SyphilisPhase 3SY-DOXYNCT04838717
Clinical Trial of Doxycycline VS BPG for Early Syphilis (SY-DOXY)
A Phase 3 study testing BPG and Doxycycline in people with Syphilis, run by Assistance Publique - Hôpitaux de Paris at 7 sites in France.
Trial summary
According to European and US Centers for Disease Control and Prevention (CDC) guidelines, the recommended treatment for uncomplicated early syphilis in adults (i.e. primary, secondary and early latent) is a single intramuscular injection of 2.4 million units of benzathine benzylpenicillin G (BPG). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Syphilis
- What is being tested?
- BPG 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
- 200 participants
- Where
- 7 sitesFrance
- Study dates
- 6 Dec 2021to 23 Jul 2025
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged ≥ 18 years
- Patients who, after the nature of the study has been explained to them, and before any protocol-specific procedures are performed, give informed consent in writing, in accordance with local regulatory requirements
- Patients with or without HIV infection and with syphilis infection in the early stages according to CDC criteria (primary syphilis, secondary syphilis and early latent syphilis of less than one year's duration)
- Patients with a positive non-treponemal assay result
- Patients available for participation and follow-up during the 6 months of the study
- Patients covered by the French health insurance system
Who cannot join
- Individuals with a history of known hypersensitivity to doxycycline or any other antibiotic of the tetracycline family, BPG (hypersensitivity to the active substance benzathine benzylpenicillin, to other penicillins, to soy phospholipids, peanuts or any of the excipients in the product ; history of severe immediate hypersensitivity reactions (eg anaphylaxis) to other beta-lactams (examples: cephalosporins, carbapenemes or monobactams), lidocaïne (hypersensitivity to lidocaine hydrochloride, amide-linked local anesthetics, or any of the excipients listed in SPC) and / or any of the excipients of the specialties used in the study
- Patients with a negative non-treponemal assay result
- Patients receiving an anticoagulant therapy
- Individuals with contraindications for either of the study drugs
- Individuals treated with retinoids by general route
- Individuals with early and late neurosyphilis
Show all 13Show fewer
- Individuals requiring doxycycline treatment
- Individuals with late syphilis, whether or not latent (e.g. cutaneous)
- Individuals with thrombocytopenia or coagulation disorders contraindicating intramuscular injections
- Women who are pregnant or breast-feeding, or of childbearing age not using or planning to use acceptable birth control measures;
- Individuals under a measure of legal protection or unable to consent
- Individuals participating in any clinical trial with another investigational product in the 28 days preceding the first study visit or intending to participate in another clinical study at any time during the course of this study.
- Recent exposure
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
France7 sites
CHRU Jean Minjoz
Besançon, 25000
Hôpital Henri Mondor
Créteil, 94000
Hôpital de la Croix Rousse
Lyon, 69000
Hôpital Hotel Dieu
Paris, 75001
Hôpital Saint Louis - GeGIDD
Paris, 75009
Hôpital Saint Louis - SMIT
Paris, 75009
CHU Toulouse - Hôpital de la Grave - GeGIDD
Toulouse, 34000
About this study
Official title: A Randomized Non-Inferiority Clinical Trial of Doxycyline Vs BPG for Early Syphilis
According to European and US Centers for Disease Control and Prevention (CDC) guidelines, the recommended treatment for uncomplicated early syphilis in adults (i.e. primary, secondary and early latent) is a single intramuscular injection of 2.4 million units of benzathine benzylpenicillin G (BPG). Recent reviews have also recommended BPG as the first-line treatment of early syphilis, reporting a success rate of more than 90% over a large panel of studies. This form of the drug provides weeks of treponemicidal levels of penicillin in the blood, but does not efficiently cross the blood-brain barrier.
