An Operationally Seamless Phase 2/3 Randomized, Open-label, Multicenter, Active-Controlled Study to Evaluate the Safety and Efficacy of Bictegravir/Lenacapavir Versus Stable Baseline Regimen in Virologically Suppressed People With HIV-1 on Stable Complex Treatment Regimens

The primary objective of this study is to evaluate the **efficacy** of switching to a bictegravir (BIC) + lenacapavir (LEN) regimen versus continuing on a stable baseline regimen (SBR) in virologically suppressed individuals with Human Immunodeficiency Virus (HIV-1) infection. This is determined by the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 24 in Phase 2 and at Week 48 in Phase 3. The clinical relevance of this objective lies in its potential to offer a simplified and effective treatment option for individuals who are currently on complex treatment regimens, thereby improving adherence and long-term health outcomes.

Secondary objectives include:

• Phase 2: Evaluating the efficacy of three treatment regimens in virologically suppressed individuals with HIV-1, as determined by viral load suppression rate and CD4 cell count at Week 24.
• Evaluating the safety and tolerability of the three treatment groups through Week 24.
• Assessing the pharmacokinetics of BIC and LEN for participants receiving BIC 75 mg + LEN 25 mg and BIC 75 mg + LEN 50 mg.
• Phase 3: Evaluating the efficacy of two treatment groups in virologically suppressed individuals with HIV-1, as determined by viral load suppression rate and CD4 cell count at Week 48.
• Evaluating the efficacy of BIC/LEN in participants from Treatment Group 1, as determined by viral load suppression rate and CD4 cell count at Week 96.
• Evaluating the safety and tolerability of the two treatment groups through Week 48.
• Evaluating the safety and tolerability of BIC/LEN in participants from Treatment Group 1 through Week 96.

The clinical trial involves a total of **541 participants** diagnosed with **Human Immunodeficiency Virus (HIV-1) infection**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their virologically suppressed status, having documented plasma HIV-1 RNA levels of less than 50 copies/mL during treatment with their baseline regimen for a minimum of six months prior to the screening visit. The trial includes individuals currently on a complex antiretroviral regimen due to previous viral resistance, intolerance, or contraindication to existing single-tablet regimens. Participants must not have documented or suspected resistance to bictegravir and must have an estimated glomerular filtration rate of at least 15 mL/min according to the Cockcroft-Gault formula, provided they are not on renal replacement therapy. The trial population also includes vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics.

The clinical trial is designed to evaluate the **efficacy** and safety of a regimen involving **bictegravir** and **lenacapavir** in individuals with **Human Immunodeficiency Virus (HIV-1) infection** who are virologically suppressed on complex treatment regimens. This study is structured as a Phase 2/3, randomized, open-label, multicenter, active-controlled trial. The trial will assess the proportion of participants with HIV-1 RNA levels ≥ 50 copies/mL at specified weeks, using the US FDA-defined snapshot algorithm as a primary endpoint. The trial is expected to commence recruitment on February 1, 2024, and conclude by November 3, 2028.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as documented plasma HIV-1 RNA levels < 50 copies/mL for at least six months prior to screening. Following randomization, participants will attend follow-up visits at regular intervals to monitor virological response, safety, and any treatment-emergent adverse events. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

The expected duration of participant involvement in the trial is up to 48 weeks, with the possibility of extension for some participants in Phase 3. Conditions that may lead to early termination from the study include the development of resistance to **bictegravir**, significant adverse events, or withdrawal of consent. The trial will utilize **film-coated tablets** containing the active substances, administered orally, with dosing regimens tailored to the specific phase and treatment group. The trial aims to provide valuable insights into the potential benefits of switching to a **bictegravir/lenacapavir** regimen in maintaining virological suppression in individuals with HIV-1.

The clinical trial involves the administration of several investigational medicinal products, primarily focusing on **lenacapavir sodium** and **bictegravir**. The first experimental medication is GS-6207 tablets, available in two dosages: 25 mg and 50 mg. These are film-coated tablets containing **lenacapavir sodium** as the active substance, manufactured by Gilead Sciences Inc. The tablets are administered orally, with a maximum daily dose of 25 mg for the 25 mg tablets and 50 mg for the 50 mg tablets. The maximum treatment period for both dosages is 24 weeks. The total maximum dose for the 25 mg tablets is 4200 mg, while for the 50 mg tablets, it is 8400 mg.

Another investigational product is GS-9883 tablets, which contain **bictegravir** as the active ingredient. These are also film-coated tablets, with a dosage of 75 mg per tablet. The administration route is oral, with a maximum daily dose of 75 mg and a total maximum dose of 12600 mg over a 24-week treatment period. This product is also developed by Gilead Sciences Inc.

The study also includes a fixed-dose combination (FDC) tablet containing both **bictegravir** and **lenacapavir**. This combination is presented as film-coated tablets, with the treatment period extending up to 48 weeks. The specific dosing schedule for this FDC is not detailed in the provided data.

Additionally, Sunlenca 300 mg film-coated tablets are part of the trial, containing **lenacapavir** as the active substance. These tablets are administered orally, with a maximum daily dose of 600 mg and a total maximum dose of 1200 mg over a 2-week treatment period. This product is manufactured by Gilead Sciences Ireland UC.

As a comparator treatment, the trial includes the use of direct-acting antivirals, classified under the ATC code J05A. These are administered orally, with a maximum daily dose of 2000 mg and a total maximum dose of 33600 mg over a 24-week period. The specific formulation and active substances for this comparator are not detailed in the provided data.

All investigational products are of chemical origin, and participant compliance with the dosing schedule is monitored throughout the trial. The trial aims to evaluate the efficacy and safety of switching to a regimen involving **bictegravir** and **lenacapavir** in virologically suppressed individuals with HIV-1, compared to continuing on a stable baseline regimen.

The efficacy of the clinical trial will be assessed by evaluating the proportion of participants with **HIV-1** RNA levels ≥ 50 copies/mL at specified timepoints. In Phase 2, the primary endpoint is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 24, while in Phase 3, it is assessed at Week 48. These assessments will be conducted using the United States Food and Drug Administration (FDA)-defined snapshot algorithm.

Secondary endpoints include the proportion of participants with HIV-1 RNA < 50 copies/mL at Weeks 24 and 48, as well as changes from baseline in CD4 cell count at these timepoints. Additionally, the trial will monitor the proportion of participants experiencing treatment-emergent adverse events (AEs) through Weeks 24 and 48. Pharmacokinetic parameters such as Cmax, AUCtau, and Ctau for bictegravir (BIC) and lenacapavir (LEN) will also be evaluated.

For participants in Treatment Group 1, further assessments will be conducted at Week 96, including the proportion with HIV-1 RNA ≥ 50 copies/mL, changes in CD4 cell count, and the incidence of treatment-emergent AEs. These efficacy parameters will be measured and analyzed at the specified timepoints to determine the effectiveness of the bictegravir/lenacapavir regimen compared to the stable baseline regimen in virologically suppressed individuals with HIV-1.