Clinical trial NCT04050540
Conditions: HIV Infections HIV/AIDS Neisseria Gonorrheae Infection Chlamydia Trachomatis Infection Syphilis Infection
Keywords: Sexually Transmitted Infections
Sponsor: University of Washington
Start date: 2020-02-05; Completion date: 2022-10-30
Enrollment: 449 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized clinical trial of doxycycline post-exposure prophylaxis (dPEP) to reduce bacterial STIs among Kenyan women taking pre-exposure prophylaxis (PrEP). The overarching goal is to assess the effectiveness of dPEP on incidence of STIs while also balancing acceptability, cost, and impact on tetracycline resistance to inform public health policy. Participants will be randomized to receive dPEP and standard of care or the standard of care only. Questionnaires, focus group discussions, SMS, and in-depth interviews will be used to study acceptability and changes sexual behavior due to dPEP.

Detailed description:
This study is an open-label 1:1 randomized clinical trial of doxycyline PEP to reduce bacterial STIs - Neisseria gonorrhoeae, Chlamydia trachomatis, and T. pallidum (syphilis) - among Kenyan women taking PrEP. Participants will be counseled about the preliminary effectiveness data from IPERGAY, and the potential for resistance in STIs or other bacteria.

The primary study objectives are to 1) evaluate the effectiveness of doxycycline PEP (dPEP) to reduce STI infections in HIV-uninfected Kenyan women taking HIV PrEP; 2) assess the safety, tolerability, and acceptability of dPEP; 3)assess adherence to dPEP; 4) investigate the impact of dPEP on tetracycline resistance in N. gonorrhoeae and C. trachomatis; 5) measure the cost of dPEP and estimate the cost per case averted, budget impact, and affordability

Subjects will be randomized 1:1 to dPEP versus standard of care; randomization will be done in variable-sized blocks and using opaque envelopes opened at randomization. Participants assigned to dPEP will be instructed to take doxycycline 200 mg (two 100mg capsules) orally within 24 hours and up to 72 hours after each condomless sex act (consistent with IPERGAY) as frequently as daily if indicated but not more than once daily.

At Months 0,3,6 and 9, women randomized to dPEP will receive doxycycline, sufficient for up to daily use for 3 months (i.e., 180 capsules). Unused capsules will be counted at each quarterly follow-up visit and additional doxycycline will be provided. Participants will also be offered single- or multi-dose pill carriers for ease of dosing dPEP following exposures. All participants will receive quarterly visits for standard of care prevention services and collection of clinical and behavioral data, for a total of 12 months of follow-up.

Arms: arm 1: Participants assigned to dPEP will be instructed to take doxycycline 200 mg (two 100mg capsules) orally within 24 hours and up to 72 hours after each condomless sex act arm 2: Participants assigned to Standard of Care
Interventions: intervention 1: Doxycycline
Intervention descriptions: intervention 1: 200 mg of doxycycline to be taken orally within 24 hours and up to 72 hours after each condomless sex act

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
 
 
 
PrEP and dPEP: Doxycycline post-exposure prophylaxis for prevention of sexually transmitted 
infections among Kenyan women using HIV pre-exposure prophylaxis 
 
 
 
Funded by: US National Institutes of Health 
 
 
 
 
Version 6.0 
 
May 04, 2021 
 
 
 


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Table of Contents 
 
GLOSSARY ........................................................................................................................................................... 4 
SUMMARY ............................................................................................................................................................ 5 
1.0 
BACKGROUND AND SIGNIFICANCE ............................................................................................... 6 
Background ....................................................................................................................................................... 6 
Rationale ............................................................................................................................................................ 8 
2.0  
STUDY DESIGN ..................................................................................................................................... 9 
3.0 
OBJECTIVES ......................................................................................................................................... 10 
4.0   SELECTION AND ENROLLMENT OF PARTICIPANTS ........................................................................ 11 
Inclusion criteria ............................................................................................................................................. 11 
Exclusion criteria ............................................................................................................................................ 11 
Recruitment ..................................................................................................................................................... 11 
5.0 
 STUDY TREATMENT ......................................................................................................................... 11 
Study product .................................................................................................................................................. 11 
Safety of doxycycline ....................................................................................................................................... 11 
Doxycline dispensing and administration ..................................................................................................... 12 
Concomitant Medications .............................................................................................................................. 12 
HIV pre-exposure prophylaxis (PrEP), STI treatment, and contraceptives ............................................. 12 
Study visits ....................................................................................................................................................... 14 
Instructions for evaluations ........................................................................................................................... 15 
6.0 
ADVERSE EVENTS (AE) AND STUDY MONITORING ............................................................... 20 
Adverse Event Collection Requirements .............................................................................................. 20 
Study Monitoring ............................................................................................................................................ 21 
8.0 
CLINICAL MANAGEMENT ISSUES ................................................................................................. 21 
Toxicity ............................................................................................................................................................. 21 
9.0 
CRITERIA FOR DISCONTINUATION ............................................................................................... 22 
Premature Study Treatment Discontinuation .............................................................................................. 23 
Premature Study Discontinuation ................................................................................................................. 23 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................................... 23 
Outcome measures .......................................................................................................................................... 23 
Statistical power and analysis ........................................................................................................................ 23 
Endpoint adjudication .................................................................................................................................... 25 
12.0 
PARTICIPANTS .................................................................................................................................... 25 
Institutional Review Board (IRB) Review .................................................................................................... 25 


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Study records ................................................................................................................................................... 25 
13.0 
BIOHAZARD CONTAINMENT .......................................................................................................... 27 
 
STUDY TEAM 
 
Kenya Medical Research Institute, Kisumu, Kenya 
 
 
Elizabeth Bukusi, MBChB, PhD, Co-Principal Investigator 
Josephine Odoyo, KRCHN, MPH 
Zachary Kwena, PhD 
Kevin Oware, MA 
 
 
University of Washington, Seattle, WA 
 
Jared Baeten, MD, PhD, Co-Principal Investigator 
Jane Simoni, PhD 
Olusegun Soge, MSc, PhD 
Connie Celum, MD, MPH 
Ruanne Barnabas, MBChB, DPhil 
Deborah Donnell, PhD 
Jenell Stewart, DO, MPH 
Scott McClelland, MD, MPH 
Caitlin Scoville, MPH 
Lauren Violette, MPH 
 
 
University of California San Francisco, San Francisco, CA 
 
Monica Gandhi, MD, MPH 
 
 
National AIDS & STI Control Programme, Kenya Ministry of Health, Nairobi, Kenya 
 
Catherine Ngugi, MBChB 
 


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GLOSSARY  
 
AE 
Adverse event 
AMR 
antimicrobial resistance 
ART 
Antiretroviral therapy  
CDC 
Centers for Disease Control 
COVID-19 
Coronavirus Disease 2019 
CT 
Chlamydia trachomatis 
DAIDS 
Division of AIDS 
DALY 
Disability-adjusted life year 
dPEP 
Doxycycline post-exposure prophylaxis 
DSMB 
Data safety and monitoring board 
FGD 
Focus group discussion 
GEE 
Generalized estimating equations 
HAL 
Hair Analytical Laboratory 
HIV 
Human Immunodeficiency virus 
HSV 
Herpes simplex virus 
IATA 
International Air Transport Association 
ICER 
Incremental cost effectiveness ratio 
IDI 
In-depth interviews 
IH 
Intracranial hypertension 
IRB 
Institutional Review Board 
IPV 
Intimate partner violence 
KEMRI 
Kenya Medical Research Institute 
LARC 
Long acting reversible contraceptives 
LMP 
Last menstrual period 
MOH 
Ministry of Health 
MSM 
Men who have sex with men 
NAAT 
Nucleic acid amplification test  
NASCOP 
National AIDS & STI Control Programme 
NG 
Neisseria gonorrhoeae 
PCR 
Polymerase chain reaction 
PEP 
Post-exposure prophylaxis 
PID 
Pelvic inflammatory disease 
PLWH 
People living with HIV  
PPB ECCT 
Pharmacy and Poisions Board Expert Committee on Clinical Trials 
PPE 
Personal protective equipment 
PrEP 
Pre-exposure prophlaxis 
RPR 
Rapid Plasma Reagin  
SAE 
Serious Adverse Event 
SMS 
Short message service 
SOP 
Standard operating procedures 
STIs 
Sexually transmitted infections 
TDF/FTC 
Tenofovir/Emtricitabine 
tetR 
Tetracycline resistant 
UCSF 
University of California San Fransisco 
UW 
University of Washington 
VCT 
Voluntary counseling and testing 


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SUMMARY 
 
PrEP and dPEP: Doxycycline post-exposure prophylaxis for prevention of sexually transmitted 
infections among Kenyan women using HIV pre-exposure prophylaxis 
 
 
Design:  
Open-label 1:1 randomized clinical trial of doxycyline PEP to reduce bacterial STIs – 
Neisseria gonorrhoeae, Chlamydia trachomatis, and T. pallidum (syphilis) – among 
Kenyan women taking PrEP. We will also use quantitative questionnaires, focus group 
discussions, SMS, and in-depth interviews to study acceptability and changes in sexual 
behavior due to dPEP. 
 
Study Population:  550 Kenyan women aged ³18 and £30 years old taking PrEP randomized to dPEP and 
standard of care vs. standard of care alone 
 
 
Study Sites:  
KEMRI RCTP – Lumumba clinic 
 
Primary Study Objectives:  
1. Evaluate the effectiveness of doxycycline post-exposure prophylaxis (PEP) to reduce STI 
infections in HIV-uninfected Kenyan women taking HIV PrEP 
2. Assess the safety, tolerability, and acceptability of dPEP 
3. Assess adherence to dPEP 
4. Investigate the impact of dPEP on tetracycline resistance in N. gonorrhoeae and C. trachomatis 
5. Measure the cost of dPEP and estimate the cost per case averted, budget impact, and 
affordability. 
 
Approach:  We will conduct an open-label randomized trial of dPEP versus standard of care (STI screening 
and treatment and risk-reduction counseling without dPEP) among 550 women taking PrEP (1:1 
allocation, 223 per arm). Women will be followed for 12 months, with quarterly STI testing, 
treatment, and adherence counseling. STI testing will be blinded. The trial will have >80% power 
to detect a 50% reduction in curable STI incidence, overall and for C. trachomatis alone, the most 
common curable STI. We will use multidisciplinary science to measure a) tolerability and safety of 
dPEP (including effects on sexual behavior), b) acceptability, including challenges and motivators, 
of dPEP use, c) self-reported and objective measures of adherence to dPEP and PrEP, and d) 
occurrence of antimicrobial resistance in N. gonorrhoeae and C. trachomatis isolates using 
rigorous molecular methods. Finally, we will estimate cost per incident STI case and 
complications averted taking into account nonadherence and antimicrobial resistance.  
 


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1.0 
BACKGROUND AND SIGNIFICANCE 
 
Background 
 
African women face disproportionate risk from overlapping epidemics of HIV and bacterial STIs. More 
than two million persons become newly infected with HIV each year, the majority in sub-Saharan Africa.1 
Young African women (under age 30) face disproportionate HIV risk, accounting for more than half of new 
infections on that continent, and with incidence rates that are often double or more than their male age-
mates.2-4 At the same time, African women also face a disproportionate burden of sexually transmitted 
infections (STIs). Globally, the World Health Organization (WHO) estimates that 358 million new cases of four 
curable sexually transmitted infections – three bacterial pathogens (Chlamydia trachomatis, Neisseria 
gonorrhoeae, Treponema pallidum [etiologic cause of syphilis]), plus the parasite Trichomonas vaginalis – are 
acquired worldwide.5-7 Overall, the global burden of STIs is greatest in low- and middle-income countries, and 
the overlapping epidemics of HIV and bacterial STIs in Africa have been recognized since the earliest days of 
the HIV epidemic.8-12 The consequences of bacterial STIs on sexual and reproductive health can be profound: 
pelvic inflammatory disease (PID), chronic pelvic pain, tubal infertility, pregnancy complications, fetal and 
neonatal death, and increased susceptibility to HIV.8,11,13-17 These consequences are overwhelmingly borne by 
women.  
 
PrEP is an effective, recommended, and impactful strategy for HIV prevention. The past decade has 
witnessed monumental strides in the development of highly-effective HIV prevention interventions, including 
antiretroviral pre-exposure prophylaxis (PrEP).18-21 In 2015, WHO issued guidance recommending TDF-
containing PrEP as a prevention option for all persons at high risk for acquiring HIV.22 At the individual level, 
HIV protection is on the order of 90-100% in both women and men when adherence is high, as demonstrated 
by studies measuring tenofovir in blood samples.18,19,23 PrEP adherence and HIV prevention effectiveness 
have been high in open-label demonstration projects among serodiscordant couples, men who have sex with 
men (MSM), and African women (the last a notable contrast to results seen in clinical trials),24-28 hypothesized 
to be a result of offering a strategy with demonstrated safety and effectiveness, and without a placebo.28-32  
 
PrEP is emerging into a global context with unprecedented rates of curable STIs. PrEP reduces incident 
HIV but was not expected to prevent other STIs, including gonorrhea, chlamydia, or syphilis. In high-income 
countries, like the US, the past decade has seen an explosion in the incidence of bacterial STIs among 
MSM.33-35 The scale-up of PrEP in the US and other settings with MSM-predominant epidemics is concurrent 
with this STI rise, although several other major transitions are also occurring, including evidence for 
antiretroviral treatment as prevention (and the undetectable=untransmittable [U=U] campaign)36,37 and 
changing trends in sexual mixing patterns.38,39 HIV and STIs overlap in transmission pathways through sexual 
exposure; thus, it is not surprising that high STI rates are seen among persons who use PrEP. The role of 
PrEP in driving changes in sexual behavior and increased risk for STI acquisition among MSM using PrEP has 
been a source of substantial scientific and public health debate.35,40,41  
 
Post-exposure prophylaxis using the antibiotic doxycycline (dPEP) has been proposed as a novel STI 
prevention strategy. A recent open-label clinical trial among MSM in France (IPERGAY) found a 47% relative 
reduction in new bacterial STIs (specifically, either C. trachomatis, N. gonorrhoeae, or T. pallidum) among 
PrEP users who also took doxycycline following every sexual encounter.42 This reduction was driven by 
reductions in incident C. trachomatis (70% reduction) and T. pallidum infections (73% reduction). The use of 
post-exposure doxycycline to prevent infections is already standard, recommended practice – for example, 
after tick exposure in areas of high Lyme disease prevalence or after flooding in leptospirosis endemic areas; 
doxycycline is also used as malaria pre-exposure prophylaxis for travelers.43-45 The concept of STI prophylaxis 
has a long history (Table 1).42,46,47 Several studies on single dose or monthly antibiotics, among female sex 
workers in Asia and Africa, demonstrated reduced disease burden;48-53 a meta-analysis showed a statistically 
significant impact on incidence of curable STIs in 13 of 14 studies included.47 The IPERGAY results42 were 
striking in the overall reduction in incident STIs, good tolerability and safety, high adherence to dPEP, and 
continuation (both >90%), and without a significant change in sexual behavior in the intervention arm.42 We, 


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like the IPERGAY investigators, think an open-label design among PrEP users (who have already made one 
prevention-oriented decision by taking PrEP) is scientifically most appropriate for this evaluation. Moreover, 
while dPEP may be able to prevent STIs, it carries important risks that could counter its benefits; global debate 
about the balance of these potential risks and benefits requires data to inform policy and implementation.54 
 
The potential emergence of antimicrobial resistance selected by intermittent antibiotic use is an 
important concern for STI PEP. Following the initial study of empiric single-dose antibiotics to reduce 
gonorrhea among sex workers in the Philippines, follow-on studies showed some women (12%) reported self-
prescribing antibiotics for empiric treatment, and high rates of penicillin-resistant N. gonorrhoeae were 
associated with self-prescription.55 Today, multi-drug resistant N. gonorrhoeae is a growing international public 
health issue.56-61 Notably, the IPERGAY results found no reduction in gonorrhea, which was expected given 
the high percentage (56%) of N. gonorrhoeae in Europe are already resistant to tetracyclines.42,62 In Africa, 
antimicrobial resistance data are more sparse, but high prevalence (73-97%) detection of plasmid mediated 
tetracycline-resistant N. gonorrhoeae has been seen, including in our preliminary results from Kenya.56,57,63,64 
Importantly, and in contrast, C. trachomatis has never been reported to express resistance to doxycycline 
worldwide, although Chlamydia suis with tetracycline resistance has been documented in pigs.65-67 Rigorous 
studies are needed to quantify resistance in populations exposed to dPEP and whether dPEP use results in 
additional resistance.  
 