However, despite the use of BPG for almost 70 years and its status as the gold standard treatment for early syphilis, the need to administer this antibiotic parenterally has led to the use of second-line oral antibiotics, including firstgeneration macrolides, and then second-generation macrolides, such as azithromycin. Several African studies have shown 1 g azithromycin bid treatment for one day to be effective against early syphilis, but most authors agree that azithromycin should not generally be used as resistance to this macrolide is highly prevalent in Western countries. Moreover, a recent study by our group showed that more than 80% of the treponemal strains isolated in France harbor the mutation conferring resistance to azithromycin. The use of this alternative would, therefore, be highly unlikely to be effective in France. Tetracycline antibiotics have also been proposed as an alternative in patients with a contraindication for BPG or other forms of penicillin. Doxycycline, at a dose of 100 mg orally twice daily for 14 days, has been endorsed as a preferred alternative treatment, but few data are available concerning its efficacy. This issue is crucial, for two main reasons: there has been a recrudescence of early syphilis in most western countries over the last 20 years, increasing the need for BPG, and two periods of BPG shortage were experienced in 2013 and 2017, leading to the use of alternative treatments due to the temporary unavailability of BPG or its limitation to cases in which no other treatment was possible. Data for the manufacturing and distribution of antibiotics are not publicly available, but reports of limited availability, shortages, and price increases for old antibiotics suggest that the current system is too fragile to provide what should be a given in modern medicine: access to effective treatment for common and potentially severe bacterial infections. The recurrence of BPG shortages over the last five years has created an urgent need to demonstrate that doxycycline is safe, or at least as safe as BPG, for treating early syphilis. The investigators hypothesize that the recommended doxycycline regimen is not inferior to BPG and plan to test this hypothesis in a randomized clinical trial.
- Conditions
- Syphilis
- Being tested
- BPG, Doxycycline
- Keywords
- early syphilis, Doxycycline, Benzathine benzyl penicillin G
- Medical subject headings
- Syphilis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BPGDrug
intramuscular injection of 2.4 million units
DoxycyclineDrug
Oral: at a dose of 100 mg bid for 14 days
| Study group | Role | What they receive |
|---|---|---|
| BPG Arm | Active comparator | BPG injections will be performed at the participating center Receives: Drug: BPG; Drug: Doxycycline |
| Doxycycline Arm | Experimental | Dispensing of Doxycycline 100 mg is carried out at one time at V0 - Inclusion visit. Receives: Drug: BPG; Drug: Doxycycline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Demonstrate, with a high level of evidence, that doxycycline, administered orally at a dose of 100 mg bid for 14 days, is non-inferior to a single intramuscular injection of 2.4 million IU BPG for the treatment of early syphilis
Assessed on the basis of a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6 (commonly used to define cure in real-life settings) or a subsequent negative result in the non-treponemal test if the original test gave a results of 1/2 at inclusion.
Measured: 6 months
Secondary outcomes (4)
Evaluate tolerance to the two regimens in terms of severe adverse events (SAEs)
SAEs will be reported to the study sponsor
- Photosentive reactions will be classified as minor, moderate, severe or very severe
- Immediate hypersensitivity reaction will be classified as urticarial, angioedema or anaphylactic shock
Jarisch-Herxeimer reactions will be evaluated at visit 1 (14 days ± 2 days)
Measured: 6 months
Evaluate adherence to the doxycycline regimen
Adherence to doxycycline treatment will be evaluated on the basis of:
- A tablet count at visit 1 (14 days ± 2 days)
- The noting of tablet intake in the diary for the 14 days of the treatment period
Measured: 6 months
Evaluate the impact of the two regimens on other STDs at month 6
- PCR for CT, MG and NG will be performed systematically at month 6 on urine, or specimens from the throat or anus, depending on the sexual risk factors of the subject
- HIV, hepatitis B serology, hepatitis C serology
Measured: 6 months
demonstrate that doxycycline is non-inferior to a single intramuscular injection of BPG in titer in the non-treponemal assay (VDRL or RPR)
Response will be defined as a four-fold decrease (2 dilutions) in titer in the non-treponemal assay (VDRL or RPR) at month 6 relative to the assay performed before treatment. The two assays (before treatment and at month 6) should be performed in the same laboratory.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2021
- Study start6 Dec 2021
- Primary completion23 Jul 2025
- Study completion23 Jul 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for SyphilisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe 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
- 200 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Responsible party
- Sponsor
- Investigators
- Nicolas DUPIN, PhD & MD, Principal investigator, APHP Assistance Publique des Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04838717
- Sponsor's protocol ID
- APHP180588
- Other IDs
- 2019-003278-21, 2019
- Acronym
- SY-DOXY
- Status last verified
- Oct 2025
- First submitted
- 29 Jan 2021
- Last updated
- 20 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Sagut P, Khamdan F, Al Awadhi A, Hua-Liang Lim J, Chosidow O, Elston DM. Dermatology images: Syphilis. J Am Acad Dermatol. 2024 Oct;91(4):774-779. doi: 10.1016/j.jaad.2024.06.039. Epub 2024 Jun 22. No abstract available.
