Phase 4 Comparative Trial of Benzathine Penicillin G for Treatment of Early Syphilis in Subjects With or Without HIV Infection

This is a phase 4, randomized, open-label, multicenter trial to evaluate the efficacy of a
single injected dose of BPG 2.4 MU (Arm 1) compared to three successive weekly injected doses
of BPG 2.4 MU (Arm 2) for treatment of early syphilis in HIV-infected and HIV-uninfected
subjects. The study will enroll 560 adults (to achieve 420 evaluable subjects) aged 18 years
or older with untreated early syphilis (primary, secondary, or early latent). It will be
conducted at 9 sites in the US and last for 48 months with patient participation duration of
12 months. The primary objective is to compare the serological response to therapy in
subjects with early (primary, secondary, or early latent) syphilis treated with Benzathine
Penicillin G (BPG) 2.4 million units (MU) once or weekly for three successive weeks. The
secondary objectives are: 1) to determine if the difference in response to therapy between
treatment arms by Month 6 differs among subjects with or without HIV infection; 2) to
determine the impact of multiple BPG injected doses on subject adherence to scheduled
follow-up visits; 3) to determine the incidence and manifestations of the Jarisch-Herxheimer
reaction among subjects treated for early syphilis with BPG; 4) to collect prospective data
up to Month 12 on the serological response to therapy in subjects treated for early syphilis
with either BPG regimen; 5) to compare epidemiological characteristics of early syphilis
among subjects with or without HIV infection.

Inclusion Criteria:

1. Subject is aged 18 years or older.

2. Subject has provided informed consent.

3. Subject has untreated primary*, secondary**, or early latent*** syphilis.

*Primary syphilis is characterized by the presence of an ulcerative lesion at a
potential site of inoculation (while classically solitary, shallow, painless and with
an indurated, clean base, primary lesions may be multiple, may vary considerably in
appearance, and/or may not be painless) or by darkfield, acceptable polymerase chain
reaction (PCR), or direct fluorescence antibody-T. pallidum (DFA-TP) positive ulcers.

**Secondary syphilis is characterized by classical palmar/plantar rash, condylomata
lata, mucous patches, etc. or by darkfield, acceptable PCR, or DFA-TP positive
lesions.

***Early latent syphilis is characterized by current reactive serologic tests for
syphilis (STS) and a documented non-reactive STS, or documented sexual exposure to an
individual known to have primary, secondary, or early latent syphilis diagnosed within
the last 12 months.

4. Subject either has a newly reactive non-treponemal test (such as an RPR test) or a
history of syphilis and a current increase in RPR titer of two or more dilutions
(i.e., four-fold).

5. If subject is of childbearing potential, subject has a negative urine or serum
pregnancy test.

6. Subject is willing to have an HIV test, participate in HIV counseling, and return to
clinic for follow-up.

7. In the opinion of the investigator, subject is able and willing to comply with study
procedures, including receipt of three BPG injected doses if randomized to Arm 2.

8. If female, subject must be of non-childbearing potential* or must be using an
acceptable method of birth control** to avoid becoming pregnant.

- Non-childbearing potential is defined as being post-menopausal for at least 1
year, status after bilateral tubal ligation, or status after bilateral
oophorectomy, or status after hysterectomy.

- Subject must agree to avoid becoming pregnant by using one of the following
acceptable methods of birth control for the entire duration of participation
in the trial:

- Intrauterine contraceptive device; OR

- Oral contraceptives; OR

- Hormonal injections; OR

- Hormonal implants; OR

- Contraceptive patches; OR

- Monogamous relationship with vasectomized partner; OR

- Exclusively same-sex relationships; OR

- Use of condoms by the male partner; OR

- Abstinence

Exclusion Criteria:

1. Subject previously enrolled in this trial.

2. Subject has latent syphilis of unknown duration, late latent syphilis, or evidence of
neurosyphilis, including ocular syphilis.*

*e.g., eye pain/redness, recent ocular change, and/or changes in visual acuity

3. Subject has a known or suspected allergy or hypersensitivity to penicillin or other
beta-lactam antibiotics.

4. Subject has a known or suspected STI other than syphilis requiring treatment with a
drug active against T. pallidum.

5. 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 (e.g.,
quinolones, sulfonamides, trimethoprim, metronidazole, spectinomycin) will be allowed.

6. Subject has suspected or known ongoing drug use that might interfere with study
participation and follow-up treatment.

7. Subject is breastfeeding.

8. Subject has used any investigational drugs in the past 30 days.

9. Subject has any other condition that, in the opinion of the investigator, would
interfere with participation in the study.