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

A Phase 4 Comparative Trial of Benzathine Penicillin G 2.4 Million Units Administered as a Single Dose Versus Three Successive Weekly Doses 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 Benzathine Penicillin G (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 human immunodeficiency virus (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.

This is a phase 4, randomized, open-label, multicenter trial to evaluate the efficacy of a single injected dose of Benzathine Penicillin G (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 human immunodeficiency virus (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 compliance with study product and adherence to the corresponding scheduled 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 human immunodeficiency virus (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 Benzathine Penicillin G (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 sexually transmitted infection (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 an investigational drug in the past 30 days that might interfere with safety or efficacy assessment.

   *If the subject has used any investigational drugs in the past 30 days, contact the Principal Investigator, Division of Microbiology and Infectious Diseases (DMID) Clinical Project Manager, DMID Medical Officer, and FHI 360 to confirm eligibility.

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