 
Doxycycline PEP could be especially impactful for African women using PrEP. Essentially all global 
conversation about dPEP for STI prevention has been 
directed towards MSM in high-income settings, but the 
benefits might be especially great for women in Africa 
(Table 2). Due to limited availability of etiologic STI 
testing in Africa, few studies have assessed STI risk 
among PrEP-using women in Africa, but we have led 
three pivotal PrEP projects among young African women 
that also contribute some of the only information about 
both STI prevalence and incidence that population (Table 
3).27,68-70 In those studies, we are seeing very high STI 
rates, already comparable to those seen among PrEP-
using MSM in the US. Thus, African women already carry a striking burden of STIs, reflecting likely high rates 
in male partners as well, low ability to negotiate condom use, and great need for prevention. PrEP roll-out 
provides an opportunity to impact both HIV and STI rates in African women. First, the consequences of STIs 
(PID, tubal infertility, complications of pregnancy) are arguably substantially greater than those faced by MSM 
with pharyngeal or rectal STIs. Second, the current standard of care in Africa for STI diagnosis is syndromic 
management, which has very poor sensitivity (<20%) compared to etiologic testing69 and low positive 
predictive value (approx. 50%);71,72 STI PEP could be an inexpensive intervention in settings where testing is 
unavailable or unaffordable. Third, STI prevention is valued – women in PrEP trials report that a prime 
motivation 
for 
their 
participation was access to 
STI 
services.73,74 
Fourth, 
doxycycline is affordable and 
accessible in Africa. Fifth, 
dPEP would be woman-
Table 1. Evidence base for antibiotic prophylaxis for STI prevention 
 
Study 
Population 
Intervention 
Results 
Molina 
et al.  
MSM taking PrEP, 
France (n=232) 
Single-dose 200 mg doxycycline 
after condomless sex vs. no 
medication (open label) 
47% reduction in curable STIs, with greatest reductions for chlamydia 
(70%) and syphilis (73%). Medication was well-tolerated & highly 
acceptable. Limited assessment of resistance in STIs.  
Bolan 
et al.  
 HIV+ MSM with history 
of syphilis, US (n=30) 
100 mg doxycycline daily vs. no 
medication (open label) 
73% reduction in STIs. No self-reported behavior change. 
Steen 
et al. 
Female sex workers, 
multinational 
(meta-analysis of 14 
studies) 
Single dose or monthly antibiotic 
treatment (most used 
azithromycin with ciprofloxacin or 
cefixime) 
40-60% reduction in Neisseria gonorrhoeae & 47-62% reduction in 
Chlamydia trachomatis. No evidence of risk compensation. Few studies 
assessed STI antibiotic resistance.  
Table 2. Potential benefits of dPEP for African women  
 
Benefit 
Rationale  
High need 
High burden of STIs and their consequences  
Bypass 
unavailable 
diagnostics 
Syndromic assessment is standard; etiologic 
testing is rarely done; dPEP could prevent STIs 
that would otherwise go undetected 
Valued 
Women report high value to quality STI services 
Affordable 
Doxycycline available in Africa, at a price that is 
affordable, even for women to self-pay 
Woman-
controlled 
Women control their own STI prevention  
Table 3. High STI rates among young African women in three vanguard PrEP cohorts 
 
 
Chlamydia trachomatis 
Neisseria gonorrhoeae 
MTN-020/ASPIRE (phase III dapivirine ring 
trial) [Baeten, protocol chair] 
Prevalence = 12% 
 
Incidence = 27% per year 
Prevalence = 4% 
 
Incidence = 11% per year 
HPTN 082 (PrEP demonstration project) 
[Celum protocol chair, Baeten, co-I]  
Prevalence = 29% 
 
Incidence = 33% per year 
Prevalence = 8% 
 
Incidence = 14% per year 
POWER (PrEP implementation project) 
[Baeten/Celum, protocol chairs, Bukusi, co-I] 
Prevalence = 26% 
 
Incidence = 53% per year 
Prevalence = 10% 
 
Incidence = 20% per year 
Note: Syphilis prevalence was <2% in these studies, with incidence <5% per year – emphasizing that the burden of STIs 
in this population is cervical infections. HSV-2 seroprevalence was ~50%. 


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controlled, in contrast to other STI prevention strategies like male condoms and partner notification which rely 
on partner participation.  
 
Novel hair testing to assess adherence. Prior work by Dr. Gandhi’s UCSF Hair Analytical Laboratory (HAL), 
has shown that hair antiretroviral levels are a robust biomarker of adherence to treatment and prevention,75-108 
hair levels of TFV and FTC are a long-term metric of exposure to PrEP drugs,76,78,86,96,97,107-110 and doxycycline 
hair level similarly measure exposure over time.111 The HAL uses liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) for testing. The HAL has found high rates of acceptability and feasibility (>95%) of 
collecting hair samples in African and Asian settings,79,80,85,90,103,108 and among U.S. adolescents87 and 
women.100,101,108 Our group has had extensive experience with hair collection across several studies and have 
found it acceptable. In this study, participants will have a hair sample (50-100 strands) collected at each follow 
up. 
 
State-of-the-art assessment of antimicrobial resistance. Over the past 14 years, Dr. Soge has worked 
extensively in the field of gonococcal antimicrobial resistance (AMR). Dr. Soge’s laboratory characterizes 
molecular mechanisms of AMR in N. gonorrhoeae isolates and is a core laboratory for CDC’s national 
gonococcal AMR surveillance project,59,112-114 and he has identified isolates with unique AMR profiles.115-117 
Preliminary results from frozen STI+ endocervical swab samples from Kenyan women in our Partners PrEP 
Study19 (i.e., *not* using dPEP) were tested for tetracycline resistance using the molecular methods: 50 with N. 
gonorrhoeae and 10 with C. trachomatis. Detection of tetracycline-resistance was high for N. gonorrhoeae 
(tet(M)=48/50, 96%), suggesting resistance may be at a ceiling in the community already, prior to dPEP use, 
but also that dPEP may not be effective against N. gonorrhoeae. No C. trachomatis organisms had resistance 
(tet(C)=0/10, 0%). 
 
Mathematical modeling and costing studies help to define optimal models for PrEP delivery. Led by Dr. 
Barnabas, we have used costing methods and mathematical modeling to address key questions related to how 
to best deliver PrEP. For serodiscordant couples.118 we found the cost of PrEP per infection averted is 
significantly offset by future savings in ART costs, especially time-limited PrEP – used prior to and early after 
ART initiation by an HIV infected partner, when risk is highest.119 These results were a key basis for designing 
our “PrEP as a bridge to ART” strategy in the Partners Demonstration Project. Second, we used methods for 
development of clinical prediction rules to derive a risk scoring tool for couples.120 Our work has been a model 
for risk scores for other populations121 – for example, the VOICE score for women at risk121 – and for 
programmatic prioritization of subpopulations for PrEP.28,122,123 Third, micro-costing, time and motion work, and 
mathematical modeling have helped define the annual cost of PrEP (~US$100) for the Kenya Ministry of 
Health.124,125  
 
PrEP scale-up among African women is expanding rapidly. In 2017, Kenya was one of the first countries in the 
world to launch a national PrEP program, making PrEP available through the Kenya Ministry of Health to all 
populations at risk for HIV. Early data, including our own, show that there is substantial demand and many 
women are able to adhere to and persist with PrEP. We hypothesize that women engaging in PrEP are a 
priority population for prevention of curable STIs, given high incidence, interest in longitudinal preventative 
services, and willingness to take pills for prevention. Nesting into Kenya’s national PrEP services, we propose 
an evaluation of the benefits, risks, and costs of dPEP among women, in the first trial of this intervention for 
this population. While dPEP has potential as a novel prevention strategy, we recognize important potential 
risks, including safety, acceptability, adherence, and selection of antibiotic resistance, any/all of which may 
overwhelm its benefits. The results of this work will have immediate implications for the global epidemic of STIs 
and for PrEP programs. 
 
Rationale 
 
Rationale for a randomized trial 
We posit that there is equipoise to conduct a randomized evaluation at this time: while dPEP has demonstrated 
efficacy in one trial, it was relatively small in size and limited to MSM in France. Data specific to women are 
needed to know if dPEP is effective and safe. Additionally, the potential disadvantages of dPEP, such as 


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antibiotic resistance, tolerability, and low adherence, have not been studied in women and justify the use of a 
control arm. Randomization in 1:1 allocation will be the most efficient for evaluating efficacy of dPEP and 
balancing unknown acceptability. Like IPERGAY, we propose that an open-label design allows for optimal 
evaluation of effectiveness. First, the open-label model directly addresses questions about acceptability, as 
participants will react to dPEP itself, not a blinded, potentially placebo version. Second, an open-label design is 
likely to result in greater (and more realistic) adherence – in placebo-controlled trials of PrEP among African 
women, adherence was very low, and subsequent qualitative studies found concerns about receiving a 
placebo as a principal reason, with greater adherence in recent open-label studies.122,126-128 Third, the design 
will directly allow assessment of sexual behavior changes (i.e., disinhibition) related to STI PEP, which could 
overwhelm dPEP’s benefits and is only assessable if subjects know if they are actually taking active dPEP. 
 
Rationale for evaluation of Kenyan women 
Prior work on doxycycline post-exposure prophylaxis against bacterial STIs has only been studied in men 
having sex with men in France. The proposed study will focus on enrolling women, who far disproportionately 
bear the global burden of morbidity and mortality from sexually transmitted infections. Thus, this work will 
ensure that this potential prevention strategy is justly studied in women, and a specific focus on women is 
justified.  
 
Doxycycline safety 
Safety was a key consideration for the development and evaluation of PrEP, and similarly should be part of STI 
PEP assessment. Data evaluating PrEP use in women at all stages of reproductive planning (desiring 
pregnancy, achieving pregnancy, and in combination with hormonal contraceptives) have demonstrated safety, 
much of it from our team.28,31,129-132 Doxycycline is well-tolerated and recent data show strong safety when used 
by women, including in early pregnancy.44 Early data on tetracycline found bone and tooth effects when used 
in late pregnancy, and cautions were extended to the entire tetracycline class, including doxycycline, despite 
lack of drug-specific data.133 Tetracyclines are safe for use in lactating women but are not recommended at 
high doses or extended courses due to theoretical risk of infant tooth discoloration.134,135 Expert opinion is now 
calling for reconsideration of doxycycline use in pregnant and lactating populations given significant differences 
between doxycycline and tetracycline and lack of evidence showing adverse events with doxycycline exposure 
in pregnant women.136 For women who do not desire pregnancy, there are no estrogen/progesterone and 
doxycycline drug-drug interactions, so doxycycline use will not alter hormonal contraceptive effectiveness.132
 
 
Potential for drug resistance  
The potential for inducing drug-resistant STIs is an important concern for dPEP. On one hand, antibiotic 
resistance to tetracycline-class drugs is selected relatively easily in some bacteria (e.g., N. gonorrhoeae); on 
the other hand, resistance for N. gonorrhoeae is common globally, making additional resistance selection 
unlikely, but other organisms (e.g., C. trachomatis) have never demonstrated resistance. Syphilis (Treponema 
pallidum) is at risk of developing tetracycline resistance; however, we anticipate very low rates (<2%) of 
syphilis and thus in this population the risk of developing resistance is very low. Moreover, if dPEP is 
successful in preventing STIs, resistance may not occur, as selection should only happen if infection is 
established and replication occurs despite antibiotic pressure. Overall, we feel there are both important knowns 
and unknowns that define equipoise for this question, and we have put strong strategies in place to manage 
and mitigate potential resistance risks. 
 
2.0  
STUDY DESIGN 
 
Overview: The overarching goal is to assess the effectiveness of dPEP on incidence of STIs while also 
balancing acceptability, cost, and impact on tetracycline resistance to inform public health policy. Participants 
will be randomized 1:1, and will receive dPEP and standard of care or the standard of care only. Participants 
will be counseled about the preliminary effectiveness data from IPERGAY, and the potential for resistance in 
STIs or other bacteria.  
 


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Randomization and follow-up: Participants will be randomized 1:1 to dPEP versus standard of care; 
randomization will be done in variable-sized blocks and using an online randomization system. Participants 
assigned to dPEP will be instructed to take doxycycline 200 mg (two 100mg capsules) orally within 24 hours 
and up to 72 hours after each condomless sex act (consistent with IPERGAY) as frequently as daily if indicated 
but not more than once daily. At Months 0/3/6/9, women randomized to dPEP will receive doxycycline, 
sufficient for nearly daily use for 3 months (i.e., 100 capsules). Unused capsules will be counted at each follow-
up visit (Months 3/6/9/12) and additional doxycycline will be given to total 180 capsules if needed. The 
medication, doxycycline hyclate, will be purchased from a quality-controlled supplier and with consultation by 
the Kenya National AIDS and STI Control Programme. Participants will also be offered single- or multi-dose pill 
carriers for ease of dosing dPEP following exposures. All participants will receive quarterly visits for standard of 
care prevention services and collection of clinical and behavioral data, for a total of 12 months of follow-up.  
 
Study visits: Every 3 months, study visits will include STI screening, behavioral questionnaires, hair sample 
collection, and swab collection for archived samples. Women may return to the study clinic for interim visits for 
any reason and will undergo STI testing and treatment if STI symptoms are present. Participants with a new 
STI diagnosis will return for prompt treatment, provided on-site. Laboratory testing will be conducted by staff 
blinded to randomization assignment, and STIs will be reviewed by an Endpoint Adjudication Committee 
blinded to treatment arm. All participants diagnosed with an STI will either receive same day treatment or 
return to the research clinic for treatment, using WHO/Kenya standard therapies, avoiding doxycycline options, 
and a second visit two weeks following completion of STI treatment will be done for test of cure; this mitigates 
potential risk to participants and the community if resistance is selected. 
 
