Phase 2a Randomized, Double-Blind, Placebo-Controlled Study of N-Acetylcysteine Amide in Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease

The primary objective of this study is to evaluate the **safety** and **tolerability** of NPI-001 (AT-001) when administered orally to patients with **Alzheimer's Disease** (AD). This is clinically relevant as ensuring the safety and tolerability of a therapeutic agent is crucial before considering its efficacy in a broader patient population. Additionally, the study will utilize MRI imaging to assess ARIA H and ARIA E in the brain, which are important markers for potential adverse effects related to amyloid-targeting therapies.

Secondary objectives include:

• Assessing biomarker-based efficacy in response to NPI-001, focusing on the reduction of toxic amyloid oligomers in plasma.
• Determining any reduction or reversal of amyloid accumulation in the brain.
• Evaluating the effects of NPI-001 on phospho Tau217 (pTau217) and total Tau (tTau) protein levels in plasma, as well as the pTau/tTau ratio.
• Assessing the effects on neurofilament light chain (NFL) levels in plasma.
• Evaluating the impact of NPI-001 on the cognitive status of patients with AD.
• Characterizing the pharmacokinetic parameters of NPI-001 in a subset of participants.

These secondary objectives aim to provide a comprehensive understanding of the potential therapeutic effects and mechanisms of action of NPI-001 in Alzheimer's Disease, which could inform future clinical applications and therapeutic strategies.

The clinical trial involves participants diagnosed with **Alzheimer's Disease**, specifically those with mild cognitive impairment (MCI) or mild dementia due to the condition. The study population includes both male and female subjects aged between 50 and 84 years. Participants are required to have a Clinical Dementia Rating (CDR) of 0.5 or 1.0 and must be receiving standard care for Alzheimer's Disease. The trial does not involve a vulnerable population. Participants must be willing to undergo baseline and follow-up blood tests, MRI, and amyloid PET scan evaluations of the brain. They should also have a spouse, close relative, or caregiver as a study partner who lives with or supervises their care. The **Mini-Mental State Examination (MMSE)** score for participants should be greater than 21 and less than 28. Additionally, participants must be on stable doses of any concomitant medications for at least three months prior to screening, with the expectation that these doses will remain stable throughout the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety, tolerability, and biomarker-based efficacy of NPI-001 (AT-001) in subjects with **Alzheimer's Disease**. The trial will involve participants aged 50 to 85 years who have mild cognitive impairment or mild dementia due to Alzheimer's disease. The study will be conducted over an estimated duration of 12 months, with the recruitment phase expected to start in April 2025 and conclude by October 2026.

Participants will be randomly assigned to receive either the active treatment, **acetylcysteine amide**, or a placebo, both administered orally in tablet form. The maximum daily dose of the active treatment is 1500 mg. The trial will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits at 3, 6, 9, and 12 months to monitor safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the 12-month treatment period.

The primary endpoints of the study include the assessment of treatment-emergent adverse events, serious adverse events, and changes in clinical laboratory values, electrocardiograms, physical examinations, and vital signs. Secondary endpoints focus on the reduction of toxic amyloid oligomers, amyloid accumulation in the brain, and changes in neuropsychological test scores. Participants will also undergo MRI and amyloid PET scans to evaluate changes in brain structure and function.

Participant involvement is expected to last for the entire 12-month duration of the study unless early termination is warranted. Conditions that may lead to early withdrawal include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent. The study aims to provide valuable insights into the potential therapeutic benefits of NPI-001 in managing Alzheimer's disease.

The clinical trial involves the administration of **N-acetylcysteine amide** (NPI-001), an experimental medication formulated as a tablet. This compound is chemically derived and is provided by Arctic Therapeutics EHF. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum daily dose is 1500 mg, with a total maximum dose of 1500 mg over a treatment period of up to 12 weeks. The primary objective is to assess the safety and tolerability of NPI-001 in patients with mild cognitive impairment or mild dementia due to Alzheimer's disease. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the treatment regimen.

The study also includes a **placebo** control, which is a white oral tablet containing lactose, micro-crystalline cellulose, croscarmellose sodium, and stearic acid as excipients. The placebo is designed to match the experimental medication in appearance and administration route to maintain the double-blind nature of the trial. The placebo is administered orally, and its use is critical for comparing the effects of the experimental treatment against a non-active substance. Compliance with the placebo regimen is monitored similarly to the experimental treatment to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of **Treatment-Emergent Adverse Events** and Serious Adverse Events, alongside clinical laboratory values, electrocardiogram results, physical examinations, vital signs, and ARIA MRI classification. Secondary endpoints focus on biomarker-based efficacy, including the reduction of toxic amyloid oligomers in plasma samples at 3, 6, 9, and 12 months of therapy, and the reduction of amyloid accumulation in the brain following 12 months of therapy. Additional secondary endpoints involve the reduction of pTau217 and pTau217/tTau ratio, and NFL in plasma samples at specified intervals, as well as changes in neuropsychological assessments such as the Neuropsychological Test Battery (NTB), Clinical Dementia Rating (CDR) Scale, ADAS-Cog, and ADL (ADCS-ADL-MCI) after 12 months of therapy.

Plasma concentrations of NPI-001 will be measured after the first intake on eight occasions up to 24 hours to determine pharmacokinetic parameters such as Cmax, Tmax, and AUC0-24h, along with the apparent T1/2. The Mini Mental State Examination (MMSE) and Columbia Suicide Severity Rating Scale (C-SSRS) will also be used to assess changes following 12 months of therapy. These assessments will be conducted at various timepoints, including baseline and follow-up visits, to ensure comprehensive data collection and analysis of the efficacy of NPI-001 in subjects with Mild Cognitive Impairment (MCI) or mild dementia due to Alzheimer's disease.