Clinical trial NCT03660488
Conditions: Syphilis Early Syphilis
Keywords: syphilis cefixime penicillin
Sponsor: University of California, Los Angeles
Start date: 2018-09-03; Completion date: 2021-01-30
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of the study is to evaluate the efficacy of oral cefixime as an alternative treatment for syphilis infection.

One hundred adult patients (≥18 years old) with syphilis infection (positive Treponema Pallidum Particle Agglutination assay and RPR titer ≥ 1/8) will be recruited. Participants will be randomized (1:1) to receive either the standard of care Penicillin or Cefixime.

During the study, participants will visit the clinic up to 5 times; at baseline visit, at 3, 6, 12 months after treatment initiation. Participants of the cefixime group will be required to visit the clinic 14 days after treatment initiation. In each visit, participants will be asked about current symptoms and do laboratory tests for syphilis (RPR). Subjects who have a 4-fold decrease (from study entry RPR) in RPR titers from baseline at 6 months will be considered a positive treatment response.

Detailed description:
Syphilis is a major issue worldwide causing 5.6 million new cases of syphilis worldwide, of which over 900,000 are pregnant women. It is also responsible for congenital infections causing fetal loss or stillbirth or, in a live-born infant, neonatal death, prematurity and low birth weight. Penicillin is the currently used treatment. However, lack of penicillin and alternatives to treatment often hinder treatment and prevention efforts.

Cefixime is an FDA-approved, orally administered third-generation cephalosporin that is currently used for the treatment of a wide range of infections, including urinary tract infections. Our goal is to evaluate the efficacy and safety of oral cefixime as an alternative treatment for syphilis infection.

One hundred adult patients (≥18 years old) with syphilis infection will be recruited. Eligible participants will have laboratory-confirmed syphilis infection with a positive Treponema pallidum Particle Agglutination (TPPA) assay and RPR (Rapid Plasma Reagin ) titer ≥ 1/8. Participants will be randomized (1:1) to receive either the standard of care Penicillin or Cefixime.

During the study, participants will visit the clinic 5 times; at baseline visit, demographic, clinical information and laboratory test results for syphilis will be recorded and treatment will start. Depending on the study group, the treatment plan will be oral Cefixime 400mg, twice per day for ten consecutive days or one dose of intramuscular Penicillin. Patients will be required to visit the clinic two weeks after treatment initiation to verify adverse effects. Follow up visits will occur at 3, 6 and 12 months after treatment initiation. In each visit, participants will be asked about current symptoms, interval sexual history, concomitant antibiotic use and possible adverse reactions. Subjects will also have a venipuncture blood specimen collected for syphilis testing (RPR). Subjects who have a 4-fold decrease (from study entry RPR) in RPR titers from baseline at 6 months will be considered a positive treatment response.

Arms: arm 1: Patients of the "Penicillin Group" will receive the standard of care treatment. This is one intramuscular injection of 2.4 million units Benzathine Penicillin G. The group will consist of 50 patients. arm 2: Patients of the "Cefixime Group" will receive Cefixime 400 mg, per os, one tablet, two times per day, for ten consecutive days. The study team will provide the medication.

The group will consist of 50 patients.
Interventions: intervention 1: Cefixime 400 milligram Oral Capsule [Suprax] intervention 2: Benzathine Penicillin G
Intervention descriptions: intervention 1: The intervention group will receive Cefixime 400mg, one tablet twice per day, for ten consecutive days intervention 2: The control group will receive Benzathine Penicillin G 2.4 Million Units intramuscularly for treatment of syphilis. Penicillin is the indicated treatment for syphilis infection

Protocol documents:
Prot_SAP_001.pdf: 
Page 1 of 20 
Clinical Efficacy of Cefixime for Treatment of Early Syphilis 
1 
NCT:03660488 
2 
August 10, 2020 
 
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Page 2 of 20 
Clinical Trial Protocol to Evaluate the Efficacy of Cefixime in the 
4 
Treatment of Early Syphilis  
5 
 
6 
 
7 
Authors: SN Mehta1, C. Stafylis1, D. Tellalian2, P. Burian2, C. Okada2, C. Millner2 , C. Mejia3 JD 
8 
Klausner1,2  
9 
 
