Evaluation of MK-1942 as Adjunctive Therapy in Mild to Moderate Alzheimer's Disease: A Phase 2a/2b Randomized, Placebo-Controlled Study

The primary objective of this clinical study is to assess the **efficacy** of MK-1942 at doses of 5 mg and 15 mg, administered twice daily, as an adjunctive therapy in participants with mild to moderate Alzheimer's disease dementia. This will be evaluated by comparing the change in the ADAS-Cog11 score with that of a placebo at Week 12. Additionally, the study aims to evaluate the safety and tolerability of MK-1942 as an adjunctive therapy. The primary objective is clinically relevant as it seeks to determine the potential cognitive benefits and safety profile of MK-1942, which could contribute to improved management of Alzheimer's disease dementia.

Secondary objectives include: - Assessing the efficacy of MK-1942 at 5 mg and 15 mg bid as adjunctive therapy on the ADCS-CGIC Overall score compared with placebo at Week 12. - Evaluating the efficacy of MK-1942 at 5 mg and 15 mg bid as adjunctive therapy on the ADCS-ADL Total score as compared with placebo at Week 12.

The clinical trial involves a total of **318 participants** diagnosed with mild to moderate Alzheimer's disease (**AD** dementia), as defined by the NINCDS-ADRDA criteria. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants are required to have a Mini-Mental State Examination (MMSE) score between 12 and 22 at screening. All participants are on a stable regimen of acetylcholinesterase inhibitors (AChEI) therapy for the management of AD dementia, which must have been maintained for at least three months prior to the study and remain constant throughout the trial. The selection process ensures that participants have a designated study partner capable of providing comprehensive information about their cognitive and functional status. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted as part of the study criteria.

The clinical trial is a **randomized**, **placebo-controlled** study designed to evaluate the safety and efficacy of MK-1942 as an adjunctive therapy in participants with mild to moderate **Alzheimer's disease** dementia. The trial is structured as a Phase 2a/2b study, with a primary objective to assess the efficacy of MK-1942 at doses of 5 mg and 15 mg twice daily, compared to placebo, based on the Alzheimer's Disease Assessment Scale-11-item cognitive subscale (ADAS-Cog11) score at Week 12. Additionally, the study aims to evaluate the safety and tolerability of MK-1942. The trial is expected to run from November 28, 2022, to May 12, 2026, with participant involvement lasting up to 12 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a Mini-Mental State Examination (MMSE) score between 12-22 and stable use of acetylcholinesterase inhibitors (AChEI) therapy. Following the screening, participants will be randomized to receive either MK-1942 or placebo. Study visits will occur at regular intervals to monitor efficacy and safety, with assessments including the ADAS-Cog11 score and the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) score. The end-of-study visit will conclude the participant's involvement, with final assessments and evaluations conducted.

Participants are expected to remain in the study for the full 12-week duration unless conditions arise that necessitate early termination, such as adverse events or withdrawal of consent. The primary endpoints include changes in the ADAS-Cog11 score and the number of participants experiencing adverse events or discontinuing the study due to adverse events. Secondary endpoints focus on the ADCS-CGIC overall score and changes in the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) total score at Week 12. The trial is conducted under the sponsorship of Merck & Co. Inc., with MK-1942 administered in the form of hard capsules via the oral route.

The clinical trial involves the administration of **MK-1942**, an experimental medication developed by Merck & Co. Inc. The pharmaceutical form of **MK-1942** is a hard capsule, and it is administered orally. The dosage regimen includes a maximum daily dose of 30 mg, with a total maximum dose of 2422 mg over a treatment period of 12 weeks. The active substance, **MK-1942**, is of chemical origin, and the trial aims to evaluate its efficacy and safety as an adjunctive therapy in participants with mild to moderate Alzheimer's Disease Dementia. The medication is not a paediatric formulation and is not classified as an orphan drug.

In addition to the experimental treatment, a placebo is used as a comparator in this study. The placebo is designed to mimic the appearance of the **MK-1942** capsule but contains no active substance. The placebo is administered in the same manner as the experimental drug, ensuring that the study remains double-blind. The use of a placebo allows for a controlled comparison to assess the true efficacy and safety of **MK-1942**.

The efficacy of MK-1942 as an adjunctive therapy in participants with mild to moderate **Alzheimer's Disease** dementia will be assessed using several parameters. The primary endpoint for evaluating efficacy is the change from baseline in the Alzheimer's Disease Assessment Scale-11-item cognitive subscale (ADAS-Cog11) score at Week 12. This scale is a widely recognized tool for measuring cognitive function in Alzheimer's Disease and will be used to determine the cognitive improvements attributable to the treatment. Secondary endpoints include the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) overall score at Week 12 and the change from baseline in the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) total score at Week 12. These endpoints will provide additional insights into the global impression of change and the impact on daily living activities.

The efficacy assessments will be conducted at specified timepoints, with the primary focus on Week 12. The ADAS-Cog11, ADCS-CGIC, and ADCS-ADL scores will be collected and analyzed to evaluate the treatment's impact on cognitive function, global impression, and daily living activities. The trial will also monitor the number of participants experiencing adverse events and those discontinuing the study intervention due to adverse events, providing a comprehensive view of the treatment's safety and tolerability alongside its efficacy.