Study population: This study will enroll approximately 550 Kenyan women aged ³18 and £30 years old taking 
PrEP.  PrEP use is an eligibility criterion for enrollment because we hypothesize that women engaging in PrEP 
are a priority population for prevention of curable STIs, given high incidence, interest in longitudinal 
preventative services, and willingness to take pills for prevention. Aligning with Kenya’s national PrEP services, 
we propose an evaluation of the benefits, risks, and costs of dPEP among women, in the first trial of this 
intervention for this population. However, participants may opt to stop PrEP use at any time during the study 
without affecting their involvement in the study. Any HIV-uninfected participants who subsequently seroconvert 
will be managed clinically by the study site according to local practice (appropriate counseling, clinical 
evaluation and immediate linkage to clinical and psychosocial services). These participants will also be 
retained in the study unless they choose to discontinue study participation.  
 
3.0 
   
OBJECTIVES 
 
Primary Study Objectives:  
1) Evaluate the effectiveness of doxycycline post-exposure prophylaxis (dPEP) to reduce STI infections in 
HIV-uninfected Kenyan women taking HIV PrEP. 
2) Assess the safety, tolerability, and acceptability of dPEP. 
3) Assess adherence to dPEP. 
4) Investigate the impact of dPEP on development of tetracycline resistance in N. gonorrheae and C. 
trachomatis. 
5) Measure the cost of dPEP and estimate the cost per case averted, budget impact, and affordability. 
 
Secondary Study Objectives: 
1) Investigate the impact of dPEP on development molecular markers of tetracycline resistance (tetR) in 
Mycoplasma genitalium and nasopharyngeal carriers of S. aureus and other commensal organisms 
from swabs from all participants, stored for future evaluation. 
2) Assess the effect of dPEP on the vaginal microbiome through quantitative polymerase chain reaction 
(PCR) and Lactobacillus and other flora resistance to doxycycline from vaginal swabs from all 
participants, stored for future evaluation. 


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3) Assess the effect of indole producing organisms in the vaginal microbiome on the effect of dPEP from 
quarterly vaginal swabs from all participants, stored for future evaluation. 
 
4.0   SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
Inclusion criteria 
1) Willing and able to give written informed consent 
2) Age ≥18 years and 30 years old 
3) Female sex at birth  
4) HIV-seronegative, according to national HIV testing algorithm 
5) Has a current prescription for PrEP, according to the national guidelines of Kenya. 
 
Exclusion criteria 
1) Pregnant 
2) Breastfeeding a child 
3) Allergy to tetracycline class 
4) Current medications which may impact doxycycline metabolism or that are contraindicated with 
doxycycline, as per the prescribing information. These include systemic retinoids, barbiturates, 
carbamazepine, phenytoin, and warfarin.  
5) Recent use of prolonged (more than 14 day course) antibiotics in the month prior to enrollment 
6) Active, clinically significant medical or psychiatric conditions that would interfere with study 
participation, at the discretion of the site investigator or designee. 
 
Recruitment  
We will be recruiting from clinics providing PrEP in Kisumu. The experienced community outreach team at the 
study site in Kisumu employs community-based mobilization strategies, including engaging community health 
volunteers, gate keepers, peer to peer mobilization, youth peer providers and ambassador models, use of 
printed and electronic IEC materials, social media (WhatsApp and Facebook), radio talk shows in English, 
Kiswahili, and the local DhoLuo dialects, active participation in local social events for information sharing, and 
partnering with learning institutions to give health talks and to provide study related information. Careful 
attention to confidentiality is made in the recruitment process and potential participants are never approached 
individually in group settings or public messaging. Recruitment messaging is screened for cultural and 
community acceptability to reduce risk of stigma for study participants. Potential particiapants who are not 
interested in the study or do not meet study eligibility crtieria, may be notified of alternative studies that they 
may be elgibile for, or provided information about where to access standard of care for HIV prevention and STI 
services.  
 
5.0 
 STUDY TREATMENT  
 
Study product  
Generic immediate release doxcycyline hyclate 100 mg capsules will be provided by the study to participants 
randomized to open-label dPEP. Doxycycline hyclate is a standard formulation of doxycycline that is widely 
avaible internationally and FDA approved for the treatment of a number of infectious conditions. Doxycycline 
hyclate will be purchased from a quality-controlled supplier in Kenya and with consultation by the Kenya 
National AIDS and STI Control Programme. To ensure consistency and quality of the doxycycline, we will use 
the same formulation of drug for the duration of the trial and work with suppliers able to provide evidence of 
following good manufacturing practices.  
 
Safety of doxycycline  
Doxycycline is an antibiotic that can be used for prolonged periods of several months in the treatment of acne 
or in the prevention of malaria. The tolerance of repeated-dose of doxycycline in this 12-month study should 
therefore be acceptable.  


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The possible side effects of doxycycline are137,138 
• Gastrointestinal: nausea, diarrhea, epigastric pain, and candidiasis 
• Esophageal disorders: dysphagia, pill esophagitis, and rarely esophageal ulceration. Risk for 
esophageal irritation can be reduced by taking doxycycline capsules at least one hour before bedtime 
(to avoid being lying down with doxycycline intake) at a meal with a glass of water (100 ml).  
• Skin reactions including maculopapular, erythematous, and photosensitivity skin reactions.  
 
Doxycline dispensing and administration 
Doxycycline will be dispensed at each 3 month visit or in shorter intervals per patient prefence, with additional 
dispensation as needed to replace lost medication or provide additional medication when needed. Capsules 
should be stored at room temperature (59-86o F) to the extent feasible. Participants will be instructed to take 2 
pills of 100 mg doxycycline as soon as possible after condomless sexual contact, ideally within 24 hours but no 
later than 72 hours after sex. Participants will be instructed to take a maximum of 200 mg in a 24 hour period. 
For particiants reporting sexual encounters on consecutive days, 200 mg of doxycycline will be recommended 
to be taken until within 24 (and up to 72) hours after the last sexual encounter. Study staff will instruct 
participants on procedures for replacement of lost medication. Doxycycline may be taken on an empty stomach 
or with food, and it is advised to take with a large glass of water and to taking at least 60 minutes before bed to 
reduce risk of esophageal irritation. All participants randomized to dPEP will be advised on potential side 
effects and their management. 
 
Concomitant Medications  
Participants randomized to dPEP should report current and new medications to the study team to ensure no 
concern for drug interactions with doxycycline. The prescribing information for doxycycline hyclate should be 
reviewed to ensure no potential for drug interactions. Medications that interact with doxycycline include 
barbiturates, carbamazapine, phenytoin, methoxyflurane, acitretin, isotretinoin, and warfarin. Additionally, 
medications that interact with doxycycline when taken at the same time include medictions that contain cations 
(iron, aluminum, calcium, or magnesium) and ideally should be separated 2 hours before or after doxycycline. 
 
HIV pre-exposure prophylaxis (PrEP), STI treatment, and contraceptives 
PrEP, STI treatment, and contraceptives will be provided by the study and will be accessible through the study 
clinic or local MOH following the standard of care. All participants diagnosed with an STI will return to the 
research clinic for treatment, using WHO/Kenya standard therapies, avoiding doxycycline options (i.e. 
azithromycin, ceftritriaxone, penicillin G benzathine, and metronidazole as needed by pathogen diagnosed) 
and a second visit two weeks following completion of STI treatment will be done for test of cure; this mitigates 
potential risk to participants and the community if resistance is selected. The study site will provide 
contraceptives and PrEP.  
 


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6.0  
STUDY PROCEDURES 
Study Visit Month 
S 
0 
3 
6 
9 
12 
 
Study coordination 
 
Obtain informed consent 
X 
 
 
 
 
 
Screen for inclusion/exclusion 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Collect updated contact information 
X 
X 
X 
X 
X 
X 
Reimbursement 
X 
X 
X 
X 
X 
X 
 
Questionnaires 
 
Demographic information 
X 
X 
 
 
 
 
Behavioral questionnaire 
 
X 
 
X 
 
X 
HIV risk perception 
 
X 
X 
X 
X 
X 
Social Harms and IPV 
 
X 
X 
X 
X 
X 
Sexual behavior and exposure history 
 
X 
X 
X 
X 
X 
PrEP adherence  
 
X 
X 
X 
X 
X 
dPEP adherence (timeline follow-back calendar) 
 
 
X a 
X a 
X a 
X a 
Fertility intention  
 
X 
X 
X 
X 
X 
Quality of Life 
 
X 
X 
X 
X 
X 
 
Clinical Study Care 
 
Medication review 
X 
X 
X 
X 
X 
X 
General symptom assessment 
 
X 
X 
X 
X 
X 
WHO pregnancy checklist 
X 
 
X 
X 
X 
X 
STI symptom assessment 
X 
X 
X 
X 
X 
X 
Supply condoms 
X 
X 
X 
X 
X 
X 
Contraception counseling and provision/referral 
X 
X 
X 
X 
X 
X 
Risk reduction counseling 
X 
X 
X 
X 
X 
X 
dPEP pill count and refill 
 
 
Xa 
X a 
X a 
X a 
 
Sample collection  
 
HIV testing (rapid test) 
X 
 
X 
X 
X 
X 
Urine pregnancy testing (rapid test) 
X b 
X 
X b 
X b 
X b 
X b 
Syphilis testing (serum RPR) 
 
X 
X 
X 
X 
X 
Creatinine (serum) 
 
Xb 
Xb 
Xb 
Xb 
Xb 
CT/NG testing and resistance (endocervical swabs) c 
 
X 
X 
X 
X 
X 
Hair PrEP and doxycycline drug levels 
 
X 
X  
X 
X  
X 
Trichomonas screening (vaginal swab) 
 
X 
X 
X 
X 
X 
 
Archive 
 
Microbiome testing (vaginal swab) 
 
X 
X 
X 
X 
X 
BV testing (vaginal swab) 
 
X 
X 
X 
X 
X 
M. genitalium screening and resistance (endocervical swab) 
 
X 
X 
X 
X 
X 
Pharyngeal microbiome and resistance (pharyngeal swab) 
 
X 
 
 
 
X 
Rectal microbiome and resistance (rectal swab) 
 
 
 
 
 
X 
Rectal CT screening (rectal swab) 
 
 
 
 
 
X 
HSV-2 testing (serum) 
 
X 
 
 
 
X 
Y chromosome DNA testing (vaginal swab) 
 
X 
X 
X 
X 
X 
S. aureus resistance screening (nasal swab) 
 
X 
X 
X 
X 
X 
S = screening visit 
aintervention arm only 
bif clinically indicated 
cParticipants diagnosed with an STI will return 2 weeks following treatment for test of cure 


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Study visits  
 
Specific study procedures are detailed in Table 6.0. 
Visits will take place at enrollment and quarterly 
thereafter, up to 12 months; we will conduct tracing 
in the case of missed visits to ensure high retention. 
Interim visits may take place if participants present 
for diagnosis and treatment of STI, 2 weeks 
following treatment of STI for test of cure, for 
subgroup 
of 
participants 
completing 
in-depth 
interviews or focus group discussions, or for 
evaluation of possible doxycycline associated 
adverse events. All participants will receive quarterly 
visits for standard of care prevention services and 
collection of clinical and behavioral data, for a total 
of 12 months of follow-up. We will use electronic 
data capture (CommCare or REDCap). 
 
 
Screening Visit:  
Potential participants will be screened for inclusion and exclusion criteria, and those eligible will be invited 
to enroll. Oral and written informed consent will be obtained for screening and enrollment. Participants 
will be screened for symptoms of STIs, and treated empirically if symptomatic (per Kenyan National 
Guidelines). Participants will also be screened for HIV, following national HIV testing guidelines, at the 
screening visit; pregnancy will be assessed using the WHO pregnancy checklist and a pregnancy test will 
be done if indicated by the checklist. 
 
Enrollment Visit:  
The enrollment visit will be as soon as the following day after the screening visit and as late as 28 days 
following the screening visit. Demographic, behavioral, and facilitators/barriers information will be 
collected at enrollment. Pelvic exam for baseline STI testing and sample storage will be done at 
enrollment and prevalent STIs will be treated. Full medical review of symptoms and medications, blood 
testing (up to 20mL of blood drawn), hair sample, and nasal and pharyngeal swabs will be collected at 
enrollment. Pregnancy testing will be completed for all women at enrollment.  
 
Randomization :  
Participants will be randomized 1:1 to dPEP versus standard of care; randomization will be done in 
variable-sized blocks and using a computer based randomization system, following consent and eligibility 
confirmation.   
 
Quarterly visits after enrollment : 
dPEP (intervention) group: Study visits, every 3 months, will include questionnaires, risk reduction 
counseling, PrEP and dPEP adherence counseling (including dPEP dosing information), pill count and 
refill, a blood draw (up to 10mL), HIV testing, a hair clipping, a nasal swab, a pharyngeal swab, (rectal 
swabs at the final visit only), WHO pregnancy check list (with possible urine pregnancy test), and vaginal 
and endocervical swabs. All participants will receive reimbursement for attending quarterly study visits. 
 
Standard of care (control) group: Study visits, every 3 months, will include questionnaires, risk reduction 
counseling, PrEP adherence counseling, a blood draw (up to 10mL), HIV testing, a hair clipping, a nasal 
swab, a pharyngeal swab, (rectal swabs at the final visit only), WHO pregnancy check list (with possible 
urine pregnancy test), and vaginal and endocervical swabs. All participants will receive reimbursement for 
attending quarterly study visits. 
 
Figure 1. Study visit protocol 
 
 
 


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Any participant with a positive STI result will be asked to return two weeks after treatment for a test of 
cure visit, which will include STI testing.  
 
Unscheduled interim visits:  
Women may return to the study clinic for interim visits for any reason and will undergo STI testing and 
treatment if STI symptoms are present. Additionally, participants concerned about any adverse event 
from the study drug are invited to return to study provider evaluation and management.  
 
Mobile phone SMS (optional – for participants with a phone and who agree to optional SMS component):  
Participants who consent to SMS will receive weekly SMS sent in English, Kiswahili, or DhoLuo as part 
of a momentary ecological assessment of adherence and exposure. Exposure, i.e. have penatrative 
sex without a condom,  will be referred to by a code word for added privacy: for example, “How many 
times did you dance this week?” If a participant is in the dPEP arm, they will receive a second SMS, 
“How many times did you take dPEP this week?” Encrypted transmission, password protection to open 
the surveys, and immediate deletion permit sensitive data to be collected safely.  
 
 
Time and motion observations (length of quarterly visit): 
A small random subset of participants in the dPEP group will be asked to give verbal consent to have 
their study visit observed by a study team member to record time needed to provide this intervention.  
 
Instructions for evaluations  
 
 
Questionnaires and Interviews: 
 
Quantitative data: Demographic and behavioral surveys will be administered at each visit, using 
questions we have used extensively in our prior trials (Table 4). All participants will complete 
questionnaires each study visit on faciliators and barriers to STI prevention and dPEP. 
 
 
Sexual behavior questionnaire: Participants will be asked to complete a sexual behavior questionnaire 
using timeline follow-back calendar to record number and type of sexual contacts (including condom 
use) in the past 3 months at each study visit. 
 
Fertility intention survey and counseling: All participants will receive quarterly evaluation of fertility 
intention by survey with counseling on contraceptive options and supply contraceptives if desired by 
participant. For participants not using long acting reversible contraceptives (LARC), we will use the 
WHO pregnancy checklist to screen for possible pregnancy, and if pregnancy can not be ruled out with 
the pregnancy checklist, a urine pregnancy test will be completed. 
 