 
10 
Abstract 
11 
Background: Syphilis rates have been increasing both in the US and internationally with 
12 
incidence higher among men-who-have-sex-with-men and people living with human 
13 
immunodeficiency virus (HIV) infection. Currently, benzathine penicillin is the recommended 
14 
treatment for syphilis in all patients. Global shortages and cost increases in benzathine penicillin 
15 
call for alternative treatment options. This study evaluates the efficacy of oral cefixime for the 
16 
treatment of early syphilis.  
17 
Methods: We are conducting a randomized, multisite, open-label, non-comparative clinical trial 
18 
in Los Angeles and Oakland, California. Eligible participants are ≥18 years old, with primary, 
19 
secondary or early latent syphilis (Rapid Plasma Reagin [RPR] titer ≥1:8). Patients with HIV 
20 
infection must have a viral load ≤200 copies/mL and CD4+ T cell count ≥350 cells/μl during the 
21 
past 6 months. Participants are randomized to receive either 2.4M IU benzathine penicillin G 
22 
intramuscularly once or cefixime 400mg orally twice a day for 10 days. Participants return at 3, 6, 
23 
and 12 months post-treatment for follow-up RPR serological testing. The primary outcome is the 
24 
proportion of participants who achieve ≥4-fold RPR titer decrease at 3- or 6-months post-
25 
treatment. 
26 
Discussion: Clinical trials evaluating the efficacy of alternative antibiotics to penicillin are urgently 
27 
needed.  
28 
Trial Registration: Clinicaltrials.gov, NCT03660488. Registered September 4, 2018, 
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Page 3 of 20 
https://clinicaltrials.gov/ct2/show/NCT03660488 
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31 
Keywords 
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Clinical Trial, Cefixime, Treponema pallidum, penicillin, early syphilis, syphilis 
33 
 
34 
 
35 
Administrative information 
36 
 
37 
Title {1} 
Clinical Trial Evaluating the Clinical Efficacy of Cefixime in Treatment for 
Early Syphilis 
Trial registration {2a and 2b}. 
ClinicalTrials.gov Identifier: NCT03660488 (1) 
Protocol version {3} 
Version 9; 11.20.2019 
Funding {4} 
AIDS Healthcare Foundation research grant (Grant #20181796) 
 
Author details {5a} 
1. Department of Medicine, David Geffen School of Medicine at UCLA, Los 
Angeles, CA/United States of America  
2. Department of Medicine, AIDS Healthcare Foundation, Los Angeles,  
CA/United States of America 
3. Public Health Division, AIDS Healthcare Foundation, Los Angeles, CA/ 
United States of America    
Name and contact information for the 
trial sponsor {5b} 
AIDS Healthcare Foundation 


Page 4 of 20 
Role of sponsor {5c} 
The sponsor played no part in study design; and will play no part in the 
collection, management, analysis, and interpretation of data; writing of the 
report; and the decision to submit the report for publication. 
 
 
38 


Page 5 of 20 
Introduction 
39 
Background and rationale {6a} 
40 
Syphilis rates have been increasing both in the US and internationally, with incidence higher among 
41 
men-who-have-sex-with-men and people living with human immunodeficiency virus (HIV) 
42 
infection (2-4). Currently, benzathine penicillin is the recommended treatment for syphilis in all 
43 
patients, including those living with HIV infection. Doxycycline and tetracycline are available 
44 
alternative treatments for non-pregnant patients who are allergic to penicillin (5-8).  Injectable daily 
45 
ceftriaxone is another alternative treatment that may be considered and is safe in pregnancy, as a 
46 
recent review from our team showed (9).  
47 
Existing alternative treatment recommendations are based on clinical experience, a limited number 
48 
of small clinical trials, and case series (5-7, 10). However, each regimen poses clinical challenges. 
49 
Doxycycline/tetracycline require 14 days of treatment by mouth, with tetracycline requiring four 
50 
daily doses. Ceftriaxone is administered intramuscularly, just like penicillin, but it requires daily 
51 
injections for 10-14 days, making adherence potentially problematic. In pregnancy, only benzathine 
52 
penicillin is recommended due to potential toxic effects of the alternatives or due to insufficient 
53 
efficacy data (WHO). Shortages of benzathine penicillin worldwide have led to the use of unproven 
54 
non-penicillin alternatives (10-12).  
55 
Considering the high cost and time required for developing and approving new antibiotics that can 
56 
treat syphilis in patients with and without HIV infection, a new approach for identifying new, safe, 
57 
and efficacious antibiotic treatments for syphilis is necessary. Previously Food and Drug 
58 
Administration (FDA)-approved antibiotics, that are safe and efficacious in other infections and have 
59 
a favorable pharmacologic profile suggesting activity against Treponema pallidum, may be effective 
60 
alternatives for treating syphilis.  
61 
Cefixime is an FDA-approved orally administered third-generation cephalosporin with spectrum of 
62 
activity and pharmacokinetic profile similar to that of ceftriaxone, a drug which has been used for the 
63 