PubMed 38914204
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Non-Inferiority Clinical Trial of Doxycyline Vs BPG for Early Syphilis
- ClinicalTrials.gov ID
- NCT04838717
- Acronym / sponsor ID
- SY-DOXY / APHP180588
- Conditions
- Syphilis
- Keywords
- early syphilis, Doxycycline, Benzathine benzyl penicillin G
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 200 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Study start
- 6 Dec 2021 (actual)
- Primary completion
- 23 Jul 2025 (actual)
- Study completion
- 23 Jul 2025 (actual)
- First posted
- 9 Apr 2021 (actual)
- 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.
According to European and US Centers for Disease Control and Prevention (CDC) guidelines, the recommended treatment for uncomplicated early syphilis in adults (i.e. primary, secondary and early latent) is a single intramuscular injection of 2.4 million units of benzathine benzylpenicillin G (BPG). Recent reviews have also recommended BPG as the first-line treatment of early syphilis, reporting a success rate of more than 90% over a large panel of studies. This form of the drug provides weeks of treponemicidal levels of penicillin in the blood, but does not efficiently cross the blood-brain barrier.
However, despite the use of BPG for almost 70 years and its status as the gold standard treatment for early syphilis, the need to administer this antibiotic parenterally has led to the use of second-line oral antibiotics, including firstgeneration macrolides, and then second-generation macrolides, such as azithromycin. Several African studies have shown 1 g azithromycin bid treatment for one day to be effective against early syphilis, but most authors agree that azithromycin should not generally be used as resistance to this macrolide is highly prevalent in Western countries. Moreover, a recent study by our group showed that more than 80% of the treponemal strains isolated in France harbor the mutation conferring resistance to azithromycin. The use of this alternative would, therefore, be highly unlikely to be effective in France. Tetracycline antibiotics have also been proposed as an alternative in patients with a contraindication for BPG or other forms of penicillin. Doxycycline, at a dose of 100 mg orally twice daily for 14 days, has been endorsed as a preferred alternative treatment, but few data are available concerning its efficacy. This issue is crucial, for two main reasons: there has been a recrudescence of early syphilis in most western countries over the last 20 years, increasing the need for BPG, and two periods of BPG shortage were experienced in 2013 and 2017, leading to the use of alternative treatments due to the temporary unavailability of BPG or its limitation to cases in which no other treatment was possible. Data for the manufacturing and distribution of antibiotics are not publicly available, but reports of limited availability, shortages, and price increases for old antibiotics suggest that the current system is too fragile to provide what should be a given in modern medicine: access to effective treatment for common and potentially severe bacterial infections. The recurrence of BPG shortages over the last five years has created an urgent need to demonstrate that doxycycline is safe, or at least as safe as BPG, for treating early syphilis. The investigators hypothesize that the recommended doxycycline regimen is not inferior to BPG and plan to test this hypothesis in a randomized clinical trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| BPG Arm | Active comparator | Drug: BPG, Drug: DoxycyclineBPG injections will be performed at the participating center |
| Doxycycline Arm | Experimental | Drug: BPG, Drug: DoxycyclineDispensing of Doxycycline 100 mg is carried out at one time at V0 - Inclusion visit. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Patients aged ≥ 18 years
