SyphilisPhase 3NCT00031499
Azithromycin/Bicillin Syphilis
A Phase 3 study testing Azithromycin, Benzathine Penicillin and Doxycycline in people with Syphilis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 10 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Syphilis
- What is being tested?
- Azithromycin, Benzathine Penicillin and Doxycycline
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 593 participants
- Where
- 10 sitesin 2 countries
- Study dates
- Jun 2000to Mar 2009
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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).
Trial locations and contacts
10 sites in 2 countries.
10 sites in 2 countries
United States7 sites
Johns Hopkins Hospital - Medicine - Infectious Diseases
Baltimore, Maryland, 21287-0005
University of Alabama Hospital - Infectious Diseases
Birmingham, Alabama, 35249-0001
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514
University of North Carolina School of Medicine - Center for Infectious Diseases
Chapel Hill, North Carolina, 27599-7030
Durham County Health Department
Durham, North Carolina, 27701-3720
Indiana University
Indianapolis, Indiana, 46202
Louisiana State University Health Sciences Center - Infectious Diseases
New Orleans, Louisiana, 70112-2865
Madagascar3 sites
Laboratoire National de Reference sur le VIH/SIDA (LNR)
Analamanga, Antananarivo, 101
Hopitaly Mahabibo
Mahajanga Majunga, Mahajanga, 401
Hopitaly Kely
Toamasina, Antsiranana
About this study
Official title: A Phase III Equivalence Trial of Azithromycin vs. Benzathine Penicillin for the Treatment of Early Syphilis
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.
Read the 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.
- Conditions
- Syphilis
- Being tested
- Azithromycin, Benzathine Penicillin, Doxycycline
- Keywords
- Azithromycin, Syphilis, Penicillin
- Medical subject headings
- Syphilis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzithromycinDrug
Single 2 gram oral dose (4 tablets) at Day 1.
Benzathine PenicillinDrug
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.
DoxycyclineDrug
Baseline visit, 28 capsules dispensed, for a dose of 100 mg twice a day (BID).
| Study group | Role | What they receive |
|---|---|---|
| Azithromycin | Experimental | Azithromycin 2.0 gram single oral dose. Receives: Drug: Azithromycin |
| Benzathine Penicillin | Active comparator | Benzathine penicillin 2.4 million units administered intramuscularly. Doxycycline will be administered if the patient is allergic to Benzathine Penicillin. Receives: Drug: Benzathine Penicillin; Drug: Doxycycline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Month 6.
Secondary outcomes (1)
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.
Measured: Months 9, 12, and 24.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2002 (estimated)
- Study startJun 2000
- Primary completionAug 2007
- Study completionMar 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for SyphilisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 593 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00031499
- Sponsor's protocol ID
- 99-005
- Status last verified
- Apr 2013
- First submitted
- 6 Mar 2002
- Last updated
- 29 Apr 2013
- Results posted
- No
Publications
Sena AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P, Langley C, McNeil L, Hook EW. Predictors of serological cure and Serofast State after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011 Dec;53(11):1092-9. doi: 10.1093/cid/cir671. Epub 2011 Oct 12.
PubMed 21998287Hook EW 3rd, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC, Martin D, Langley C, McNeil L, Wolff M. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010 Jun 1;201(11):1729-35. doi: 10.1086/652239.
PubMed 20402591
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III Equivalence Trial of Azithromycin vs. Benzathine Penicillin for the Treatment of Early Syphilis
- ClinicalTrials.gov ID
- NCT00031499
- Acronym / sponsor ID
- 99-005
- Conditions
- Syphilis
- Keywords
- Azithromycin, Syphilis, Penicillin
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 593 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- Jun 2000
- Primary completion
- Aug 2007 (actual)
- Study completion
- Mar 2009 (actual)
- First posted
- 7 Mar 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Azithromycin | Experimental | Drug: AzithromycinAzithromycin 2.0 gram single oral dose. |
| Benzathine Penicillin | Active comparator | Drug: Benzathine Penicillin, Drug: DoxycyclineBenzathine penicillin 2.4 million units administered intramuscularly. Doxycycline will be administered if the patient is allergic to Benzathine Penicillin. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (11 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzithromycinSingle 2 gram oral dose (4 tablets) at Day 1. | Drug | Azithromycin |
| Benzathine PenicillinSupplied 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 | Benzathine Penicillin |
| DoxycyclineBaseline visit, 28 capsules dispensed, for a dose of 100 mg twice a day (BID). | Drug | Benzathine Penicillin |
Primary outcome
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.
Time frame: Month 6.
1 secondary outcome
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.
Time frame: Months 9, 12, and 24.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2013.
- Results publication: PubMed 21998287Sena AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P, Langley C, McNeil L, Hook EW. Predictors of serological cure and Serofast State after treatment in HIV-negative persons with early syphilis. Clin Infect Dis. 2011 Dec;53(11):1092-9. doi: 10.1093/cid/cir671. Epub 2011 Oct 12.
- Results publication: PubMed 20402591Hook EW 3rd, Behets F, Van Damme K, Ravelomanana N, Leone P, Sena AC, Martin D, Langley C, McNeil L, Wolff M. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis. 2010 Jun 1;201(11):1729-35. doi: 10.1086/652239.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
10 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Azithromycin, Benzathine Penicillin and Doxycycline in people with Syphilis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 10 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Apr 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States, Madagascar. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: Month 6.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00031499, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2013.