Page 6 of 20 
treatment for syphilis (13). Cefixime is clinically used for uncomplicated urinary tract infections, 
64 
upper respiratory tract bacterial infections and in the treatment of uncomplicated Neisseria 
65 
gonorrhoeae genital infection (14).  To our knowledge, it has never been studied as a treatment for 
66 
early syphilis.  
67 
Cefixime has a well-studied pharmacokinetic profile (14-19). Unlike other alternatives for syphilis, 
68 
adverse event profiles are favorable with cefixime in non-pregnant as well as pregnant patients (20, 
69 
21) . Nearly 40-50% of the dose is absorbed when it is given orally, whether administered with or 
70 
without food. Peak concentrations occur between 2 and 6 hours following oral administration of a 
71 
single 400mg tablet. A single 400mg tablet produces an average peak concentration of approximately 
72 
3.7μg/mL (range 1.3-7.7μg/mL). Typical blood levels of cefixime after a single dose of cefixime 400 
73 
mg by mouth are 4.84 μg/ml maximum at 4 hours and above 1.0 μg/ml at 12 hours. Serum protein 
74 
binding is concentration independent with a bound fraction of approximately 65%. Cefixime is 
75 
moderately distributed into extracellular water/tissue pools.  Its half-life averages to 3-4 hours but 
76 
may range up to 9 hours in healthy volunteers. Approximately 50% of the absorbed dose is excreted 
77 
unmodified in the urine within 24 hours and nearly 10% is excreted in bile (10).  
78 
We therefore believe that cefixime’s pharmacokinetic similarity to ceftriaxone and its safety in the 
79 
treatment of pregnant women could potentially make it a viable option in the treatment of early 
80 
syphilis.  
81 
 
82 
Objective {7} 
83 
The primary objective of our study is to determine the efficacy of cefixime 400mg, taken orally two 
84 
times a day (BID) for 10 consecutive days. Our hypothesis is that cefixime would be an efficacious 
85 
treatment for early syphilis.   
86 
 
87 
Trial design {8} 
88 


Page 7 of 20 
This is a randomized, open-label, non-comparative pilot clinical trial. Participants will be randomly 
89 
assigned (1:1 allocation) to receive either the standard of care benzathine penicillin injection or 10-
90 
days of oral cefixime. The study will require 2 years to be completed and each participant will be part 
91 
of the study for one year. 
92 
 
93 
Methods: Participants, interventions and outcomes 
94 
Study setting {9} 
95 
The study will take place in 3 primary care HIV healthcare clinics and 1 wellness center of the 
96 
AIDS Healthcare Foundation in Los Angeles and Oakland, California. Healthcare clinics offer HIV 
97 
and sexually transmitted infection (STI) primary care services while wellness centers are walk-in 
98 
comprehensive sexual health clinics that offer HIV/STI screening services, STI treatment and other 
99 
prevention services.   
100 
 
101 
Eligibility criteria {10} 
102 
The inclusion criteria are:  
103 
1) Clinically or laboratory confirmed new cases of early syphilis (primary, secondary, early 
104 
latent syphilis) with a plasma Rapid Plasma Reagin (RPR) ≥ 1:8 
105 
2) 18 years of age or older, capable of providing informed consent 
106 
3) HIV infected individuals must have CD4 T cll count≥350 cells/mm3 and be virologically 
107 
suppressed (viral load < 200 copies/mL) during the past 6 months  
108 
4) Able to travel to clinic once a day or be available for phone calls or receive text message for 
109 
at least 7-10 days 
110 
The exclusion criteria are:  
111 
1) Allergy to cefixime or penicillin 
112 
2) Pregnancy or a positive pregnancy test 
113 


Page 8 of 20 
3) Serofast RPR titer (prior titer ≥1:8 without history of 4-fold titer decline) 
114 
4) Recent (within the past 7 days) or concomitant antimicrobial therapy with activity against 
115 
syphilis, namely azithromycin, doxycycline, ceftriaxone or other beta lactam antibiotics (e.g. 
116 
amoxicillin) 
117 
5) A medical condition or other factor that might affect their ability to follow the protocol 
118 
 
119 
Who will take informed consent? {26a} 
120 
Patients must provide written, informed consent before any study procedures occur (randomization, 
121 
blood sample collection, treatment). Consent will be obtained by a study team member in a private 
122 
examination room.  
123 
 
124 
Additional consent provisions for collection and use of participant data and biological 
125 
specimens {26b} 
126 
Patients will also sign a Health Insurance Portability and Accountability Act (HIPAA) release form 
127 
allowing access to clinical and laboratory data, including their HIV test results.  
128 
 
129 
Interventions 
130 
Explanation for the choice of comparators {6b} 
131 
This is a pilot, non-comparative clinical trial designed to collect preliminary efficacy data. It 
132 
includes an “experimental arm” of participants receiving cefixime and a contemporaneous “control 
133 
arm” of participants receiving benzathine penicillin. The study was not designed to be adequately 
134 
powered to show a statistically significant difference in the efficacy between the penicillin and 
135 
cefixime arms.  
136 
 
137 
Intervention description {11a} 
138 


Page 9 of 20 
Eligible participants who provide their consent are randomized to the two arms of the study. 
139 
Initially, the study team collects demographic (age, gender, race, ethnicity, contact, sexual 
140 
orientation) and clinical information (most recent RPR titer, CD4 T cell count, HIV viral load). A 
141 
venipuncture blood sample is collected by trained clinic staff and it is sent to the laboratory for 
142 
testing. Testing is conducted on serum using the Arlington scientific RPR test kit (Arlington, 
143 
Virginia) (22). Participants are randomly assigned to the two treatment groups. Participants 
144 
assigned to the penicillin arm will receive 1 dose of 2.4M IU benzathine penicillin G on the day of 
145 
enrollment. Participants who are assigned to the cefixime arm will be given 20 capsules of oral 
146 
cefixime 400mg on the day of enrollment to take for the following 10 days. Study staff observed 
147 
receipt of the first dose. Subjects in the cefixime arm will then be asked to return for a clinical 
148 
assessment or have a phone call assessment with the study team member 2 weeks following 
149 
enrolment.  
150 
Study staff will follow up with all participants at 3, 6, and 12 months. In each follow up, 
151 
participants are asked questions regarding symptoms, antibiotic use in the past 3 months and 
152 
number of sex partners with whom they had condom-less sex in the past 3 months.  A new 
153 
venipuncture blood sample is also collected for RPR testing 
154 
  
155 
Criteria for discontinuing or modifying allocated interventions {11b} 
156 
Participants may request to leave the study or they may be withdrawn due to study-related adverse 
157 
events. If a subject is discontinued from study participation due to an adverse event, they will be 
158 
evaluated by the study clinicians for the need of additional treatment for syphilis. Safety data will 
159 
be collected on any subject who is withdrawn from the study. 
160 
Participants in both study groups may receive additional treatment with penicillin, if they show no 
161 
response to treatment (stable or absence of 4-fold decline at 6 months).   
162 
 
163 


Page 10 of 20 
Strategies to improve adherence to interventions {11c} 
164 
To ensure retention of participants, follow-up visits will be scheduled to coincide with routine clinic 
165 
appointments for HIV care or preventive sexual health appointments, which occur every three 
166 
months. In addition, study staff will contact participants, either over the phone or via text message, 
167 
before their scheduled follow-up appointment. Finally, participants will receive reimbursement for 
168 
their time and transportation in the form of a gift card. 
169 
 
170 
Relevant concomitant care permitted or prohibited during the trial {11d} 
171 
Usual HIV care and treatment for the participant will continue throughout the trial. Concomitant 
172 
antibiotic use during the participation in the study duration of the trial will be recorded.  
173 
 
174 
Provisions for post-trial care {30} 
175 
Once participants complete the study, they will be able to continue receiving clinical care from the 
176 
clinics. Participants study records will be reviewed and if necessary, additional treatment for 
177 
syphilis will be administered according to the standard of care protocol. 
178 
 
179 
Outcomes {12} 
180 
The primary outcome is the successful treatment of early syphilis by the 3-, or 6-month follow-up. 
181 
The participants’ RPR titer will be used as the primary measure of outcome. Successful treatment is 
182 
defined as an equal or greater than 4-fold RPR titer decrease, from baseline to 3 or 6 months after 
183 
treatment.  
184 
 
185 
Participant timeline {13} 
186 
Participants will be part of the study for 12 months. Study evaluations will occur at 3, 6- and 12-
187 
months post-treatment. See Figure 1 for the participant timeline for the trial.  
188 
189 


Page 11 of 20 
Figure 1: Participant Enrollment and Follow-Up Schedule  
190 
 
191 
 
192 
Sample size {14} 
193 


Page 12 of 20 
The primary analysis will compute the proportion of subjects with a 4-fold decrease (from study 
194 
entry RPR) in RPR titer from baseline at 6 months in the per protocol analysis population. If we 
195 
assume a sample size of 40 and the proportion of subjects with a 4-fold decrease in RPR from 
196 
baseline at 6 months to be 0.9 (90%), we would have a 95% confidence interval of (0.76, 0.97). To 
197 
calculate the number of subjects required to enroll to reach 40 evaluable subjects in the PP analysis 
198 
population, the assumptions that 20% of subjects will be excluded from the PP analysis population 
199 
(due to loss to follow-up or non-compliance with study medication schedule). Under that 
200 
assumption, enrolling 50 subjects will provide 40 subjects in the PP analysis population.  
201 
 
202 
Recruitment {15} 
203 
Participant recruitment will occur in 4 AIDS Healthcare Foundation (AHF) Clinics based in Los 
204 
Angeles, California and Oakland, California. Study clinicians will review the medical and 
205 
laboratory records of syphilis cases returning for treatment before the scheduled clinical visit and if 
206 
the participant fulfils the eligibility criteria, they will be invited to participate in the study.  
207 
 
208 
Assignment of interventions: randomization 
209 
Sequence generation {16a} 
210 
After consent, participants are randomly assigned to the study arms with a 1:1 allocation. We will 
211 
use a simple randomization method with a shuffled deck of sealed envelopes that contain a card 
212 
with the assigned treatment. The cards are created before the enrollment period and distributed to 
213 
each of the study sites.  No other factors will be taken into consideration for randomization.  
214 
Concealment mechanism {16b} 
215 
The envelopes containing the randomization cards are sealed, thus the team member conducting 
216 
enrollment does not know the content of the envelope. 
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Page 13 of 20 
Implementation {16c} 
218 
The study staff will ask the participant to select a sealed envelope from the shuffled deck. After 
219 
selecting the envelope, the participant will reveal the treatment to themselves and the study staff.  
220 
 
221 
Assignment of interventions: Blinding 
222 
Who will be blinded {17a} 
223 
This is an open label clinical trial, while neither the participants nor the study staff will be blinded 
224 
to the assigned treatment, staff performing statistical analyses will be masked to treatment 
225 
assignment. 
226 
Procedure for unblinding if needed {17b} 
227 
Not applicable. 
228 
Data collection and management 
229 
Plans for assessment and collection of outcomes {18a} 
230 
A venipuncture blood sample will be collected at 3, 6, and 12 month visits and it will be tested for 
231 
RPR titer.. Study data collected on baseline include basic demographic information, sexual history, 
232 
laboratory tests (CD4 count, viral load, RPR titer). On each follow up visit, sexual history, 
233 
antibiotic use, symptoms and the RPR titer will be collected. Data will be collected on paper data 
234 
collection forms and will be entered into Research Electronic Data Capture (REDCap) (23, 24).   
235 
Plans to promote participant retention and complete follow-up {18b} 
236 
Study follow-up visits are scheduled to coincide with routine clinic appointments within AHF. 
237 
Study staff will send participants a 1 month, 2 week, and 1 day notification prior to their follow-up 
238 
appointment.  
239 
Data management {19} 
240 


Page 14 of 20 
Participant data will be collected on paper data collection forms and entered into RedCap. Data that 
241 
will be entered into RedCap include participant information (name, date of birth, medical record 
242 
number, contact information) and laboratory results.  
243 
Confidentiality {27} 
244 
Redcap servers are encrypted, HIPAA-compliant, password protected and accessible only by 
245 
designated study members. Hard copy data collection forms will be stored into a locked cabinet 
246 
with limited access only to designated members.  
247 
 
248 
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or 
249 
molecular analysis in this trial/future use {33} 
250 
There are no plans in this trial to evaluate or store biological specimen for genetic or molecular 
251 
analysis for future use.  
252 
 
253 
Statistical methods 
254 
Statistical methods for primary and secondary outcomes {20a} 
255 
The primary analysis for the main outcome will be conducted on the “Per Protocol” (PP) 
256 
population. This will include participants who satisfy the inclusion and exclusion criteria, 
257 
completed treatment (i.e. received the penicillin injection or received all of the cefixime pills), 
258 
report no adverse events, returned for follow-up visits (3 and/or 6 months) and have an evaluable 
259 
RPR result.  
260 
For each treatment group, we will calculate the proportion of PP participants who achieved a 4-fold 
261 
RPR titer decrease at 3, or 6-months post-treatment and the exact binomial 95% confidence 
262 
interval.  
263 
 
264 


Page 15 of 20 
Interim analyses {21b} 
265 
A summary of the enrollment progress, treatment success proportions, adverse events and protocol 
266 
deviations will be provided to the Data Safety Monitoring Board members.  
267 
 
268 
Plans to give access to the full protocol, participant level-data and statistical code {31c} 
269 
The protocol of the study is publicly available on clinicaltrials.gov (NCT03660488). Deidentified 
270 
data will be available upon request to the study Primary Investigator.  
271 
 
272 
Oversight and monitoring 
273 
Composition of the coordinating center and trial steering committee {5d} 
274 
The immediate study research team based in the University of California of Los Angeles meet on a 
275 
weekly basis. The immediate team is joined by a wider team of AHF study clinicians, based in 
276 
study clinics, who also meet on a weekly basis.  
277 
 
278 
Composition of the data monitoring committee, its role and reporting structure {21a} 
279 
The Data and Safety Monitoring Board (DSMB) will be composed of a physician, biostatistician, 
280 
regulatory affairs specialist/ethicist and will oversee the study throughout the 2-year study period. 
281 
They will review study activities every 6 months. The committee will review safety data and 
282 
clinical efficacy reports and report their decision to the Primary investigator.  
283 
 
284 
Adverse event reporting and harms {22} 
285 
The study site investigators will report serious adverse events and adverse events to the responsible 
286 
IRB for that study site in accordance with respective IRB policies and procedures. Follow-up 
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Page 16 of 20 
information to a reported adverse event will be submitted to the IRB as soon as the relevant 
288 
information is available.  
289 
 
290 
Frequency and plans for auditing trial conduct {23} 
291 
The trial and individual clinic sites will be audited at least once during the duration of the study by 
292 
the study sponsor (AIDS Healthcare Foundation). 
293 
 
294 
Plans for communicating important protocol amendments to relevant parties (e.g. trial 
295 
participants, ethical committees) {25} 
296 
Amendments will be submitted to the IRB according to policies and guidance. Any protocol 
297 
changes will be promptly communicated to the IRB, the DSMB and the study team.  
298 
 
299 
Dissemination plans {31a} 
300 
We plan to disseminate study results through peer-reviewed journal publications and conference 
301 
presentations. Study findings will also be shared with relevant clinical and scientific groups.  
302 
 
303 
Discussion 
304 
This is a randomized, non-comparative, pilot study evaluating the efficacy of daily oral cefixime 
305 
400mg for 10 days for the treatment of early syphilis. To our knowledge, this is the first study 
306 
assessing the efficacy of cefixime for early syphilis. As syphilis rates increase and penicillin 
307 
shortages continue to occur in the United States and worldwide, alternative treatments that are 
308 
efficacious for both pregnant and non-pregnant populations, regardless of HIV status are needed (6-
309 
8). Already approved and antibiotics in clinical use with favourable pharmacokinetic profile, such 
310 


Page 17 of 20 
as cefixime, should be clinically evaluated for alternative treatment options.  
311 
Data from this pilot study could be used as a foundation to assess the clinical effectiveness for 
312 
cefixime in early syphilis treatment.  Currently, our study is being conducted among non-pregnant 
313 
individuals. However, subsequent clinical studies should also include women and pregnant women 
314 
to address the gap in the treatment of maternal syphilis.  
315 
 
316 
Trial status 
317 
Recruitment was initiated in September 16th, 2018 and is currently ongoing. The current protocol 
318 
version is version 9 (11/20/2020).  
319 
 
320 
Declarations 
321 
Authors’ contributions {31b} 
322 
SM led the writing of the manuscript. CS led the proposal and protocol development and 
323 
contributed to the writing of the manuscript. DT, PB, CO, and CM contributed to clinical and 
324 
logistical aspects of protocol development.  JDK led the proposal and protocol development and 
325 
developed the treatment algorithm for the protocol. All named authors adhere to the authorship 
326 
guidelines of Trials. All authors have approved the final manuscript and agreed to publication. 
327 
 
328 
The database for this study was supported by NIH National Center for Advancing Translational 
329 
Science (NCATS) UCLA CTSI Grant Number UL1TR001881.  
330 
Funding {4} 
331 
The trial is funded by AHF (Grant #20181796). The funding body had no role in the design of the 
332 
study, collection of data or the writing of this paper, nor will the funding body have a role in 
333 
analysis, interpretation of data or in writing future manuscripts.  
334 


Page 18 of 20 
 
335 
Availability of data and materials {29} 
336 
The datasets analyzed during the current study are available from the corresponding author on 
337 
reasonable request.  
338 
 
339 
Ethics approval and consent to participate {24} 
340 
The study was approved by Western IRB (IRB# 20181796) and UCLA IRB (IRB# 18-000665).  
341 
 
342 
Consent for publication {32} 
343 
Not applicable  
344 
Competing interests {28} 
345 
The authors declare that they have no competing interests. 
346 
 
347 
Author details 
348 
1. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA/United 
349 
States of America  
350 
2. Department of Medicine, AIDS Healthcare Foundation, Los Angeles, CA/United States of 
351 
America  
352 
3. Public Health Division, AIDS Healthcare Foundation, Los Angeles, CA/United States of 
353 
America 
 
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References 
355 
1. 
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 
356 
(US). - Identifier NCT03660488, Cefixime for Alternative Syphilis Treatment; 2018 Sep 6 [cited 
357 
2020 April 29]; Available from: https://clinicaltrials.gov/ct2/show/NCT03660488 
358 
2. 
Braxton J, Grey J, Harvey A, Kidd S, Presley RJ, Ramirez V, et al. Syphilis surveillance 
359 
supplement 2013–2017 for Sexually transmitted disease surveillance 2017. 2019. 
360 
3. 
Kojima N, Klausner JDJCer. An update on the global epidemiology of syphilis. 
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2018;5(1):24-38. 
362 
4. 
World Health Organization. WHO guidelines for the treatment of Treponema pallidum 
363 
(syphilis). 2016. 
364 
5. 
Clement ME, Okeke NL, Hicks CBJJ. Treatment of syphilis: a systematic review. 
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2014;312(18):1905-17. 
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6. 
Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AMJCID. Doxycycline compared with 
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benzathine penicillin for the treatment of early syphilis. 2006;42(6):e45-e9. 
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