A Randomized Non-Inferiority Trial of Doxycycline Monohydrate Versus Benzathine Benzylpenicillin for the Treatment of Early Syphilis

The primary objective of this study is to demonstrate that **doxycycline** 100 mg administered twice daily for 14 days is non-inferior to a single intramuscular injection of 2.4 million IU of **benzathine benzylpenicillin** (BPG) for the treatment of early **syphilis**. This is evaluated by achieving a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6, which is a widely accepted definition of cure in clinical practice. The clinical relevance of this objective lies in providing an alternative oral treatment option for early syphilis, which could enhance patient compliance and accessibility.

Secondary objectives include:

• Evaluating the tolerance of the two regimens in terms of severe adverse events (SAEs).
• Assessing adherence to the doxycycline regimen.
• Evaluating the impact of the two regimens on other sexually transmitted diseases at month 6.
• Demonstrating that doxycycline is non-inferior to a single intramuscular injection of BPG in titer in the non-treponemal assay (VDRL or RPR) at month 3.

The clinical trial focuses on the treatment of **early syphilis** and includes both male and female participants. The study population comprises adults aged 18 years and older, with no specific mention of an upper age limit. Participants are required to have a positive non-treponemal assay result and must be available for participation and follow-up over a six-month period. The trial does not include a vulnerable population, and participants may have or not have HIV infection. All participants must be covered by the French health insurance system. The sponsor has not provided information regarding the total number of participants in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, non-inferiority study comparing the efficacy of **doxycycline** and benzathine benzylpenicillin (BPG) in the treatment of early syphilis. The trial will involve adult participants aged 18 years and older, who have been diagnosed with early syphilis, including primary, secondary, and early latent stages, as per CDC criteria. The study aims to demonstrate that a 14-day course of 100 mg doxycycline taken orally twice daily is non-inferior to a single intramuscular injection of 2.4 million IU of BPG. The primary endpoint is defined as a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6, which is a widely accepted measure of cure.

The trial will be conducted over an estimated duration from December 2021 to June 2026, with participant involvement lasting approximately six months. The study will include an initial screening visit to confirm eligibility, followed by randomization into one of the two treatment arms. Participants will undergo regular follow-up visits to monitor treatment adherence, particularly for those in the doxycycline group, where adherence will be assessed through tablet counts between weeks 1 and 2. Additional follow-up visits will occur at month 3 and month 6 to evaluate the secondary endpoints, including the occurrence of serious adverse events (SAEs), other sexually transmitted diseases (STDs), and changes in non-treponemal assay titers.

The end-of-study visit at month 6 will conclude the participant's involvement, provided there are no conditions necessitating early termination, such as withdrawal of consent or significant protocol deviations. Participants must be available for the entire study duration and covered by the French health insurance system. The trial is not categorized as low intervention and is conducted under Phase 3, with the investigational medicinal product used outside its marketing authorization. The study is conducted in compliance with local regulatory requirements, ensuring informed consent is obtained from all participants prior to any protocol-specific procedures.

The clinical trial involves the administration of **DOXYCYCLINE SANDOZ 100 mg**, a **tablet** formulation containing the active substance **doxycycline monohydrate**. This medication is administered orally at a dosage of 100 mg twice daily (bid) for a maximum treatment period of 14 days. The total maximum daily dose is 200 mg, with a cumulative maximum dose of 2800 mg over the treatment period. The medication is produced by SANDOZ and is classified under the ATC code J01AA02. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The comparator treatment in the study is **EXTENCILLINE 2.4 MUI**, a **suspension for injection** containing the active substance **benzathine benzylpenicillin**. This medication is administered as a single intramuscular injection with a dosage of 2.4 million international units (MUI). The administration is performed once, with no further doses required, and the total maximum dose is 2.4 MUI. This product is manufactured by LABORATOIRES DELBERT and is classified under the ATC code J01CE08. The administration of this treatment will be conducted under controlled conditions to ensure accurate delivery of the dose.

Both treatments are chemical in origin and have been authorized for use in the trial. The study aims to evaluate the non-inferiority of doxycycline compared to benzathine benzylpenicillin for the treatment of early syphilis, with the primary outcome being a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6. Compliance and administration accuracy will be closely monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed by evaluating the treatment outcomes of **early syphilis** using specific endpoints. The primary endpoint is defined as a four-fold decrease in titer in the non-treponemal assay (VDRL or RPR) at month 6, compared to the baseline results obtained before treatment. This endpoint is a widely accepted measure of cure in real-life settings. The assays will be conducted in the same laboratory to ensure consistency and accuracy in the results.

Secondary endpoints include the occurrence of serious adverse events (SAEs) in both treatment groups, adherence to doxycycline as measured by a tablet count between weeks 1 and 2 during planned visits, the occurrence of other sexually transmitted diseases (STDs) in the two groups at month 6, and the evolution of the titer obtained in the non-treponemal assay at month 3. These secondary endpoints will provide additional insights into the safety and effectiveness of the treatments being compared.