Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Abacavir Sulfate, Lamivudine, and Dolutegravir Sodium in Amyotrophic Lateral Sclerosis

The primary objective of this study is to evaluate the **efficacy** of Triumeq compared to placebo on overall survival in participants with **Amyotrophic Lateral Sclerosis (ALS)**. This is defined as death from any cause, assessed at 24 months or after a minimum of 212 events. The clinical relevance of this objective lies in its potential to extend survival in ALS, a progressive neurodegenerative disease with limited treatment options.

Secondary objectives include:

• Assessing the effect of Triumeq versus placebo on a combined assessment of survival and measures of daily functioning (CAFS).
• Evaluating the impact on measures of daily functioning.
• Investigating the effect on respiratory function.
• Examining changes in plasma creatinine levels.
• Determining the time to reach advanced disease stages.
• Evaluating the safety and tolerability of Triumeq administered orally to participants with ALS.
• Assessing changes in cognitive functioning and quality of life.
• Collecting research blood and urine samples for post-trial explanatory analyses, including markers such as urinary P75ECD, plasma neurofilament light and heavy chain, HERV-K, and genotyping.

The clinical trial involves a total of **300 participants** diagnosed with **amyotrophic lateral sclerosis** (ALS). The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific criteria, including a confirmed diagnosis of ALS according to the Gold Coast Criteria and the ability to provide informed consent. Lifestyle considerations include the requirement for participants taking taurursodiol supplements to discontinue use if they contain sodium phenylbutyrate, and those on Riluzole must have a stable dose or have ceased use prior to the baseline visit. Women of childbearing potential must adhere to strict contraceptive measures and undergo pregnancy testing. The trial does not impose specific restrictions on diet or physical activity, but participants must manage their intake of antacids around the administration of the study medication. The selection process ensures a representative sample of the ALS population, focusing on individuals capable of complying with trial procedures.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 3 study designed to evaluate the efficacy of Triumeq in patients with **amyotrophic lateral sclerosis** (ALS). The primary objective is to assess the impact of Triumeq on overall survival, defined as death from any cause, over a period of 24 months or until a minimum of 212 events occur. The trial involves the administration of Triumeq 50 mg/600 mg/300 mg film-coated tablets, with a placebo group receiving capsules that match the appearance and taste of crushed Triumeq tablets. The trial is expected to conclude by September 2026, with recruitment having commenced in March 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ALS according to the Gold Coast Criteria, and the ability to provide informed consent. The baseline visit will follow, where participants will be randomized to receive either the active treatment or placebo. Follow-up visits will be scheduled at regular intervals to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments of daily functioning, respiratory function, plasma creatinine levels, and clinical disease stage, among other parameters. The end-of-study visit will mark the conclusion of the participant's involvement, where final evaluations will be conducted.

The expected length of participant involvement is up to 24 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The study will ensure that all participants are informed of the potential risks and benefits, and that they comply with the trial procedures, including the use of effective contraception for women of childbearing potential. The trial will adhere to rigorous safety assessments, including physical examinations, laboratory evaluations, and monitoring of adverse events, to ensure the well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Triumeq**, a combination medication consisting of **abacavir sulfate**, **lamivudine**, and **dolutegravir sodium**. Triumeq is provided in the form of film-coated tablets, with each tablet containing 50 mg of dolutegravir sodium, 600 mg of abacavir sulfate, and 300 mg of lamivudine. The medication is administered orally, with a maximum daily dose of one tablet. The treatment period extends up to 24 months. The tablets are manufactured by VIIV Healthcare B.V. and are authorized under the marketing authorization number EU/1/14/940/001. The trial aims to evaluate the efficacy of Triumeq in participants with **amyotrophic lateral sclerosis** (ALS).

The study also includes a placebo control group. The placebo capsules are designed to match the appearance and taste of crushed Triumeq tablets, ensuring blinding in the trial. The placebo is administered orally, following the same dosing schedule as the active treatment, with a maximum daily dose of one capsule. The placebo serves as a comparator to assess the efficacy of Triumeq in improving overall survival in ALS patients. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of Triumeq in the treatment of **Amyotrophic Lateral Sclerosis (ALS)** will be assessed through a randomized, double-blind, placebo-controlled Phase 3 trial. The primary endpoint for evaluating efficacy is overall survival, defined as the time to mortality from any cause. This will be measured over a period of 24 months or after a minimum of 212 events. Secondary endpoints include a combined assessment of survival and daily functioning using the ALSFRS-R(30) total score, respiratory function measured by vital capacity (% predicted of normal according to the GLI-2012 reference standard), plasma creatinine levels, and clinical disease stage as defined by the King’s Staging Scale and the ALS Milano-Torino staging systems (MITOS, derived from ALSFRS-R(30)).

Additional secondary endpoints involve safety assessments, including physical examinations, clinical laboratory evaluations, vital signs, and the frequency of adverse events (AEs) or serious adverse events (SAEs). Tolerability will be assessed by study medication discontinuation rates. Cognitive function will be evaluated using the total scores on the ECAS(32), and quality of life will be measured using the Visual Analogue Scale and EQ-5D-5L(35). Laboratory parameters such as urine P75ECD, plasma neurofilament light and heavy chain, HERV-K expression, and genotyping (UNC13a / C9orf72) will also be analyzed. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to ensure comprehensive assessment of the treatment's impact on ALS.