Evaluation of Cabotegravir Sodium and Oral Emtricitabine/Tenofovir Disoproxil for HIV Pre-Exposure Prophylaxis in Men Who Have Sex with Men in France

The primary objective of this study is to compare the sustained use of **pre-exposure prophylaxis (PrEP)** over time among participants randomized to receive cabotegravir versus those receiving oral TDF/FTC-based PrEP at Month 12. This objective is clinically relevant as it aims to evaluate the long-term adherence and effectiveness of different PrEP regimens, which is crucial for the prevention of **HIV** in high-risk populations.

Secondary objectives include:

• Comparing sustained PrEP use over time between cabotegravir and oral TDF/FTC-based PrEP at Month 24.
• Describing the causes of non-sustained PrEP use at Months 12 and 24.
• Comparing PrEP coverage of the last reported condomless anal sexual intercourse before study visits at Months 12 and 24.
• Comparing changes from baseline in participant satisfaction with their PrEP regimen at Months 12 and 24.
• Comparing changes from baseline in sexual risk behaviors at Months 12 and 24.
• Comparing the incidence of sexually transmitted infections at Months 12 and 24.
• Comparing changes from baseline in weight, blood pressure, fasting lipid levels, and HOMA index at Months 12 and 24.
• Evaluating the safety of the drug in each study group at Months 12 and 24.
• Evaluating injection site reactions among participants receiving CAB-LA at Months 12 and 24.
• Evaluating fidelity to study visits in each study group at Months 12 and 24.
• Evaluating the proportion of participants who switch their PrEP regimen within each study group at Months 12 and 24.
• Evaluating the time covered by a PrEP prescription in each study group at Months 12 and 24.
• Measuring drug concentrations in each study group at Months 12 and 24.
• Evaluating HIV incidence within each study group at Months 12 and 24.
• Describing antiretroviral drug resistance in participants who acquired HIV during the study at Months 12 and 24.
• Evaluating the use of psychoactive substances within each study group.
• Evaluating the quality of life and mental health within each study group.
• Evaluating PrEP perceptions and knowledge within each study group.
• Evaluating the use of community peer support and patient therapeutic education in each group.
• Conducting ancillary studies on qualitative social science components, rectal tissue HIV-1 permissibility, and medico-economic analysis to further understand the implications of PrEP use.

The clinical trial focuses on **HIV prevention** and involves a study population consisting of cisgender men who have sex with men, aged 18 years and older. The trial does not include female participants and does not target a vulnerable population. Participants were selected based on their previous use of oral TDF/FTC based PrEP within the past six months, either daily or on-demand, with a documented prescription. Additionally, participants must be affiliated with or beneficiaries of a social security scheme as per the Public Health Code. The sponsor has not provided information regarding the total number of participants. The trial aims to compare the sustained use of PrEP over time between those randomized to cabotegravir versus oral TDF/FTC based PrEP at Month 12.

The clinical trial is designed to evaluate the efficacy of **cabotegravir** for HIV prevention in men who have sex with men. This is a randomized, controlled, double-blind trial comparing the long-acting injectable form of cabotegravir with oral TDF/FTC-based pre-exposure prophylaxis (PrEP). The trial aims to assess sustained PrEP use over a 24-month period, with primary endpoints measured at Month 12 and secondary endpoints at Month 24. The trial is expected to commence recruitment in September 2024 and conclude by March 2029.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age, sexual orientation, and previous PrEP use. The inclusion visit will also involve obtaining informed consent. Follow-up visits are scheduled at baseline, 6, 12, 18, and 24 months, with additional visits for those receiving the injectable form of cabotegravir. These visits will include assessments of PrEP adherence, sexual behavior, and health parameters such as weight, blood pressure, and lipid levels. The end-of-study visit will occur at Month 24, where final evaluations will be conducted.

Participant involvement is expected to last up to 24 months, with conditions for early termination including non-compliance with study protocols, adverse events, or withdrawal of consent. The trial will monitor for occurrences of HIV infection, drug resistance, and adverse reactions, ensuring participant safety and data integrity. The study will also collect data on PrEP satisfaction, quality of life, and mental health through self-administered questionnaires. The trial's rigorous design and comprehensive data collection aim to provide valuable insights into the long-term use of cabotegravir for HIV prevention.

The clinical trial involves the administration of **Apretude 30 mg film-coated tablets**, which contain the active substance **cabotegravir sodium**. These tablets are manufactured by VIIV Healthcare B.V. and are administered orally. The dosage is set at 30 mg per day, with a maximum treatment period of one month. The pharmaceutical form is a film-coated tablet, ensuring ease of ingestion and controlled release of the active ingredient. Participant compliance is monitored through regular follow-ups and pill counts to ensure adherence to the dosing schedule.

Another treatment in the trial is **Apretude 600 mg prolonged-release suspension for injection**, also produced by VIIV Healthcare B.V. This formulation contains **cabotegravir** and is administered via intramuscular injection. The dosage is 600 mg, with a maximum treatment period of 24 months. The prolonged-release suspension allows for sustained drug release, reducing the frequency of administration and potentially improving compliance. Participants receive injections at specified intervals, and adherence is monitored through scheduled clinic visits and injection records.

The comparator treatment in the study is **Truvada 200 mg/245 mg film-coated tablets**, containing the active substances **emtricitabine** and **tenofovir disoproxil**. Manufactured by Gilead Sciences Ireland Unlimited Company, these tablets are administered orally. The dosage is 500 mg per day, with a treatment period extending up to 24 months. As a standard-of-care therapy, Truvada serves as a benchmark for evaluating the efficacy of the experimental treatments. Compliance is assessed through regular follow-ups, pill counts, and participant self-reports.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the completion of all protocol visits at Month 12 with a documented pre-exposure prophylaxis (PrEP) prescription of either **cabotegravir** (CAB) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) aligned with the randomization arm. Secondary endpoints include the completion of all protocol visits at Month 24 with a documented PrEP prescription, as well as various measures of PrEP use and adherence over time.

Secondary endpoints will also evaluate the causes of non-sustained PrEP use, such as missing follow-up visits, temporary or permanent PrEP discontinuation, and switching to a different PrEP regimen. Additional assessments will include PrEP coverage of the last condomless anal sexual intercourse, satisfaction with the PrEP regimen, and the number of sexual partners and condomless anal sexual intercourse occurrences, all collected through self-administered questionnaires and study electronic case report forms (eCRFs).

Other secondary endpoints involve the occurrence of sexually transmitted infections, weight, blood pressure, fasting lipid levels, and the Homeostatic Model Assessment (HOMA) index at specified timepoints. The trial will also monitor the occurrence of Grade 2 or higher clinical or laboratory drug-related adverse events, injection site reactions, and participants' perception of pain and injection site reactions. Drug concentrations in plasma and dried blood spots will be measured at various intervals to assess adherence and pharmacokinetics.

Additional assessments include the occurrence of HIV infection, HIV drug resistance mutations, use of psychoactive drugs, quality of life, mental health, PrEP knowledge score, and the use of community peer support and therapeutic patient education. These parameters will be evaluated using validated scales and questionnaires at baseline, 12, and 24 months, ensuring a comprehensive assessment of the trial's efficacy outcomes.