Table 4. Data collection on facilitators of and barriers to STI prevention and dPEP: all have been used in our prior work (Table 5) 
Structural                           E=enrollment, Q=quarterly, 6=Month 6 visit, 12=Month 12 visit 
Socioeconomic status 
employment (E), income (E), presence of running water/electricity/metal roof/TV/phone at home (WAMI) (E) 
Individual 
Demographic factors 
age (E), race/ethnicity/tribe (E), educational level (E), time spent traveling for clinic visit (E, 6, 12) 
Alcohol use 
# days in last week consumed, rapid alcohol problems screen–quantity frequency (RAPS4-QF) (E, 6, 12)  
Depression 
somatization, obsessive-compulsive, interpersonal sensitivity, anxiety and depression (HSCL-D) (E, 6, 12)  
HIV risk perception 
what do you think is your risk of getting (giving) HIV and STIs from (to) your partner? (4 item Likert scale) (E, Q)  
Prevention strategies 
perceived dPEP efficacy for STI prevention, perceived PrEP efficacy for HIV prevention (E, Q)  
Social Harms 
physical, social and economic social harms (E, Q)  
Dyadic 
Relationship 
partnership status (E, Q), social support (Modified UNC-Duke) (E, 6, 12), partner violence (E, Q)  
Sexual behavior 
sex frequency (E, Q), condom use (E, Q), sexual power (E, 6, 12)  
Fertility intention 
# of children (E), current pregnancy (E, Q), goal # of children and fertility intentions (E, Q)  
HIV stigma 
scale plus disclosure (e.g., serodiscordant status) to family/friends/religious leaders & adverse effects (E, 6, 12)  


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Qualitative work: Qualitative data collection will include serial in-depth individual interviews (n=40) and 
focus group discussions (n=4 focus groups; approximately 48 participants) in the dPEP arm. Semi-
structured qualitative interview guides will provide a general structure for discussion.139 The serial IDI 
will be conducted soon after enrollment to get information on early experiences and at Months 6 and 12 
after participants have experienced dPEP; focus group discussions will be conducted at study exit. 
Interviews will be conducted using the participants’ preferred language (English, Dholuo, or Kiswahili). 
Participants will be sampled for the qualitative interviews to include diversity in relationship status, 
adherence level, and participation in transactional sex (stratified-purposive sampling).  
 
 
Clinical study care 
Review of current medications: All participants will have current medications reviewed at screening for 
possible drug interaction with doxycycline. At subsequent quarterly visits, participants randomized to 
dPEP will have current medications reviewed and any new medications will be assessed for possible 
drug interactions. 
 
STI symptom screen: Participants will be asked about current STI symptoms including vaginal 
discomfort, dysuria, rash, vaginal discharge, rectal pain, pelvic pain, and genital lesions. 
 
General symptom assessement: At each visit, participants in both study arms will be asked about 
possible 
doxycycline 
side 
effects, 
including 
esophagitis, 
rash, 
gastrointestinal 
symptoms, 
photosensitivity, headache, and vaginal yeast infection. Control arm participants will be asked about 
these symptoms to establish a comparator for non-specific symptoms which can occur in the absence 
of doxycycline.  
 
Risk reduction counseling: At each visit, staff will counsel participants about risk reduction and HIV and 
STI prevention and will receive condoms. 
 
Pill count and dPEP adherence assessment: Participants assigned to dPEP will be asked to bring their 
doxycycline blister packs in at each visit for a pill count. While completing the timeline follow-back 
calendar to record sexual exposures will be asked when dPEP was taken and if each sex act were 
covered by dPEP in the past 3 months. 
 
PrEP adherence assessment and counseling: All participants will receive quarterly PrEP adherence 
assessment (Likert scale) and adherence counseling. 
 
Sample collection and outcome measures:  
Primary study outcome STI testing: A pelvic exam will be performed at enrollment and all quarterly 
study visits for all participants. Participants will be encouraged to coordinate study visits prior to or 
following menstration and participants presenting during menstration will be rescheduled to return the 
following week. 
 
N. gonorrhoeae/C. trachomatis: The enrollment visit and quarterly follow-up visits, every 3 
months, will include a provider-collected endocervical swab to test for STIs. We have focused 
on cervical STIs since they are the source of morbidity in women and rectal/pharyngeal STI 
testing is not standard of care in Africa. We will collect a rectal swab on the final visit to further 
open inquiry into the theoretical role of rectal STIs among the participants. Women may return 
to the study clinic for interim visits for any reason and will undergo STI testing and treatment if 
STI symptoms are present. Participants with a new STI diagnosis will return for prompt 
treatment, provided on-site. Testing will be conducted by staff blinded to randomization 
assignment, and STIs will be reviewed by an Endpoint Adjudication Committee blinded to 
treatment arm. All participants diagnosed with an STI will be treated same day or return to the 
research clinic for treatment, using WHO/Kenya standard therapies, avoiding doxycycline 


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options, and a second visit two weeks following completion of STI treatment will be done for test 
of cure; this mitigates potential risk to participants and the community if resistance is selected.  
 
RPR: The enrollment visit and quarterly follow-up visits, every 3 months, will include blood 
sample collection for syphilis serology testing (incident infection=4-fold rise in non-treponemal 
RPR titer). RPR should be conducted at least 30 days after last syphilis treatment and must be 
interpreted in the context of prior test results and current symptoms and exposure history. The 
need for treatment will be based on the clinical assessment of the site investigator based on the 
serological data and clinical findings. All syphilis endpoints will determined by the Endpoint 
Adjucation committee. 
 
Adherence: All participants will receive 1:1 adherence counselling for PrEP with individualized barrier 
identification and problem-solving assistance. Participants in the dPEP arm will receive 1:1 adherence 
counselling as well as reminders on their daily PrEP tablet bottle as a reminder to assess personal 
need for dPEP on that day.140,141 A number of measures will be used to determine adherence: 
Self-reported measures: Sexual behavior and, for those assigned to the dPEP arm, pill-taking 
behavior, will be measured by timeline follow-back calendar142 at each follow-up visit to assess 
exposures and dPEP use. Because dPEP is an exposure-driven medication, adherence is 
dependent on use of dPEP following each exposure.  
 
Real-time behavioral measurement (optional): Weekly SMS will be sent in English, KiSwahili or 
DhoLuo as part of a momentary ecological assessment of adherence and exposure. Exposure 
(i.e., condomless sex) will be referred to by a code word for added privacy: for example, “How 
many times did you dance [have sex without a condom] this week?” [If in the dPEP arm] “How 
many times did you take dPEP this week?” We have used real-time SMS data collection in 
multiple prior PrEP studies in Kenya;32,143,144 cell phones are very common in Kenya 
(outnumbering citizens). Encrypted transmission, password protection to open the surveys, and 
immediate deletion permit sensitive data to be collected safely. Studies of PrEP demonstrated 
that there was improved comfort with reporting sexual behavior via SMS, though objective 
adherence measures were far superior to self-report.144  
 
Objective measures: Hair drug levels will be measured to more objectively assess quantitative 
exposures to dPEP, for several analyses. Hair samples (50-100 strands) will be collected 
following consent to collection and confirmed eligibility for hair collection (occipital hair >0.5cm 
in length with absence of bleaching) from all participants at each visit (Months 0/3/6/9/12). Hair 
samples will be shipped to Dr. Monica Gandhi’s UCSF Hair Analytical Laboratory (HAL). 
 
Costing: We will estimate incremental costs, incurred and averted, of adding dPEP to PrEP. Activity-
based micro-costing studies will be conducted to estimate costs incurred (e.g., start-up activities, 
training, and dPEP) and costs averted (diagnosis and treatment of symptomatic STIs, infertility, and 
adverse pregnancy outcomes). Also, cost data will be collected from the study budget, published 
reports, and the literature. Time and motion studies will be conducted by observing visits and staff time 
spent on dPEP initiation and adherence counseling, and clinical procedures. The total time required for 
the intervention will be estimated, adjusting for time spent on research activities. Using these data, the 
time and costs for dPEP will be estimated. We will adapt compartmental, dynamic models to simulate 
STI transmission in Kisumu; and capture the movement of individuals from the susceptible 
state/compartment to infected, treated, and return to the susceptible compartment as well as capturing 
the proportion of individuals moving from infected to PID and further possible complications (infertility, 
ectopic pregnancy, and fetal complications).8,13,145-148 The model is stratified for age, sexual activity, 
marital status, and adherence to dPEP. The model is continuous for age and time and can capture 
trends in time (e.g., changes in STI testing) and age (e.g., behavior change with age). Each STI 
(chlamydia, gonorrhea, and syphilis) will be modeled separately with STI specific parameters and a 
model structure to capture the distinct epidemiology and biology of that specific STI. STI acquisition is a 


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function of dPEP use by susceptible individuals who are taking PrEP, contact with an infectious 
partner(s), coital frequency, STI transmission probability, and condom use. dPEP impacts the force of 
infection (l), thus modifying STI incidence. The model will be parameterized using demographic, 
behavioral, intervention uptake, and mobility data collected during the study and from the literature. The 
model will be validated using independent estimates of STI/HIV prevalence and incidence from these 
populations. To estimate DALYs associated with STIs, we will use the 2013 Global Burden of Diseases 
estimates for infectious diseases and abdominopelvic complications, including female infertility in a low-
and-middle-income setting.149,150 The model is programmed in Matlab (MathWorks, Natick, MA). 
 
Archived Samples: 
 
Stored Nasal and pharyngeal swabs: We will archive (at -80C) samples at each visit for potential future 
testing, including for studies of commensal Staphylococcus aureus and other organisms detection and 
resistance. 
 
Stored vaginal swabs: We will archive (at -80C) samples at each visit for potential future testing, 
including vaginal Gram stain and vaginal swabs for studies of bacterial vaginosis, vaginal microbiome 
and detection of Y chromosome DNA (as a biologic marker of unprotected intercourse for sensitivity 
analysis of exposure in adherence and objective marker of potential change in sexual behavior). 
 
Stored endocervical swabs: We will archive (at -80C) samples at each visit for potential future testing, 
including residual sample from NAAT testing (for testing for Mycoplasma genitalium, an emerging STI, 
which should not be prevented by dPEP. 
 
Stored rectal swabs: We will archive (at -80C) samples at the final visit for potential future testing, 
including C. trachomatis infection or colonization of the rectum from NAAT testing and microbiome 
resistance patterns.  
 
Stored serum: We will archive (at -80C) samples at Enrollment and Month 12 for potential future 
testing, including HSV-2 testing.  
 
Laboratory Procedures: 
 
Samples will be tested within Kenya where feasible. Any samples that require specialized testing will be 
shipped to the University of Washington (UW) or the University of California San Fransisco (UCSF) as 
described below.  
 
STI testing: 
All STI screening will be completed with point-of-care testing in Kisumu, Kenya (Cepheid GeneXpert) or 
in the laboratory of Dr. McClelland in Mombasa, Kenya, operating with external quality assurance for 
>10 years (Aptima Combo 2). Endocervical swabs will be tested for C. trachomatis and N. gonorrhoeae 
by nucleic acid amplification testing (NAAT). Vaginal swabs will be tested for Trichomonas vaginalis by 
NAAT (Cepheid GeneXpert). 
 
Hair testing: 
Hair samples from all participants will be collected. A subset will be shipped from University of 
Washington to Dr. Monica Gandhi’s University of California San Francisco Hair Analytical Laboratory 
(HAL), which uniquely is able to do the required testing. Samples from three groups of participants will 
be analyzed: 1) 50 participants in the dPEP arm for dPEP and PrEP drug levels at each follow-up visit 
(Months 3/6/9/12),  2) any dPEP arm participant with incident STI, and 3) 10% all-comers (n=50) at 
enrollment (Month 0) and 5% of control arm at follow up visits (Months 3/6/9/12). Samples will be 
analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) testing for doxycycline 
hair level exposure over time (by hair segments representing weekly exposures) and hair levels of TFV 


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and FTC are a long-term metric of exposure to PrEP. Testing of additional samples may be done if the 
results of this pre-defined sample warrant.  
 
Resistance testing:  
Endocervical samples – baseline and follow-up, from both arms – with a positive NAAT result for C. 
trachomatis and/or N. gonorrhoeae, will be shipped to the University of Washington laboratory of Dr. 
Soge for molecular testing. DNA will be purified from residual endocervical NAAT samples and 
endocervical swabs using the High Pure DNA Kit (Roche Diagnostics, Indianapolis, IN). The impact of 
dPEP on C. trachomatis and N. gonorrhoeae resistance will be measured by comparing the overall 
rates of doxycycline-resistant events occurring in the dPEP arm to rates in the control arm, at baseline 
and separately during follow-up adjusted for medical factors that confound the dPEP-resistance risk 
relationship.  
 
Testing for tetracycline resistance among N. gonorrheae  
Molecular characterization of N. gonorrhoeae will include strain typing using the internationally 
frequently used N. gonorrhoeae multiantigen sequencing typing (NG-MAST) system;151 and detection of 
tetR including plasmid-mediated tet(M); and chromosomally-mediated resistance determinants: mtrR 
(A39T, G45D, G45S, −35delA and −10insTT), rpsJ (V57M), porB (G120K, A121D/N), and pilQ (E666K) 
by PCR and sequencing.152 Well-characterized positive control strains and negative controls will be 
included in all PCR assays.153 The detection of the plasmid-encoded tet(M) gene and/or tetR genetic 
resistance determinants is indicative of phenotypic resistance to tetracycline, doxycycline, and 
minocycline.153 All samples with the same NG-MAST sequence types will be further differentiated by 
multilocus sequence typing. Whole genome sequencing will be conducted on endocervical swabs from 
patients with the same strain types and tetR genotypes and rigorous investigation of single nucleotide 
polymorphisms associated with novel resistance mechanisms will be performed.154  
 
Molecular testing for tetracycline resistance genes in C. trachomatis  
The horizontally acquired genomic island which encodes the tetracycline efflux pump tet(C), found in 
Chlamydia suis strains from pig,155 is the only reported tetR determinant in the genus Chlamydia.156 
Therefore, we will screen for the presence of tet(C) in all samples found to be positive for C. 
trachomatis; and use real-time PCR assays for genotyping of C. trachomatis including 
Lymphogranuloma venereum (LGV) associated L-serovars L1, L2, or L3.157-159 
 
Management and treatment of gonorrhea, chlamydia, and syphilis  
Participants found to have a diagnosis of chlamydia, gonorrhea, or syphilis will be contacted by study staff or 
provider regarding their new diagnosis. Participants will be offered prompt treatment (single dose azithromycin 
tablets, ceftriaxone intramuscularly (IM) once + single dose azithromycin tablets, benzathine penicillin G 
intramuscularly once) at the study clinic. Participants with clinical concern for complicated STI (i.e., PID) will be 
offered prolonged treatment (single dose IM ceftriaxone and 2 week course of azithromycin and 
metronidazole). All participants treated for a bacterial STI will then return to the study clinic two weeks following 
STI treatment for test of cure. Participants will be encouraged to tell partners to also be treated per Kenya 
guidelines. Should patients develop signs or symptoms of an STI at any point in the study they may come to 
the study clinic for additional testing (including for trichomonas, BV, or candida infections) and treatment if 
needed. Study visits will include testing for Trichomonas vaginalis for prompt treatment with Metronidazole if 
detected. Flexible clinic scheduling is available to promote high rates of follow-up. We will make efforts to 
retain all subjects at their final visit to meet standard of care in addition to ensuring complete information is 
available for the entire population and to ensure all have a final STI assessment.  
 
