Azithromycin/Bicillin Syphilis

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00031499

Collaborator

(none)

593

Enrollment

Locations

Arms

105

Duration (Months)

59.3

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if azithromycin, a drug approved for treatment of other infections, is as effective for syphilis (a sexually transmitted disease) as the standard treatment. Approximately 600 healthy adults, who are HIV-negative, ages 18 to 55 years of age, with primary, secondary or early latent syphilis, will participate in this research study. Volunteers will be enrolled in 5 U.S. cities and in Madagascar. Participants will be chosen randomly (by chance) to receive 1 of 2 study drugs: benzathine penicillin given (2 shots in the buttocks) or 4 tablets of azithromycin. Subjects who report a history of a penicillin allergy will be given either 2.0 g of oral azithromycin or 100 mg doxycycline taken orally, twice a day for 14 days. Over 2 years, 10 visits will be required. Procedures will include blood samples, physical exams, and swabs of sores.

Condition or Disease	Intervention/Treatment	Phase
Syphilis	Drug: Azithromycin Drug: Benzathine Penicillin Drug: Doxycycline	Phase 3

Detailed Description

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. 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. Although the study endpoint will be determined at 6 months, all participants, will have follow-up visits for 2 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; or failure.

Study Design

Study Type:

Interventional

Actual Enrollment :

593 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III Equivalence Trial of Azithromycin vs. Benzathine Penicillin for the Treatment of Early Syphilis

Study Start Date :

Jun 1, 2000

Actual Primary Completion Date :

Aug 1, 2007

Actual Study Completion Date :

Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azithromycin Azithromycin 2.0 gram single oral dose.	Drug: Azithromycin Single 2 gram oral dose (4 tablets) at Day 1.
Active Comparator: Benzathine Penicillin Benzathine penicillin 2.4 million units administered intramuscularly. Doxycycline will be administered if the patient is allergic to Benzathine Penicillin.	Drug: Benzathine Penicillin Supplied in pre-filled syringes containing 1.2 million units of benzathine penicillin; 2.4 million units administered intramuscularly at Day 1, in one or both buttocks. Drug: Doxycycline Baseline visit, 28 capsules dispensed, for a dose of 100 mg twice a day (BID).

Arm

Intervention/Treatment

Experimental: Azithromycin

Azithromycin 2.0 gram single oral dose.

Drug: Azithromycin

Single 2 gram oral dose (4 tablets) at Day 1.

Active Comparator: Benzathine Penicillin

Benzathine penicillin 2.4 million units administered intramuscularly. Doxycycline will be administered if the patient is allergic to Benzathine Penicillin.

Drug: Benzathine Penicillin

Supplied in pre-filled syringes containing 1.2 million units of benzathine penicillin; 2.4 million units administered intramuscularly at Day 1, in one or both buttocks.

Drug: Doxycycline

Baseline visit, 28 capsules dispensed, for a dose of 100 mg twice a day (BID).

Outcome Measures

Primary Outcome Measures

Cure of syphilis defined as a negative reactive serologic test for syphilis (RPR) titer or greater than or equal to a 4-fold (2 dilution) decrease in RPR titer at 6 months following treatment and resolution of all signs and symptoms of syphilis. [Month 6.]

Secondary Outcome Measures

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 titer over previous lowest result. [Months 9, 12, and 24.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

The subject is 18 to 55 years of age.
The subject has signed written informed consent.
The subject has untreated primary [darkfield or Treponema (T.) pallidum by a rapid, direct, fluorescent antibody darkfield (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).
The subject has laboratory evidence of syphilis, i.e., reactive serologic test for syphilis (RPR).
The subject is not pregnant, as documented by a negative urine or serum pregnancy test, or lactating.
The subject is willing to have an HIV test, and, participate in HIV counseling and return to the clinic for follow-up treatment.

Exclusion Criteria:

The subject does not have reactive serologic tests for syphilis.
The subject has latent syphilis of unknown duration, late latent syphilis or evidence of neurosyphilis.
The subject has a known or suspected allergy to macrolide or azalide antibiotics.
The subject has a known or suspected sexually transmitted disease (STD), other than syphilis requiring treatment with a drug, other than azithromycin, active against T. pallidum.
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 allowed).
The subject is known to be HIV positive prior to enrollment.
The subject has suspected or known ongoing drug use that might interfere with study participation and follow-up treatment.
The subject has a history of cardiovascular disease, known immunosuppression, or known AIDS, which might compromise response to therapy.
The subject is judged by the investigators to be unlikely to reliably participate in the study follow-up.
The subject has used any investigational drugs in the past 30 days.
The subject has any other condition that may impair drug absorption (malabsorption syndrome or active peptic ulcer disease).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Hospital - Infectious Diseases	Birmingham	Alabama	United States	35249-0001
2	Indiana University	Indianapolis	Indiana	United States	46202
3	Louisiana State University Health Sciences Center - Infectious Diseases	New Orleans	Louisiana	United States	70112-2865
4	Johns Hopkins Hospital - Medicine - Infectious Diseases	Baltimore	Maryland	United States	21287-0005
5	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27514
6	University of North Carolina School of Medicine - Center for Infectious Diseases	Chapel Hill	North Carolina	United States	27599-7030
7	Durham County Health Department	Durham	North Carolina	United States	27701-3720
8	Laboratoire National de Reference sur le VIH/SIDA (LNR)	Analamanga	Antananarivo	Madagascar	101
9	Hopitaly Kely	Tamatave	Antsiranana	Madagascar
10	Hopitaly Mahabibo	Mahajanga Majunga	Mahajanga	Madagascar	401