X 
(X) 
 
 
At enrollment, all procedures should be done before study intervention. 
(X) indicates events that occur as needed. 
 
 


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APPENDIX B: TOXICOLOGY TABLES 
 
 
 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Prevents daily activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily activity or 
requires  IV hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 gms/24 
hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or 
watery stools or > 800 
gms/24 hours or 
requires IV hydration 
Abdominal Pain 
Does not interfere with 
activity 
Repeated use of non-
narcotic pain reliever > 
24 hours or interferes 
with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity