Information source: National Institute of Allergy and Infectious Diseases (NIAID)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Syphilis
Intervention: Azithromycin (Drug); Benzathine Penicillin (Drug); Doxycycline (Drug)
Phase: Phase 3
Status: Active, not recruiting
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)
The purpose of this study is to determine if Azithromycin, a drug approved for treatment of
other infections, is as affective for syphilis therapy is as the usual treatment.
Approximately 600 healthy adults, who are HIV-negative, age 18 to 55 years of age with
primary, secondary or early latent syphilis, will be participating in this research study.
Volunteers will be enrolled in 4 cities of the United States and in Madagascar. Participants
will be chosen randomly (by chance) to receive one of 2 study drugs: Benzathine Penicillin
given as one dose (2 shots in the buttocks) or 4 tablets of Azithromycin. Over 2 years, 10
visits are required. Procedures will include blood samples, physical exam, and swabs of
sores. For subjects who report history of Penicillin allergy will be given either 2. 0 g of
oral Azithromycin or 100 mg Doxycycline taken orally, twice a day for 14 days.
Official title: A Phase III Equivalence Trial of Azithromycin vs. Benzathine Penicillin for the Treatment of Early Syphilis
Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study
Primary outcome: RPR titer
Secondary outcome: RPR titer
Syphilis is a disease with a worldwide distribution. It causes genital ulceration, thereby
amplifying risk for HIV acquisition and transmission and it may cause congenital infection,
spontaneous abortion, and stillbirth if untreated in pregnant women. About one third of all
cases, if untreated, result in late sequelae which include neurosyphilis, gumma formation and
cardiovascular involvement. This study will be a multi-center, randomized, open-label trial
to evaluate the efficacy of azithromycin in treating primary, secondary and early latent
syphilis in HIV (Human Immunodeficiency Virus) uninfected volunteers. Up through version 6. 0
of this protocol volunteers were only followed for 12 months. The protocol was amended
starting with version 7. 0 to include follow-up visits at month 18 and 24 in order to capture
possible "late failures." Each subject will be randomized into a treatment group. If the
subject does not have a self-reported history of penicillin allergy, the subject will be
randomized to receive either a single 2. 0 gram dose of azithromycin administered orally, or
2. 4 million units of benzathine penicillin G administered intramuscularly once. Eligible
patients who report a history of penicillin allergy will be randomized (using a separate
randomization schedule) to receive either a single dose of azithromycin or doxycycline, 100
milligrams, taken orally, twice a day for 14 days. Block randomization will be used within
each clinical center with subjects allocated in equal numbers to either standard therapy or
azithromycin. Participants found to be ineligible for study participation after they have
been randomized and treated, will be treated again with benzathine penicillin G (or
doxycycline if they are allergic to penicillin) and will continue follow-up for safety
evaluation. The treatment assignments will not be blinded. The primary outcome for this trial
is the cure of syphilis, at the 6 month post treatment visit. Irrespective of the outcome at
6 months, all participants will be encouraged to complete additional follow-up visits at 9,
12, 18 and 24 months. A subject cured at the 6 month visit who subsequently relapses or
becomes reinfected and does not meet these criteria for a cure at a later outcome visit will
still be considered cured and a success for the primary outcome. Secondary outcomes will
consist of the cure rates at 9, 12 and 24 months post treatment and the rate of relapse or
reinfection defined as cure followed by recurrent clinical manifestations or a 2-dilution
increase in RPR (reactive serologic test for syphilis) titer over previous lowest result.
Participants not cured at 6 months will be given standard therapy, either penicillin or
doxycycline depending on their allergy status. Secondary analyses will attempt to control for
loss to follow-up and reinfection. Secondary analyses will also provide useful descriptive
information on disease course and subject retention. Analyses will be conducted separately
for the cohorts allergic and not allergic to penicillin. No attempt will be made to recruit a
sufficient sample size among penicillin allergic subjects to attain the desired power for the
primary outcome. Therefore these results will be seen as preliminary to a possible future
trial and as confirmatory to the primary comparison. The study endpoint will be determined at
6 months, all participants, including those in the substudy; will have follow-up visits for
two full years. At the end of the 6 month evaluation period, all participants will have been
classified in one of the following groups: cure; clinical response/serological nonresponse;
Minimum age: 18 Years.
Maximum age: 55 Years.
1. The subject is 18 to 55 years of age.
2. The subject has signed written informed consent.
3. The subject has untreated primary (darkfield or DFA-TP positive genital ulcers),
secondary (based on classical palmar/plantar rash, condylomata lata, mucous patches,
etc. or darkfield or DFA-TP positive lesions), or early latent syphilis (e. g., current
reactive serologic tests for syphilis (STS), and a documented non-reactive STS or
documented sexual exposure to a known early latent, primary or secondary syphilis
patient in last 12 months; identification of this sexual contact must occur within 60
days of admission into the study).
4. The subject has laboratory evidence of syphilis, i. e., reactive serologic test for
5. The subject is not pregnant, as documented by a negative urine or serum pregnancy
test, or lactating.
6. The subject is willing to have an HIV test, and, participate in HIV counseling and
return to the clinic for follow-up treatment.
1. The subject does not have reactive serologic tests for syphilis.
2. The subject has latent syphilis of unknown duration, late latent syphilis or evidence
3. The subject has a known or suspected allergy to macrolide or azalide antibiotics.
4. The subject has a known or suspected STD, other than syphilis requiring treatment with
a drug, other than azithromycin, active against T. pallidum.
5. The subject has used antibiotics active against T. pallidum in the preceding 30 days.
(Note: the use of antimicrobials known to NOT be effective against T. pallidum such as
quinolones, sulfonamides, trimethoprim, metronidazole and spectinomycin will be
6. The subject is known to be HIV positive prior to enrollment.
7. The subject has suspected or known ongoing drug use that might interfere with study
participation and follow-up treatment.
8. The subject has a history of cardiovascular disease, known immunosuppression, or known
AIDS, which might compromise response to therapy.
9. The subject is judged by the investigators to be unlikely to reliably participate in
the study follow-up.
10. The subject has used any investigational drugs in the past 30 days.
11. The subject has any other condition that may impair drug absorption (malabsorption
syndrome or active peptic ulcer disease).
Locations and Contacts
Hopitaly Mahabibo, Majunga, Madagascar
Hopitaly Kely, Tamatave, Madagascar
Laboratoire National de Reference sur le VIH/SIDA (LNR), Antananarivo, Madagascar
University of Alabama at Birmingham, Birmingham, Alabama 35233, United States
Indiana University, Indianapolis, Indiana 46202, United States
Louisiana State University, New Orleans, Louisiana 70112, United States
Johns Hopkins University, Baltimore, Maryland 21287, United States
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7030, United States
Durham County Health Department, Durham, North Carolina 27701, United States
Starting date: June 2000
Ending date: February 2009
Last updated: June 19, 2008