Pregnancy, breastfeeding, and HIV seroconversion 
 
Management of dPEP with contraceptives and pregnancy:  
Contraception will be offered on-site but will not be required for study participation. The effectiveness of 
contraceptives or dPEP will not change with concomitant use. Women will be counseled on current 
Kenyan guidelines, which do not recommend use of doxycycline in pregnant women and participants 


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will stop dPEP should pregnancy occur. Women, who are not using LARC, will be screened for possible 
pregnancy at each quarterly visit using the WHO pregnancy checklist and if needed a urine pregnancy 
test will be conducted. Women will be counseled on current Kenyan guidelines, which do not 
recommend use of doxycycline in pregnant women and participants will stop dPEP should pregnancy 
occur; women can resume dPEP when no longer pregnant or breastfeeding. Pregnancies will be 
followed to completion. Any babies born to participants during the trial period will be passively followed 
for 1 year following their birth. Participants who deliver a baby during the trial will be asked to return for 
scheduled, quarterly study visits for a total of up to 12 months even though dPEP will be stopped if they 
are in the dPEP group. Additionally, they will be asked about the health of their baby at each study visit 
with continuation of questionnaire on health of their infant for first 12 months of infant’s life. 
Breastfeeding will be an exclusion criterion for the trial, to limit exposure prior to demonstration of 
effectiveness; doxycycline is generally felt to be safe at standard doses in lactating women, although no 
formal declaration of safety exists for this population. Doxycycline is well-tolerated and recent data 
emphasize a strong safety profile when used by women, including in early pregnancy. Early data on 
safety of tetracycline found potential adverse effects when used in late pregnancy (specifically, bone 
and tooth effects), and cautions were extended to the entire tetracycline class, including doxycycline, 
despite lack of drug-specific data.133,136 Expert opinion is now calling for reconsideration of doxycycline 
use in pregnancy given significant differences between doxycycline and tetracycline and lack of 
evidence showing adverse events with doxycycline exposure in pregnant women.  
 
Management of PrEP with contraceptives and pregnancy:  
PrEP and contraception have no adverse drug-drug interactions. If an HIV negative woman becomes 
pregnant while taking PrEP, careful consideration should be given to whether use of PrEP should be 
continued, taking into account the potential increased risk of HIV infection during pregnancy and post-
partum period. Available human and animal data suggest that tenofovir-based PrEP does not increase 
the risk of major birth defects overall compared to the background rate, although well-controlled data 
are limited. Current US FDA and Kenya labeling for tenofovir disoproxil fumarate/emtricitabine is 
permissive to the use of PrEP in pregnancy. If a woman becomes pregnant or breastfeeding during the 
proposed study, PrEP will continue to be offered, as is consistent with Kenya national guidelines.  
 
Management of HIV-seroconversion: 
If a participant tests HIV positive, study clinicians will follow national guidelines for discontinuing PrEP. 
Women will be referred to the nearest HIV care clinic for initiation of antiretroviral therapy. Women who 
seroconvert will remain in the study through the end of their scheduled follow-up and will be permitted 
to continue taking dPEP, if they are assigned to the intervention group. 
 
6.0 ADVERSE EVENTS (AE) AND STUDY MONITORING 
 
Adverse Event Collection Requirements 
The following AEs will be recorded on data collection forms: 
• 
All AEs that are attributed to doxycycline in the opinion of the site investigator 
• 
All AEs meeting SAE definition  
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
 
 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above 


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All AEs that are recorded must have their severity graded. To grade AEs, sites should refer to the most recent 
version of Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table).  
 
 
Study Monitoring 
 
Study Team Monitoring 
The study team will monitor the conduct of the study through monthly summary reports of arms of 
accrual, and baseline characteristics and quarterly reports of data pooled over treatment arms of data 
completeness, specimen collection, and AEs. The study team will review individual participant-level 
safety data frequently to assess the relation of all reported AEs to study treatment. On a monthly basis, 
the study team will review by-arm summaries of premature study discontinuations and premature study 
treatment discontinuations (and reasons) and AEs.  
 
DSMB  
An independent data safety and monitoring board (DSMB) will be convened for this study with 
expertise, from US and Kenya, in STIs, PrEP, and antimicrobial resistance and a biostatistician. The 
purpose of the DSMB is to monitor the study for operational futility, social harms, and efficacy. The 
DSMB will evaluate the progress of the project, including periodic assessments of accrual, retention, 
safety, performance and variation of the project sites, and other factors that can affect project 
implementation. The DSMB will review the study after approximately 1/3 and 2/3 of follow-up time with 
pre-specified stopping rules for efficacy and futility in terms of the efficacy of dPEP in reducing the 
incidence of gonorrhea, chlamydia, and syphilis overall, and the ability of the study to meet its 
objectives. The DSMB will be charged with the decision to recommend stopping the study early if 
interim analyses demonstrate emergent differences between the trial arms meeting pre-defined levels 
of significance, significant change in rate of doxycycline-resistant STIs, or significant safety concerns. 
At a minimum, a DSMB meeting must have a quorum of the chair and 2 other members. One or more 
Formal Interim Analysis meetings will be held to review data relating to relative effects of treatment on 
the trial outcomes. Patient safety and quality of trial conduct will also be reviewed at these meetings. 
The study team will carefully document any participants who become excluded from intervention arm 
due to pregnancy or are breastfeeding for careful review by DSMB for any adverse events to pregnant 
women or infants. Discussion of formal interim monitoring guidelines will be discussed at the 
Organizational Meeting prior to trial initiation. The DMSB will also consider factors external to the 
project when relevant information becomes available, such as policy changes or scientific 
developments that may have an impact on project implementation, safety, and integration of dPEP in 
the STI and HIV care clinics. 
 
The DSMB will conduct reviews every six month and convene by teleconference. Open reports 
containing accrual and retention rates, participant characteristics, serious adverse events, and social 
harms, will be sent to the protocol team and DSMB members the week prior to the DSMB meeting. 
Only the DSMB members and the unblinded biostatistician will receive password-protected closed 
reports of STI endpoints by randomization arm. The DSMB membership will be restricted to individuals 
free of apparent significant conflicts of interest. The source of these conflicts may be financial, scientific 
or regulatory in nature. Reports from all reviews will be provided for submission to overseeing 
IRBs/ECs. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
Toxicity  


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Only toxicities related to study medications provided through the study will be considered in the toxicity 
management section.  
 
Grade 1 or 2 
Participants who develop Grade 1 or 2 toxicity (per DAIDS toxicity table) felt to be related to 
doxycycyline may continue study treatment at the discretion of the site investigator with close follow-up. 
If a participant chooses to discontinue study treatment, the site should notify the study protocol team 
within 7 days.These participants will remain on study, off study treatment and have all evaluations 
performed per current clinical guidelines.  
 
Grade 3  
• 
Participants who develop a Grade 3 toxicity thought by the site investigator to be related to study 
drug should have study drug held. The participant should be reevaluated weekly until the AE 
returns to Grade ≤2, at which time study drug may be reintroduced at the discretion of the site 
investigator in consultation with the protocol team.  
• 
Participants experiencing Grade 3 toxicity requiring permanent discontinuation of study drug should 
be followed weekly until resolution of the toxicity. Participants will have premature study treatment 
discontinuation evaluations performed as noted in most up to date clinical evidence. These 
participants will remain on study, off study treatment and have all evaluations performed per current 
clinical guidelines.  
  
Grade 4 
• 
Participants who develop a Grade 4 symptomatic toxicity felt to be related to the study drug will 
have study drug permanently discontinued.  
• 
Participants experiencing Grade 4 toxicity requiring permanent discontinuation of study drug should 
be followed weekly until resolution of the AE or return to baseline. These participants will remain on 
study, off study treatment and have all evaluations performed per current clinical guidelines.  
 
Specific Management of Toxicities Related to Study-Provided Drugs 
 
Possible intracranial hypertension (IH)  
Participants taking doxycycline who report new or worsening headaches, visual changes or vision loss 
should have doxycycline temporarily discontinued and an evaluated for IH, including a fundoscopic 
exam to look for papilledema. If IH is rule out or an alternate etiology identified, doxycycline may be 
restarted, at the discretion of the site investigator. 
 
Skin erythema 
Increased photosensivity is a known possible side effect of doxycycline. Doxycycline should be 
discontinued if skin erythema develops and may reinstituted when resolved at the discretion of the site 
investigation. Any SAE should lead to permanent discontinuation of doxycycline. 
 
Fixed drug eruption 
Suspected fixed drug eruption should be evaluated for possible etiologies – if a doxycycline fixed drug 
eruption is suspected, doxycycline should be stopped.  
 
Allergic reactions 
Doxycycline should be discontinued permanently if an allergic reaction is suspected. These participants 
will remain on study, off study treatment and have all evaluations performed per current clinical 
guidelines.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 


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Premature Study Treatment Discontinuation 
• 
Requirement for prohibited concomitant medications or other contraindication to doxycycline 
• 
Occurrence of an AE requiring discontinuation of doxycycline  
• 
Request by participant to terminate study treatment 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in the toxicity 
section of the protocol 
• 
Requirement for chronic tetracycline use ( >14 days)  
• 
Pregnancy 
• 
Breastfeeding 
 
Participants who stop dPEP should be continued on study, off dPEP with continued evaluations. The 
reason for doxycycline discontinuation should be recorded.  
 
Premature Study Discontinuation 
• 
Request by the participant to withdraw 
• 
Participant judged by the investigator to be at significant risk of failing to comply with the provisions 
of the protocol as to cause harm to self or seriously interfere with the validity of the study results 
• 
At the discretion of the IRB/EC, funder, or Office for Human Research Protections (OHRP) 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
Outcome measures  
 
Primary outcome: Combined incidence of N. gonorrhoeae, C. trachomatis, or early syphilis infection by by 
laboratory-based diagnosis (e.g., positive N. gonorrhoeae or C. trachomatis based on NAAT or syphilis based 
on four-fold increase in non-treponemal titers). 
 
Secondary outcomes:  
• Safety: Safety assessment will be measured in both arms: serious adverse events (SAEs), related 
all AEs and discontinuations (in the dPEP arm only), and a standardized symptom assessment for 
doxycycline-specific side effects (e.g., nausea, pill esophagitis, photosensitivity, vaginal 
candidiasis). 
• Acceptability: Longitudinal change in qualitative themes and associated barriers and facilitators 
• Adherence: We will explore the self-reported measures and SMS data, defining adherence as the 
percentage of times that dPEP was taken following an episode of condomless intercourse. Stored 
vaginal swabs for Y chromosome testing can be available for later validation. 
• Resistance: The detection of the plasmid-encoded tet(M) gene and/or tetR genetic resistance 
determinants is indicative of phenotypic resistance to tetracycline 
• Cost: The incremental cost effectiveness ratio (ICER) per incident STI case averted and DALY 
averted 
 
Statistical power and analysis   
We propose a standard randomized superiority design, comparing dPEP to standard of care. The primary trial 
outcome will be the combined incidence of incident C. trachomatis, N. gonorrhoeae, and syphilis, compared 
between the randomization arms, to mirror the IPERGAY approach; analyses will also test each pathogen 
alone. We have been conservative in planning: first, we have planned for an STI incidence of 22% per year in 
the standard of care arm, which is less than the C. trachomatis incidence seen in our recent studies (Table 3) 
and second, we will calculate based on time to first incident STI alone, although we anticipate that some 
women will have repeat STIs contributing additional events and additional statistical power. We have planned 
for a 50% effect, comparable to the IPERGAY results and sufficiently great for public health benefit, but we 
anticipate that the C. trachomatis effect could be >50%, given universal susceptibility to doxycycline and 


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IPERGAY findings. With 80% power, 10% loss-to-follow-up, incidence of 22% vs. 11% (n=44 vs. 22 cases), 
and a two-sided alpha of 0.05, a sample size of n=550 is needed (n=275 per arm).  
 
Primary Analysis:  
We will analyze the composite endpoint of any of the three STIs as well as for C. trachomatis alone, 
and we will continue until there are sufficient C. trachomatis events (n=66) given the high incidence of 
this pathogen and its importance for reproductive morbidity (the consequence of which will be that the 
total number of events in the composite of C. trachomatis, N. gonorrhoeae, and syphilis will be greater 
than n=66). Analyses will be intention-to-treat, including women whether or not they continue dPEP (as 
well as whether or not they continue PrEP). STI incidence will be compared between arms using 
repeated measures analysis of proportions (e.g., generalized estimating equations [GEE]), given 
possibility of repeat infection within individuals. Per-protocol and adjusted analyses will be done as 
needed, controlling for potential confounders: demographics (e.g., age, education), sexual behavior 
(e.g., condom use, # partnerships), and beliefs (e.g., risk perception, dPEP/PrEP efficacy). SAS or R 
will be used. 
 
Secondary Analyses:  
 
Safety: Safety outcomes (i.e., AEs, tolerability, pregnancy, behavior) will be compared between arms 
using repeated measures analyses. 
 
Adherence: We will explore the self-reported measures and SMS data, defining adherence as the 
percentage of times that dPEP was taken following an episode of condomless intercourse. Stored 
vaginal swabs for Y chromosome testing can be available for later validation, as noted in Aim 1 above. 
For hair, we plan three analyses, focused on 1) describing overall adherence in the population, 2) 
understanding the relationship between adherence and STI protection, and 3) exploring for cross-over 
(contamination between arms) that could occur since doxycycline is available in the community. We will 
complete a descriptive analysis of nonadherence events (defined as self-report of unprotected sex in 
last 3 months corresponding with elevated pill count or undetectable hair drug level), both for dPEP 
(dPEP arm only) and for PrEP, with log binomial regression with GEE to account for repeat measures 
of adherence over time. Adjusted analyses will control for potential confounders as in Aim 1. 
 
Acceptability: Quantitative analysis will be completed using GEE to test associations between 
facilitators/barriers and randomization arm, dPEP adherence, and STI outcomes. Data will be analyzed 
to understand factors impacting acceptability of dPEP, including demographics, stigma, fertility desire, 
dPEP effect on sexual and preventative decision making. Qualitative analysis will take a longitudinal 
approach. Interview discussions will be recorded, transcribed, and translated into English. Transcripts 
will be reviewed separately by two investigators for completeness and initial theme generation. We 
routinely use rapid debriefing reports to obtain real-time information;160 formal coding and analysis will 
be performed with Atlas.ti, using inductive approach informed by theoretical framework of acceptability 
(TFA), a recently developed approach to acceptability research of medical interventions.161 The 
components of TFA are affective attitude, burden, ethicality, intervention coherence, opportunity costs, 
perceived effectiveness, and self-efficacy. Initial code generation of the transcript themes will capture 
experiences and context of dPEP use. Codes will be reviewed for consistency and inter-coder 
agreement with consensus code generation by themes. Following a similar process, transcripts from 
Months 6 and 12 will be coded with reference to the baseline codes to capture temporality of 
experiences and contexts within each participant. Codes generated from transcripts at Months 6 and 12 
will be compared across participants to establish differences and similarities across the sample. The 
code will reflect the longitudinal data and emergence of new codes. Descriptive thematic analyses will 
be done at baseline and over time.  
 
Resistance: The impact of dPEP on C. trachomatis and N. gonorrhoeae resistance will be measured by 
comparing the overall rates of doxycycline-resistant events occurring in the dPEP arm to rates in the 


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control arm, at baseline and separately during follow-up adjusted for medical factors that confound the 
dPEP-resistance risk relationship.  
 