- Patients who, after the nature of the study has been explained to them, and before any protocol-specific procedures are performed, give informed consent in writing, in accordance with local regulatory requirements
- Patients with or without HIV infection and with syphilis infection in the early stages according to CDC criteria (primary syphilis, secondary syphilis and early latent syphilis of less than one year's duration)
- Patients with a positive non-treponemal assay result
- Patients available for participation and follow-up during the 6 months of the study
Key exclusion criteria (13 listed)
- Individuals with a history of known hypersensitivity to doxycycline or any other antibiotic of the tetracycline family, BPG (hypersensitivity to the active substance benzathine benzylpenicillin, to other penicillins, to soy phospholipids, peanuts or any of the excipients in the product ; history of severe immediate hypersensitivity reactions (eg anaphylaxis) to other beta-lactams (examples: cephalosporins, carbapenemes or monobactams), lidocaïne (hypersensitivity to lidocaine hydrochloride, amide-linked local anesthetics, or any of the excipients listed in SPC) and / or any of the excipients of the specialties used in the study
- Patients with a negative non-treponemal assay result
- Patients receiving an anticoagulant therapy
- Individuals with contraindications for either of the study drugs
- Individuals treated with retinoids by general route
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 |
|---|---|---|
| BPGintramuscular injection of 2.4 million units | Drug | BPG Arm, Doxycycline Arm |
| DoxycyclineOral: at a dose of 100 mg bid for 14 days | Drug | BPG Arm, Doxycycline Arm |
Primary outcome
Demonstrate, with a high level of evidence, that doxycycline, administered orally at a dose of 100 mg bid for 14 days, is non-inferior to a single intramuscular injection of 2.4 million IU BPG for the treatment of early syphilis
Time frame: 6 months
Assessed on the basis of a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6 (commonly used to define cure in real-life settings) or a subsequent negative result in the non-treponemal test if the original test gave a results of 1/2 at inclusion.
4 secondary outcomes
Evaluate tolerance to the two regimens in terms of severe adverse events (SAEs)
Time frame: 6 months
Evaluate adherence to the doxycycline regimen
Time frame: 6 months
Evaluate the impact of the two regimens on other STDs at month 6
Time frame: 6 months
demonstrate that doxycycline is non-inferior to a single intramuscular injection of BPG in titer in the non-treponemal assay (VDRL or RPR)
Time frame: 3 months
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 20 Nov 2025.
- Derived from this study: PubMed 38914204Sagut P, Khamdan F, Al Awadhi A, Hua-Liang Lim J, Chosidow O, Elston DM. Dermatology images: Syphilis. J Am Acad Dermatol. 2024 Oct;91(4):774-779. doi: 10.1016/j.jaad.2024.06.039. Epub 2024 Jun 22. No abstract available.
- Individual participant dataSharing planned: No
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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.
Nicolas DUPIN, PhD & MD principal investigator
APHP Assistance Publique des Hôpitaux de Paris
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing BPG and Doxycycline in people with Syphilis, run by Assistance Publique - Hôpitaux de Paris at 7 sites in France.
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 13 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 20 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in France. 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?
Demonstrate, with a high level of evidence, that doxycycline, administered orally at a dose of 100 mg bid for 14 days, is non-inferior to a single intramuscular injection of 2.4 million IU BPG for the treatment of early syphilis (time frame: 6 months). 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 NCT04838717, which also lists 1 linked publication.
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 20 Nov 2025.