Cost: Using the effectiveness estimated through Aim 1 and the costing and modeling from this study, 
the incremental cost effectiveness ratio (ICER) per incident STI case averted, and disability-adjusted 
life year (DALY) averted will be estimated for dPEP compared to the control arm. Sensitivity analyses 
will address adherence, risk compensation, and programmatic issues (e.g., medication stock-outs). The 
primary analysis will be from a programmatic perspective, the purview of decision makers. Following 
suggested update to cost effectiveness definition for low-income countries, interventions will be 
considered cost-effective if the ICER is 500 USD per DALY averted.162,163 In the budget impact 
analysis, we will consider direct program costs, and ensure that measurements of programmatic costs 
reflect the opportunity cost of the resources used in delivering services.164 We will report on all costs 
using a recommended discount rate of 3% per year, as well as an alternative 5% discount rate and 
undiscounted inputs.162 This will facilitate comparison to other strategies and help decision makers to 
define priorities and allocate resources.  
 
Endpoint adjudication 
All STI endpoints will be reviewed by a blinded, independent Endpoint Adjudication Committee, following CDC 
guidelines for the diagnosis of STIs.165 Incidence of individual STIs and tetracycline resistance will also be 
evaluated.   
 
12.0 
PARTICIPANTS 
 
Institutional Review Board (IRB) Review  
The study protocol, site-specific informed consent forms, participant education and recruitment materials, and 
other requested documents—including any subsequent modifications—will be reviewed and approved by the 
UW IRB,  KEMRI SERU, and PPB ECCT in accordance with their requirements; they will be responsible for 
oversight of research conducted at the study site. Subsequent to initial review and approval, the UW IRB will 
review the study at least annually.  
 
Informed Consent  
Written informed consent will be obtained from all study participants prior to enrollment in any study-related 
activities. Participants will be offered copies of the informed consent forms. Forms will be translated into local 
languages and verified by performing an independent back-translation. Informed consent forms will be kept in 
a secure and locked location for a period of at least 3 years following completion of the trial, longer if required 
by local regulations or requirements of overseeing IRBs/ECs.  
 
Study records  
Each study site will establish a standard operating procedure for confidentiality protection. Each site will ensure 
that study records including administrative documentation and regulatory documentation as well as 
documentation related to each participant enrolled in the study, including informed consent forms, locator 
forms, case report forms, notations of all contacts with the participant, and all other source documents are 
stored in a secure manner.   
 
Confidentiality  
Every effort will be made to protect participant privacy and confidentiality to the extent possible. Personal 
identifying information will be retained at the Kisumu study site and not forwarded to the labs in Mombasa, San 
Francisco, or Seattle, or to the University of Washington team; instead, all information will be identified only by 
study ID number. The site will use their standard operating procedure for confidentiality protection that reflects 
the input of study staff and community representatives to identify potential confidentiality issues and strategies 
to address them. 
  
All study-related information will be stored securely at the study sites. All participant information will be stored 


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in areas with limited access. Data collection, administrative forms, laboratory specimens, and other reports will 
be identified only by the study ID number to maintain participant confidentiality. All records that contain names 
or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from 
study records identified by study ID number. All local databases will be secured with password-protected 
access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID 
numbers to other identifying information will be stored in a separate, locked file in an area with limited access. 
 
Risks/Benefits 
Participants may experience pain or discomfort during blood draws pelvic exams, and rectal and nasal swab 
collection. They may be embarrassed or worried about the STI and HIV testing conducted during the study. 
Participants may also have some anxiety or worry about providing a hair sample, though the technique is 
optimized to minimize visible hair removal. Study questionnaires asking information about sexual behavior or 
partners may also make the participant uncomfortable or embarrassed. All study staff are trained to provide 
professional care in both clinical sample collection and counseling and administering study questionnaires. 
Counseling will be available to participants who feel they would benefit based on their experiences in the study.  
 
Weekly SMS will be received outside of the study clinic and thus study staff cannot guarantee that someone 
other than the participant will see the message. The SMS will be coded so that if another person sees the 
message, it will not indicate the nature of the question or reveal that it is part of a research study. The 
participant may respond to the message at anytime she feels comfortable to do so, i.e. it does not require an 
immediate response. Additionally, if ever she would like to stop receiving the weekly SMS, she may request 
this from the study staff and she will be removed from the list of participants receiving the SMS. 
 
For women assigned to the dPEP group, there are known side effects, as listed in protocol section 5.0. 
Participants will be counseled on the side effcts and ways to take the medication in order to minimize the 
impact of any side effects. Participants will be encouraged to come to the study clinic if they have any concerns 
about the medication or side effects they are experiencing.  
 
Study staff will make every effort to protect participants’ privacy and confidentiality. It is possible that 
participants' involvement in the study could become known to others, and that social harms may result (i.e., 
because participants could become known as participating in a trial involving sexually active women or persons 
using PrEP).  For example, participants could be treated unfairly or discriminated against, or could have 
problems being accepted by their families and/or communities. It is possible that participants may have 
problems with their partner or experience intimate partner violence. Counseling and referrals will be available, 
if needed.   
 
Participants may benefit from their study participation as they will be receiving free STI testing and treatment 
that is not readily available in public clinics. Prompt treatment of STIs, including asymptotic STIs, is beneficial 
to women in order to reduce the risk of pelvic pain, infertility, or other problems with future pregnancies that 
can develop when STIs go untreated.  
 
Reimbursement  
 
Participants will be provided reimbursement for their travel costs and compensation of time spent during study 
visits, in accordance with local guidelines and regulatory approvals. 
 
Participants who complete SMS surveys will receive airtime after 6 months of survey completion. Participants 
who continue to attend their follow-up visits may receive tokens of appreciation, for example study related gifts 
such as t-shirts or bags.  
 
COVID-19 safety measures  
The Coronavirus Disease 2019 (COVID-19) pandemic is rapidly evolving and participant safety will remain a 
top priority in all study procedures. Study staff will follow all relevant local, national and WHO guidelines for 
minimizing exposure risk to participants, including but not limited to safety training, wearing appropriate 


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personal protective equipment (PPE), and enforcing social distancing. Specific procedures will be documented 
in a standard operating procedures (SOP) and updated as needed, particularly as more information about best 
practices for reducing COVID-19 transmission becomes available. During the consenting process, participants 
will be advised of the potential COVID-19 transmission risks related to in-person study procedures and the site 
procedures in place to minimize this risk.   
13.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with contaminated 
needles, blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and shipping and handling of all specimens for this study, as currently 
recommended by the CDC and the National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious substances, must be 
transported using packaging mandated by CFR 42 Part 72. Please refer to instructions detailed in the 
International Air Transport Association (IATA) Dangerous Goods Regulations.  
 
 
 
References 
 
1. 
Cherutich P, Kaiser R, Galbraith J, Williamson J, Shiraishi RW, Ngare C, Mermin J, Marum E, Bunnell 
R, Group KS. Lack of knowledge of HIV status a major barrier to HIV prevention, care and treatment 
efforts in Kenya: results from a nationally representative study. PLoS One. 
2012;7(5):e36797.PMC3344943 
2. 
<Unknown - Unknown - THE GAP REPORT.pdf>.  
3. 
Kamali A, Price MA, Lakhi S, Karita E, Inambao M, Sanders EJ, Anzala O, Latka MH, Bekker LG, 
Kaleebu P, Asiki G, Ssetaala A, Ruzagira E, Allen S, Farmer P, Hunter E, Mutua G, Makkan H, 
Tichacek A, Brill IK, Fast P, Stevens G, Chetty P, Amornkul PN, Gilmour J, Partnership IAHP. Creating 
an African HIV clinical research and prevention trials network: HIV prevalence, incidence and 
transmission. PLoS One. 2015;10(1):e0116100.PMC4300215 
4. 
De Cock KM, Jaffe HW, Curran JW. The evolving epidemiology of HIV/AIDS. Aids. 2012;26(10):1205-
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Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, Stevens G, Gottlieb S, 
Kiarie J, Temmerman M. Global Estimates of the Prevalence and Incidence of Four Curable Sexually 
Transmitted Infections in 2012 Based on Systematic Review and Global Reporting. PLoS One. 
2015;10(12):e0143304.PMC4672879 
6. 
WHO. GLOBAL HEALTH SECTOR STRATEGY ON SEXUALLY TRANSMITTED INFECTIONS 2016-
2021 TOWARDS ENDING STIs. WHO Bullitin. 2016 
7. 
Gilson RJ, Mindel A. Recent advances: Sexually transmitted infections. BMJ. 2001;322(7295):1160-
1164.PMC1120285 
8. 
CDC. Sexually Transmitted Infections in Developing Countries: Current Concepts and Strategies on 
Imporving STI Prevention, Treatment, and Control. Center for Disease Control. 2008 
9. 
MacLachlan E, Baganizi, E, Bougoudoga, F, Castle, S, Mint-Youbba, Z, Gorbach, P, Parker, K, Ryan, 
CA. The feasibility of integrated STI prevalence and behaviour surveys in developing countries. Sex 
Transm Dis. 2002;78:187-189 


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Who Have Delayed, Declined, or Discontinued Antiretroviral Therapy: A Randomized Controlled Trial of 
a Novel Intervention. AIDS Behav. 2015;19(10):1801-1817 


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SAP_001.pdf: 
ICRC 
 
dPEP Kenya 
Statistical Analysis Plan 
 
October 24, 2022 
 
1 
 
 
  
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
VERSION: 4.0 
24 October 2022 
 
BASED ON: 
Protocol Version 5.0 September 30, 2020 
Amendments and Dates  
CRF Date:  
 
STUDY TITLE: 
PrEP and dPEP: Doxycycline post-exposure prophylaxis for prevention of sexually transmitted 
infections among Kenyan women using HIV pre-exposure prophylaxis  
 




ICRC 
 
dPEP Kenya 
Statistical Analysis Plan 
 
October 24, 2022 
 
3 
 
 
  
 
PROTOCOL SUMMARY 
 
PREP AND DPEP: DOXYCYCLINE POST-EXPOSURE PROPHYLAXIS FOR PREVENTION OF SEXUALLY TRANSMITTED 
INFECTIONS AMONG KENYAN WOMEN USING HIV PRE-EXPOSURE PROPHYLAXIS 
 
 
Design: 
Open-label 1:1 randomized clinical trial of doxycycline PEP (dPEP) to reduce bacterial STIs – Neisseria 
gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum (syphilis) – among Kenyan women taking PrEP. 
We will also use quantitative questionnaires, focus group discussions, SMS, and in-depth interviews to study 
acceptability, adherence, and changes in sexual behavior due to dPEP. 
 
Study Population: 446 Kenyan women aged ≥18 and ≤30 years old taking PrEP randomized to dPEP and 
standard of care vs. standard of care alone 
 
Study Sites: 
KEMRI RCTP – Lumumba clinic 
Primary Study Objectives: 
1. Evaluate the effectiveness of doxycycline post-exposure prophylaxis (dPEP) to reduce STI 
infections in HIV-uninfected Kenyan women taking HIV PrEP 
2. Assess the safety, tolerability, and acceptability of dPEP 
3. Assess adherence to dPEP 
4. Investigate the impact of dPEP on tetracycline resistance in N. gonorrhoeae and C. trachomatis 
5. Measure the cost of dPEP and estimate the cost per case averted, budget impact, and 
affordability. 
 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY .................................................................................................................... 3 
TABLE OF CONTENTS....................................................................................................................... 4 
LIST OF TABLES ................................................................................................................................ 6 
LIST OF ABBREVIATIONS ................................................................................................................. 6 
1. 
INTRODUCTION ............................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 9 
2.1. 
Study Objectives .......................................................................................................... 9 
2.2. 
Study Endpoints ........................................................................................................... 9 
3. 
STUDY DESIGN ........................................................................................................... 11 
3.1. 
Summary of Study Design .......................................................................................... 11 
3.2. 
Definition of Study Drugs ........................................................................................... 12 
3.3. 
Sample Size Considerations ....................................................................................... 12 
3.4. 
Randomization ........................................................................................................... 13 
3.5. 
Clinical Assessments .................................................................................................. 13 
4. 
PLANNED ANALYSES .................................................................................................. 14 
4.1. 
Interim Analyses ........................................................................................................ 14 
4.2. 
Final Analyses ............................................................................................................. 14 
5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ........................ 15 
5.1. 
Data Presentation Conventions ................................................................................. 15 
5.2. 
Analysis Populations .................................................................................................. 15 
5.3. 
Handling of Missing Data ........................................................................................... 16 
6. 
STUDY POPULATION .................................................................................................. 17 
6.1. 
Participant Disposition ............................................................................................... 17 
6.2. 
Screen Failures ........................................................................................................... 17 
6.3. 
Protocol Deviations .................................................................................................... 17 
6.4. 
Study Termination Status .......................................................................................... 17 
6.5. 
Demographic and Baseline Characteristics ............................................................... 17 
7. 
EFFICACY .................................................................................................................... 18 
7.1. 
General Considerations ............................................................................................. 18 
7.2. 
Statement of the Null and Alternate Hypotheses ..................................................... 18 


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7.3. 
Subgroup Analyses ..................................................................................................... 18 
7.4. 
Multiple Comparisons and Multiplicity ..................................................................... 18 
7.5. 
Analysis of the Primary Efficacy Endpoint ................................................................. 18 
7.6. 
Study drug use and time on study drug in the dPEP arm .......................................... 20 
7.7. 
Analysis of Tetracycline resistance ............................................................................ 20 
8. 
SAFETY AND TOLERABILITY ........................................................................................ 22 
8.1. 
Adverse Events and Deaths ....................................................................................... 22 
8.2. 
PrEP use ..................................................................................................................... 23 
8.3. 
Tolerability ................................................................................................................. 23 
8.4. 
Acceptability .............................................................................................................. 23 
9. 
ADDITIONAL SECONDARY ENDPOINT ANALYSIS ....................................................... 25 
9.1. 
Changes in sexual frequency ..................................................................................... 25 
9.2. 
Coverage of sex acts ...................................................... Error! Bookmark not defined. 
10. 
REVISIONS TO THE SAP .............................................................................................. 26 
11. 
APPENDIX ................................................................................................................... 27 
11.1. 
Table of Contents for Data Reports ........................................................................... 27 
12. 
REFERENCES ............................................................................................................... 28 
 
 
 


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LIST OF TABLES 
 TOC \h \z \c "Table" Table 1: ........................................................................................................... List of 
Abbreviations ............................................................................................................... 6 
Table 2: 
Visit Windows (Days) ..................................................... Error! Bookmark not defined. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
 
 
AE 
Adverse event 
AMR 
antimicrobial resistance 
ART 
Antiretroviral therapy 
CDC 
Centers for Disease Control 
CT 
Chlamydia trachomatis 
DAIDS 
Division of AIDS 
DALY 
Disability-adjusted life year 
dPEP 
Doxycycline post-exposure prophylaxis 
DSMB 
Data safety and monitoring board 
FGD 
Focus group discussion 
GEE 
Generalized estimating equations 
HAL 
Hair Analytical Laboratory 
HIV 
Human Immunodeficiency virus 
HSV 
Herpes simplex virus 
IATA 
International Air Transport Association 
ICER 
Incremental cost effectiveness ratio 
IDI 
In-depth interviews 
IH 
Intracranial hypertension 
IRB 
Institutional Review Board 
IPV 
Intimate partner violence 
KEMRI 
Kenya Medical Research Institute 
LARC 
Long-acting reversible contraceptives 
LMP 
Last menstrual period 
MOH 
Ministry of Health 
MSM 
Men who have sex with men 
NAAT 
Nucleic acid amplification test 
NASCOP 
National AIDS & STI Control Programme 
GC 
Neisseria gonorrhoeae 
PCR 
Polymerase chain reaction 
PEP 
Post-exposure prophylaxis 
PID 
Pelvic inflammatory disease 
PLWH 
People living with HIV 
RPR 
Rapid Plasma Reagin 
SAE 
Serious Adverse Event 
SMS 
Short message service 


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STIs 
Sexually transmitted infections 
TDF/FTC 
Tenofovir/Emtricitabine 
tetR 
Tetracycline resistant 
UCSF 
University of California San Francisco 
UW 
University of Washington 
VCT 
Voluntary counseling and testing 
 


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1. 
INTRODUCTION 
The purpose of this document is to provide details on study populations and on how the 
variables will be derived, how missing data will be handled as well as details on statistical 
methods to be used to analyze the safety and efficacy data. This SAP only details the analysis of 
primary and key secondary objectives. 
The document may evolve over time, for example, to reflect the requirements of protocol 
amendments or regulatory requests.  However, the final SAP will be finalized, approved by the 
Protocol Chairs, and placed on file before database is locked. 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Efficacy and Safety Objectives 
1. Evaluate the effectiveness of doxycycline post-exposure prophylaxis (PEP) to 
reduce STI infections in HIV-uninfected Kenyan women taking HIV PrEP 
2. Assess the safety, tolerability, and acceptability of dPEP 
2.1.2. 
Secondary objectives 
1. Assess adherence to dPEP 
2. Investigate the impact of dPEP on tetracycline resistance in N. gonorrhoeae 
and C. trachomatis 
3. Measure the cost of dPEP and estimate the cost per case averted, budget 
impact, and affordability 
2.2. 
Study Endpoints 
2.2.1. 
Primary Efficacy Endpoints 
Effectiveness of doxycycline 
The primary endpoint is assessed using the following STI endpoints at month 3,6, 9 and 12 
visits: 
• Documented positive vaginal/cervical GC  
• Documented positive vaginal/cervical CT 
• Early syphilis infection based on four-fold increase in non-treponemal titers. 
The primary trial endpoint is any newly diagnosed STI, defined as any one of the above after the 
enrollment visit, with the exception of re-diagnosis of the same infection at a test of cure visit 
within 28 days of first treatment of a baseline or incident infections (which is considered a non-
cured infection and re-treated). Any infection newly diagnosed at an interim visit will be 
counted as a primary endpoint for the subsequent scheduled visit i.e., if a participant is 
diagnosed with new GC infection at an interim visit 40 days after their 6 month visit, this will be 
analysed as a primary 9 month endpoint. Endpoints are reviewed by committee, blinded to 
study arm, and primary endpoints designated in that review.  
2.2.2. 
Secondary Efficacy Endpoints 
Efficacy of doxycycline for individual STIs 
Effectiveness of doxycycline will also be assessed for CT and GC separately, using an incident STI 
definition that parallels the above for the specific infection.  


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2.2.3. 
Safety, tolerability and acceptability of dPEP 
• Safety:  
− serious adverse events (SAEs),  
− all related AEs (assessed in the dPEP arm only)  
• Tolerability:  
−  dPEP discontinuation (assessed in the dPEP arm only)  
− Candida yeast infection treatment (documented as fluconazole on STI treatment 
CRF) 
− Doxycycline-specific side effects (assessed via standardized symptom 
assessment: includes reports of nausea, pill esophagitis, photosensitivity) 
• Acceptability:  
− Acceptability and Optimism questionnaire (FDAO) (13 question on a 5-point 
Likert scale) 
2.2.4. 
Adherence 
Adherence is only assessed in the dPEP arm 
• Weekly SMS questions  
Weekly questions collected in participants who opted in to SMS. 
− Number of days in the last 7 days when dPEP was taken  
− Number of days in the last 7 days when participants had sex or “danced”).  
• Hair samples  
Collected quarterly  
• Quantitative amount of doxycycline in 1cm segments from cut end to tip which 
corresponds with a 4-week period of dPEP use (starting 1 week ago).   
• Self-report of coverage of sexual contacts in the prior 14 days to 3 days in the dPEP arm:  
Quarterly (timeline follow-back) adherence questionnaire.  
2.2.5. 
Tetracycline resistance 
• Molecular markers of resistance for CT after enrollment (positive CT swabs collected at 
Enrollment, Month 3, 6, 9 and 12, as well as any test of cure visits) 
• Molecular markers of resistance for GC after enrollment (positive GC swabs collected at 
Enrollment, Month 3, 6, 9 and 12, as well as any test of cure visits) 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
 
Open label 1:1 randomized trial of dPEP versus standard of care. Participants assigned to dPEP 
will be instructed to take doxycycline 200 mg (two 100mg capsules) orally within 24 hours and 
up to 72 hours after each condomless sex act as frequently as daily if indicated but not more 
than once daily.  
 
At Months 0/3/6/9, women randomized to dPEP will receive doxycycline, sufficient for nearly 
daily use for 3 months (i.e., 100 capsules). Unused capsules will be counted at each follow-up 
visit (Months 3/6/9/12) and additional doxycycline will be given to total up to 180 capsules if 
needed. The medication, doxycycline hyclate, will be purchased from a quality-controlled 
supplier and with consultation by the Kenya National AIDS and STI Control Programme. 
Participants will also be offered single- or multi-dose pill carriers for ease of dosing dPEP 
following exposures. All participants will receive quarterly visits for standard of care prevention 
services and collection of clinical and behavioral data, for a total of 12 months of follow-up. 
 
Study visits: Every 3 months, study visits will include STI screening, behavioral questionnaires, 
hair sample collection, and swab collection for archived samples. Women may return to the 
study clinic for interim visits for any reason and will undergo STI testing and treatment if STI 
symptoms are present. Participants with a new STI diagnosis will return for prompt treatment, 
provided on-site. Laboratory testing will be conducted by staff blinded to randomization 
assignment, and STIs will be reviewed by an Endpoint Adjudication Committee blinded to 
treatment arm. All participants diagnosed with an STI will either receive same day treatment or 
return to the research clinic for treatment, using WHO/Kenya standard therapies, avoiding 
doxycycline options, and a second visit two weeks following completion of STI treatment will be 
done for test of cure; this mitigates potential risk to participants and the community if 
resistance is selected. 
 
Study population: This study will enroll approximately 446 Kenyan women aged 18 and 30 years 
old taking PrEP. PrEP use is an eligibility criterion for enrollment because we hypothesize that 
women engaging in PrEP are a priority population for prevention of curable STIs, given high 
incidence, interest in longitudinal preventative services, and willingness to take pills for 
prevention. Aligning with Kenya’s national PrEP services, we propose an evaluation of the 
benefits, risks, and costs of dPEP among women, in the first trial of this intervention for this 
population. However, participants may opt to stop PrEP use at any time during the study 
without affecting their involvement in the study. Any HIV-uninfected participants who 
subsequently seroconvert will be managed clinically by the study site according to local practice 
(appropriate counseling, clinical evaluation and immediate linkage to clinical and psychosocial 
services). These participants will also be retained in the study unless they choose to discontinue 
study participation 
 


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3.2. 
Definition of Study Drugs 
The study drug is open-label doxycycline 200 mg to be taken ideally within 24 hours but no later 
than 72 hours after condomless sexual contact (oral or anal). 200 mg of doxycycline will be 
taken at most once per 24 hour period regardless of the number of sexual acts occurring during 
this time period 
3.3. 
Sample Size Considerations 
3.3.1. 
Sample Size Justifications 
The study is a 1:1 randomized superiority design, comparing dPEP to standard of care. The 
primary trial outcome will be the combined incidence of incident C. trachomatis, N. 
gonorrhoeae, and syphilis infections, compared between the randomization arms, to mirror the 
IPERGAY and Doxy PEP approach; analyses will also test CT and NG alone. Sample size was 
determined using an event driven approach (N = 66). Assuming 10% loss-to-follow-up, 
incidence of 22% for any STI in the SOC arm and a two-sided alpha of 0.05, a sample size of 
n=446 (n=223 per arm) has 80% power to detect a 50% reduction in time to first STI, i.e.  ~11% 
in the dPEP arm (n=44 vs. 22 cases). 
The trial intends to have sufficient power to detect 50% effectiveness in CT alone, and thus not 
stop before incident diagnosis of CT has occurred in 66 women (resulting in more than the 
minimum number of composite events for the endpoint of any STI).  
Sample sizes were computed using nQuery for time to first STI within one year of follow-up 
Table 2 Power Table for N = 446; 1:1 randomization dPEP: SOC 
Control arm 
incidence 
Power to detect 50% reduction 
(Number of infections for 80% 
power = 66) 
Power to detect 65% reduction 
(Number of infections for 80% 
power = 52) 
Intervention 
arm incidence 
Power 
Intervention 
arm incidence 
Power 
50% 
25.0% 
99% 
17.5% 
99% 
33% 
15.5% 
93% 
11.6% 
99% 
22% 
11.0% 
80% 
7.7% 
96% 
18% 
9.0% 
71% 
6.3% 
92% 
15% 
7.5% 
63% 
5.2% 
87% 
 


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3.3.2. 
Sample Size Re-estimation 
At the point when enrollment is near completion, the study team will evaluate the expected 
power of the trial, based on the observed rate of infections. If the rate of the primary endpoint 
is substantially lower than anticipated, sample size re-estimation would be used to restore 
power to the extent possible, through additional enrollments, increase in person-time, or 
modification of risk criteria.   
3.4. 
Randomization 
Participants will be randomized 1:1 to dPEP versus standard of care; randomization will be done 
in variable- sized blocks and using a computer based randomization system, Randomize.net, 
following consent and eligibility confirmation. 
3.5. 
Clinical Assessments 
Safety assessments are limited to the following: 
In dPEP arm only: 
• All grade 2 and higher AEs that are judged related to dPEP, in the opinion of the site 
clinician, that result in an interruption of study drug 
• All grade 3 and 4 adverse events judged to be related to doxycycline 
In both arms: 
• All AEs meeting SAE definition regardless of relationship with dPEP 
 
In this open label trial, for those randomized to receive doxycycline PEP, all AE’s and SAE’s have 
attribution recorded as doxycycline-related or not doxycycline-related, in the judgment of the 
site investigator. 


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4. 
PLANNED ANALYSES 
4.1. 
Interim Analyses 
The trial will be monitored by an independent data monitoring committee approximately every 
6 months. The trial plans to continue until we have established definitive efficacy results, 
whether effective or ineffective, for both CT alone and for any STI. Two formal interim 
monitoring times are planned, when 1/3 and 2/3 of the follow-up visits have been completed, 
with stopping rules based on consideration of both the primary outcome and the CT outcome 
alone. Because the outcomes are highly correlated, no adjustment for multiple comparisons is 
planned. O’Brien-Fleming boundaries will be used, with stopping based on the alpha spending 
corresponding to observed p-values in the efficacy analyses. Stopping for both efficacy and lack 
of efficacy will be considered; however, a decision to stop for efficacy will need to balance the 
need for evidence assessing the potential harm of acquired tetracycline resistance.    
4.2. 
Final Analyses 
 The final analysis will be conducted after database lock of all final (12 month) study visits. 


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5. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING 
5.1. 
Data Presentation Conventions 
Continuous variables (e.g. age) are summarized using descriptive statistics (the number of 
subjects with available data, the mean, standard deviation (SD), median and minimum and 
maximum). Categorical variables (e.g. preferred language) are summarized using counts and 
percentages. Percentages are calculated using the total subjects per treatment group. 
5.2. 
Analysis Populations  
5.2.1. 
Screened population 
All subjects who give informed written consent for screening but are not enrolled will be 
characterized based on reason for screen failures (e.g., lost-to-follow-up, did not meet entry 
criteria, administrative) in summary tables. These subjects will neither contribute to other data 
presentations nor participate in formal analyses. 
5.2.2. 
ITT Population 
The intent to treat (ITT) population comprises all randomized participants.  
5.2.3. 
dPEP Safety Population for dPEP 
The ‘Safety Population’ is defined as all subjects who were dispensed at least one dose of study 
medication. This population is expected to be identical to participants randomized to dPEP for 
this study. 
5.2.4. 
GC positive Population 
Post-baseline GC positive participants assessed for TCN resistance. All participants with positive 
GC will be assessed for molecular resistance  
5.2.5. 
CT positive Population 
Post-baseline CT positive participants assessed for TCN resistance. All participants with positive 
CT will be assessed for molecular resistance 
5.2.6. 
Hair population 
Participants in the dPEP arm who have hair assessed for quantitative PK assays.  
5.2.7. 
Asymptomatic STI population 
Participants who have tested positive for an STI (CT, NG, and/or TP) and “Per national 
guidelines, do abnormal findings require immediate STI treatment?” is answered “no” 
5.2.8. 
SMS responder population 
Participants who have responded to at least 4 SMS surveys 


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5.2.9. 
Subgroups 
The following subgroups will be defined by baseline characteristics 
• Age: ≤ vs > 24 years old at enrollment 
• Nulliparous: No previous live births 
• Using contraceptives: IUD, implants, DMPA, oral contraceptives 
• Any STI at baseline: Any laboratory confirmed diagnosis of GC, CT or incident syphilis 
during enrollment visit(s). 
• Transactional sex: exchanged sex for goods, services, or money in the last 3 months 
5.3. 
Handling of Missing Data 
5.3.1. 
Missing Efficacy Endpoints 
Complete case analysis will be used for the primary efficacy analysis 


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6. 
STUDY POPULATION 
6.1. 
Participant Disposition 
A consort diagram will describe the number screened, randomized, retained by visit, and 
contributing to the primary analysis endpoints by arm. Reason for screen-out and non-inclusion 
in the primary outcome will be summarized.   
6.2. 
Screen Failures 
Reason for screen failures will be summarized by arm 
6.3. 
Protocol Deviations 
A listing or summary of major protocol deviations will be provided 
6.4. 
Study Termination Status 
Reason for early study termination or study withdrawal will be enumerated and detailed. Study 
disposition at the time of a report will list those remaining in study follow-up, completed study 
follow-up, early withdrawal (including deaths). 
6.5. 
Demographic and Baseline Characteristics 
6.5.1. 
Demographics and risk characteristics 
The following baseline demographics and risk characteristics will be presented separately by 
arm for the ITT cohort. 
• Age in years 
• Education 
• Sexual risk (i.e. number of partners, transactional sex, condom use with last sex) 
• Living situation 
• Preferred language 
• Marital status 
• Number of live births 
• Earns her own income (Y/N) 
6.5.2. 
Baseline Laboratory Data 
Baseline bacterial STI diagnoses (GC/CT, Syphilis) detected by lab-based study testing will be 
reported for each cohort separately, by arm and by study site. 


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7. 
EFFICACY 
7.1. 
General Considerations 
Tabulations will be by study arm, for each quarter of study follow-up (or at visits where 
evaluated). These will be reported in only the closed report during the study.  
Inferential statistical tests will be two-sided and will be performed at alpha levels of 0.05 and 
0.10 to declare the significance of main effects and interaction effects, respectively. 
7.2. 
Statement of the Null and Alternate Hypotheses 
For enrolled women: 
• Ho:  Use of Doxycycline PEP does not have a differential effect on incidence of GC, CT 
and syphilis infections compared to the standard of care  
RR any STI (Doxy Arm/SOC Arm) = 1 
• HA:  Use of Doxycycline PEP decreases the incidence of GC, CT and syphilis infections 
compared to the standard of care. 
RR any STI (Doxy Arm/SOC Arm) ≠1 
7.3. 
Subgroup Analyses 
Subgroup analysis of the efficacy of the intervention will be conducted for 
• Age subgroups (≤/> 24) 
• Nulliparous (N/Y) 
• Using contraceptives (N/Y) 
• Any STI at baseline (N/Y) 
• Transactional sex (N/Y) 
7.4. 
Multiple Comparisons and Multiplicity 
No adjustments are planned for multiple comparisons 
7.5. 
Analysis of the Primary Efficacy Endpoint 
7.5.1. 
Primary Efficacy Analysis 
The primary analysis of efficacy will be conducted in the ITT cohort 
Endpoint definitions:  
Primary endpoint: Any incident STI at Month 3,6 9 or 12.  Repeat positive tests for the same STI 
up to 28 days after treatment of an incident infection (the window for the test of care visit) will 
not be counted as incident infections. Incident infections detected at interim visits more than 


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28 days after treatment will be treated in the analysis as if they would have been detected at a 
scheduled visit (months 3, 6, 9 and 12). Therefore, an STI diagnosed at an interim visit outside 
the treatment window is carried forward to the next scheduled visit. If a participant has more 
than one positive STI (different bacterial infections) at a scheduled visit it will be counted as one 
incident “any STI” event for that visit interval. If scheduled visits are missed, infections will be 
assigned to the next scheduled visit (i.e., the first missed scheduled visit).   
Secondary endpoints: Any GC, Any CT at Month 3, 6, 9 and 12. The same approach as defined 
for the primary endpoint will be used, restricted to each specific bacterial infection.  
 
The criteria for an incident syphilis case will include a four-fold increase in non-treponemal 
titers (e.g., the RPR) and/or a consistent clinical presentation.  
Descriptive analysis 
• The number of participants with any bacterial STI, and with each type of STI, will be 
summarized at each scheduled visit by arm 
• The number of STIs reported by each participant will be summarized at each scheduled 
visit by arm. Detail of testing and results at interim visits will also be summarized.  
• Occurrence and results of test of care visits will be summarized.  
Statistical analysis 
Comparison of STI incidence by arm will be conducted by estimating the relative risks of any STI 
over the 3, 6, 9 and 12 month visits using a modified Poisson model fitted using GEE methods to 
account for repeated observations from each participant, assuming an independent covariance 
structure, with  study arm as the only covariate[1]. The test for significance will be a two-sided 
alpha = 0.05. 95% confidence intervals will be computed using robust standard errors.  
The same analysis will be repeated for the individual STIs.  
7.5.2. 
Sensitivity Analyses of the Primary Efficacy Results 
Several sensitivity analyses are planned: 
1. Analysis restricted to time eligible for dPEP (i.e., no active pregnancy). Time in both 
arms will be censored at the study visit when a participant was determined to be not 
pregnant (from visit with first positive pregnancy test until exit without re-entry into 
risk set)  
2. Time to first STI (from randomization) using Kaplan Meier and Cox PH regression. All 
women will be treated as at risk for all STIs at randomization. It is acknowledged that 
women diagnosed with an STI at a visit are treated until cure, and thus are not 
immediately at risk. However, women re-enter the risk set when cured, thus are at risk 
prior to the next quarterly visit.   
3. Defining an STI as incident, in the case where the same STI was previously present, only 
if a negative test for the same pathogen is recorded before the positive result. The 


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primary outcome will be modified to exclude any repeat STI without a preceding 
negative result, and the statistical analysis for the primary analysis repeated.  
4. Analysis counting all individual STIs diagnosed in a quarterly interval A Poisson model 
fitted using GEE methods to account for multiple events from each participant will be 
used to estimate the change in rate of infections between arms. If necessary to achieve 
a better more fit, a zero-inflated Poisson model may be used. 
7.5.3. 
Analyses of the Primary Efficacy Results while on study drug (Per protocol) 
For the per-protocol analysis, for each cohort the dPEP arm will be restricted to study time prior 
to the first discontinuation (> 2 weeks) of study drug documented on the study dPEP CRF. The 
evaluation of the impact of doxycycline on Any STI will use the same model as specified for the 
primary analysis, but also potentially adjusted for age, baseline STI, baseline and follow-up 
sexual risk (number of partners, nulliparous, contraceptive use, transactional sex).  
7.6. 
Study drug use and time on study drug in the dPEP arm 
• Study drug dispensation (number of participants and number of pills) will be 
summarized for each study visit over time by cohort. 
• Longitudinal exposure to doxycycline will be assessed using hair collection, with a semi-
quantitative evaluation in 10% the control arm (doxycycline present vs. absent) and 
quantitative evaluation in the 100% of dPEP arm (doxycycline concentration value).   
• Proportion of time on study drug in the dPEP arm, based on discontinuations 
documented on study CRFs will be tabulated for each quarter and overall by study arm 
within each cohort.  
• Concomitant use of antibiotic use as documented in the antibiotic use log, will be 
summarized for the control and dPEP arms 
7.7. 
Analysis of Tetracycline resistance 
7.7.1. 
Analysis of TCN resistance in GC cases 
TCN resistance will be assessed in GC cases only. TCN resistant GC will be defined by the 
detection of plasmid-medicated tetM gene conferring high-level tetracycline resistance. 
Descriptive statistics: Tabulations of resistance (No GC, GC: TNC resistance testing = missing, 
not resistant, resistant) will be reported at baseline, 3, 6, 9 and 12 month visits in GC cases in 
each arm. 
Statistical analysis: Assessment of odds of resistance by arm will be assessed by estimating the 
odds of GC infection with resistance among cases detected after enrollment using logistic 
regression, adjusted for visit.  
Sensitivity analysis: molecular chromosomal mutations may lead to expression of tetracycline 
resistance. Tabulations of number of expressed chromosomally-mediated tetracycline 
resistance determinants (mtrR, rpsJ, porB, and pilQ) will be reported at baseline, 3, 6, 9, and 12-


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month visits in GC cases, among those with or without plasmid-mediated tetracycline 
resistance (i.e., detection of tetM), in each arm. 
7.7.2. 
Analysis of TCN resistance in CT cases 
The analysis of TCN resistance in CT cases will include all positive CT cases after baseline. TCN 
resistant CT will be defined by the detection of tetC gene cassette. 
Descriptive statistics: Tabulations of TCN resistance in CT cases (TNC resistance testing = 
missing, not resistant, resistant) will be reported at baseline, 3, 6, 9 and 12 month visits in each 
arm. 
Statistical analysis: Assessment of difference in odds of TCN resistance by arm across all post 
baseline visits with infection will be assessed by estimating the odds of TCN resistance using 
logistic regression, with repeated measures methods (GEE) if repeat infections occur.  
   


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8. 
SAFETY AND TOLERABILITY 
Statistical tests are not planned for adverse event comparisons between arms. Safety and 
tolerability will be assessed in the ITT cohort, given the open label nature of the cohorts. 
8.1. 
Adverse Events and Deaths 
8.1.1. 
AE Definitions 
The following AEs are recorded on eCRFs: 
• All SAEs  
• All AEs attributed to doxycycline in the opinion of the site investigator 
8.1.2. 
Adverse Event Summary Tables 
The number of SAEs will be tabulated by grade and arm.  For the dPEP arm, related AEs will be 
tabulated by grade (see below of definition of relatedness).   
8.1.3. 
Listings of Serious Adverse Events (SAE), Adverse Event Dropouts, and Death 
SAE data will be reported by related and not related.  
Participant data listing for SAEs will be by grade and arm, sorted by reported date within 
participant.  Unique information included in the listing contains SAE onset and resolution dates 
and times; verbatim description of SAE; relationship to study medication, action taken, and 
outcome.   
Participant data listing for related AEs will be by grade, sorted by reported date within 
participant.  Unique information included in the listing contains AE onset and resolution dates 
and times; verbatim description of AE; action taken, and outcome.   
A listing will present participants who discontinue study drug in the dPEP arm due to an adverse 
event, and the reasons for discontinuations: 
• Requirement for prohibited concomitant medications or other contraindication to 
doxycycline 
• Pregnancy 
• Occurrence of an adverse event requiring discontinuation of doxycycline  
• Request by participant to terminate study treatment 
• Clinical reasons believed life threatening by the physician, even if not addressed in the 
toxicity section of the protocol 
• Requirement for chronic tetracycline use (>14 days) 


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8.2. 
PrEP use 
Tabulation of time on PrEP 
Tabulations of PrEP will use the following assessments:  
• Residual hair samples of participants will be tested for quantitative tenofovir drug levels 
to measure monthly use of tenofovir disoproxil fumarate/lamivudine PrEP. 
• Reported time on PrEP prior to enrollment 
• Tabulation of PrEP use at each visits 
− Self-report of PrEP adherence (How well have you taken PrEP in the past month? 
How often do you take PrEP?) 
− PrEP dispensing (PrEP discontinued prior to visit or on PrEP prior to the visit. Has 
PrEP/PrEP dispensed) 
8.3. 
Tolerability 
Tolerability is assessed for participants on the dPEP arm through 
• a self-reported response to whether a participant did not take dPEP because of side-
effects. 
Descriptive: The Yes/No responses of dPEP side effects will be tabulated for each study visit 
among dPEP participants 
• Symptoms from the side-effect questionnaire 
Descriptive: Symptoms, collected at each visit, will be tabulated for each arm 
8.4. 
Acceptability 
Acceptability is assessed in the dPEP arm only via a 7 question acceptability questionnaire using 
a 5 point Likert scale.  
Descriptive: The scales will be converted to an acceptability score, the dPEP Acceptability and 
Optimism CRF, (using reverse coding where appropriate), and summarized by visit. Individual 
questions will also be reported in detail. This will be supplemented with qualitative interviews 
for a mixed methods analysis.  
 
8.5. 
Adherence 
Adherence is assessed as coverage of sex acts for this event-driven dosing and may have impact 
on effectiveness of medication.  
8.5.1. 
 
Coverage of sex acts 
Assessed in the dPEP arm only:  


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Measures 
• Last 14 days (up to 3 days prior to visit) calendar reporting of days taking dPEP and days 
with sex.  
• SMS: Self-reported coverage of last week: last 7 days # days with “dance” (SMS term 
used to mean sex), and # days taking dPEP. 
Definition: Acceptable coverage for a participant is defined as on 80% of days with sex, the 
participant self-reports use of dPEP within 72 hours.  
Descriptive:  
EchoMobile SMS data: Past-week use of dPEP by reported sex acts among dPEP study arm 
participants in a table over all follow-up time, excluding periods where participant is on a 
documented study drug hold.  
 
Timeline follow-back calendar: Past 2-week (day -14 to -3) participant-reported dPEP coverage 
among those with reported sex, by scheduled visit and over all follow-up time, excluding visits 
where participant is on a documented study drug hold.  
 
8.5.2. 
Longitudinal adherence-effectiveness analysis:  
Hair samples collected at quarterly follow-up study visits for all treatment group participants 
will be analyzed for quantitative hair drug levels. Based on HIV PrEP studies, we assume that 
dPEP will either be used regularly or not at all and that underdosing will be a rare occurrence. 
Because quantifying doxycycline drug hair levels is not yet standardized, we will not describe 
true event-based adherence but rather use vs. non-use.  
1. Doxycycline use (defined as detectable doxycycline in a hair sample – binary 
variable) will be analyzed using GEE to measure effect of dPEP use compared to 
nonuse in preventing STI cases (quarterly measure of any incident STI – binary 
variable).  
Secondary analyses  
2. Describe the relationship between quantitative tertials of doxycycline hair drug 
levels (low, medium, and high) and the number of dPEP doses reported in SMS in the 
4-week time period of hair sample (5 weeks prior to study visit until 1 week prior to 
study visit) by generating a scatterplot and reporting the mean number of doses 
reported per quantitative category.  
3. The mean hair drug concentration among hair samples collected at study visits 
when an incident STI (CT, NG, or TP, combined and per infection) was detected will 
be described and compared to study visits when no incident STI was detected 
among treatment group. 
 


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9. 
ADDITIONAL SECONDARY ENDPOINT ANALYSIS 
9.1. 
Changes in sexual frequency 
SMS surveys collected weekly ask all participants how many days of the last week they had 
sexual intercourse with responses ranging from 0-7. We will compare frequency of sexual 
activity over time to investigate whether they differ by arm using a GEE with Poisson 
distribution.  
9.1.1 Changes in sexual risk behavior 
Survey data collected quarterly, asking: “Was a condom used at last sex (N/Y)?” We will 
compare no sex/used condom at last sex over time to investigate whether they differ by arm 
using GEE with Poisson distribution.  
 
9.2. 
Contamination and non-use: 
Hair samples were collected at all study visits. A random 10% subset of all participants at 
enrollment visit and 10% subset of samples from follow up study visits from the standard of 
care group will be analyzed for doxycycline drug concentrations to summarize instances of  
doxycycline detection at study enrollment (prior to dPEP initiation) or in the standard of care 
group. All hair samples collected in follow up study visits in the treatment group will be 
analyzed for instances of  doxycycline non-detection, i.e., non-use (excluding participants with 
no sexual exposure reported in the last month). The percentage of participants with 
doxycycline detected in standard of care group will be compared with percentage of 
participants with doxycycline detected in dPEP arm over time, quarterly.  
 
9.3. 
STI Incidence  
Describe overall incidence rate of any STI (CT, NG, and TP) and individual STI by study arm. 
9.4. 
Prevalence and incidence of asymptomatic STIs 
The standard of care in Kenya is syndromic management of STIs. To better understand the role 
of asymptomatic STIs in this trial, symptom questions and physical exam findings will be used to 
define symptomatic vs. asymptomatic STIs (defined in 5.2.7), and the proportion of STIs that are 
detected at the time of symptoms and asymptomatic will be reported at baseline and at each 
quarter over time by study arm.  


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10. 
REVISIONS TO THE SAP 
Version 
Changes 
Date 
1.0 
 
16 March 2021 
2.0 
Correction of interim 
monitoring plan to 2 interim 
reviews at 1/3 and 2/3 of 
follow-up visits.  
10 April 2021 
3.0 
Addition of sensitivity 
analysis plans following 2/3 
interim analysis DSMB 
June 25 
4.0 
Clarification of SAP as end of 
data collection approaches 
Sept 12 


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11. 
APPENDIX 
11.1. 
Table of Contents for Data Reports 
 
This section will be completed in the next SAP version.


{Sponsor Name} 
 
{Study/Report Number} 
{Statistical Analysis Plan - Protocol #} 
 
MMM, DD, YYYY 
 
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12. 
REFERENCES 
1. 
Yelland LN, Salter AB, Ryan P. Performance of the modified Poisson regression approach 
for estimating relative risks from clustered prospective data. Am J Epidemiol. 2011;174(8):984-
92. Epub 2011/08/16. doi: 10.1093/aje/kwr183. PubMed PMID: 21841157.