A Phase 1b Dose Range Finding Study of Phenserine Compared to Donepezil in Participants With Early or Mild Alzheimer's Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Panel 1: Concentration of Biomarkers Associated with Preprogrammed Cell Death (PNCDD)
研究概览
简要总结
The goal of this clinical trial is to evaluate if phenserine can treat early or mild Alzheimer's Disease (AD) by comparing it to donepezil. This study will include participants with early or mild Alzheimer's Disease, and the main questions it aims to answer are:
How does phenserine affect exosome biomarkers of cell death compared to donepezil? What is the safety and tolerability profile of phenserine at ascending oral doses compared to donepezil? Researchers will compare participants receiving phenserine to those receiving donepezil to see if phenserine produces better pharmacodynamic outcomes and if it is safe and well-tolerated.
Participants will:
Be randomized to receive either oral phenserine or oral donepezil for a treatment duration of 8 weeks.
Undergo oral dose escalation based on tolerability. Complete regular follow-up visits every two weeks to assess pharmacodynamic, pharmacokinetic, and safety measures.
详细描述
Participants will be randomized into two groups: one group will receive phenserine, and the other will receive donepezil. The phenserine group will begin with a dosage of 5 mg twice daily, with the dose being gradually increased every two weeks as tolerated with a maximum dose of 10 mg three times daily. The donepezil group will start at 5 mg once daily, with the possibility of escalation to 10 mg once daily at Week 4.
The study is designed to last 8 weeks, with a planned total enrollment of 16 individuals from various centers across Norway. Participants will return for follow-up visits every two weeks, during which pharmacodynamic, pharmacokinetic, and safety assessments will be conducted. The final safety follow-up will occur after the completion of dosing for those who complete the study. Early termination visits will include a comprehensive safety follow-up for those who discontinue the study prematurely.
The primary objective of this study is to assess the effects of phenserine compared to donepezil on exosome biomarkers of cell death in individuals with early or mild AD. Additionally, the study aims to evaluate the safety and tolerability profile of phenserine at ascending doses up to 10 mg three times daily (QDS) in comparison to donepezil at doses up to 10 mg once daily (OD). Furthermore, the study aims to analyze steady-state blood levels of phenserine to characterize and compare dose-response relationships for pharmacodynamic outcomes and key safety assessments. Finally, the study will explore changes in specific biomarkers of Alzheimer's Disease (AD) in cerebrospinal fluid (CSF) and blood plasma, as well as assess phenserine's potential short-term effects on cognition using the FLAME Memory Composite and other cognitive sub-tests.
Participants will be enrolled at six centers across Norway. The study will also be supported by the PROTECT platform, which allows for the recruitment of individuals over 50 years of age who have demonstrated cognitive decline, making them suitable candidates for this study.
The anticipated duration of participation for each patient is 8 weeks, with the overall study expected to be completed within 9 months, accounting for a 6-month enrollment period followed by the treatment phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of AD based on the most recent NIA-AA diagnostic criteria for AD.
- •A significant change on a validated AD amyloid or tau biomarker (as determined either by visual reading of amyloid PET scans [using any of the approved ligands], or CSF Aβ 1-42 or blood p-tau 217 levels [cut-off as determined by the individual laboratory.
- •A CDR Global rating of 0.5 or 1.
- •An MRI scan within the past two years that has no findings inconsistent with AD.
- •Participants who have recently participated in other clinical trials or have been under treatment with memantine or acetylcholinesterase inhibitors (e.g., Donepezil, Rivastigmine, Galantamine) must undergo a washout period of at least 4 weeks prior to the start of the study.
- •Capacity to give informed consent based on the clinical judgement of an experienced clinician.
- •The participant has an individual who is in regular, daily contact via phone or in-person visits and who can act as a reliable study partner and provide meaningful input into rating scales.
- •Age ≥50 years.
- •Fluency in Norwegian and evidence of adequate premorbid intellectual functioning.
- •Capable of participating in all scheduled evaluations and complete all required tests.
- •Female participants must be of non-childbearing potential or have a negative serum pregnancy test up to 24 hours prior to the baseline assessments and agree to use effective birth control throughout their participation in the study from signing informed consent form until at least 30 days after last administration of phenserine or donepezil..
排除标准
- •Significant cerebrovascular disease, as indicated by clinical history, neurological examination, or on MRI (including cortical infarction or deep white matter or periventricular white matter hyperintensities with a Fazekas scale score of 3 (25).
- •Current treatment with a cholinesterase inhibitor or memantine.
- •Hypersensitivity to AChE inhibitors or related compounds: Known hypersensitivity to donepezil, piperidine derivatives, or any formulation components.
- •Participants undergoing or planning procedures requiring anesthesia with depolarizing neuromuscular blockers (e.g., succinylcholine) due to the risk of prolonged paralysis or apnea when combined with AChE inhibitors.
- •Active peptic ulcer disease or gastrointestinal bleeding, or a history of gastrointestinal ulcers or bleeding.
- •Severe cardiac conditions: Significant arrhythmias, sick sinus syndrome, supraventricular conduction abnormalities, or other cardiac rhythm disorders that could pose a risk with cholinesterase inhibitors.
- •Severe respiratory disease: Chronic obstructive pulmonary disease (COPD) or poorly controlled asthma.
- •History of urinary obstruction or bladder issues, particularly those requiring catheterization.
- •Current clinically significant depression or other mental disorders likely to affect cognition or interfere with study participation.
- •Participants using sedating drugs, if unavoidable, will be excluded from the study. However, short-acting sleep medications can be used if taken as recommended and if the participant has maintained a stable regimen for at least 3 months prior to the start of the study.
- •Current participation in any other drug trial(s).
- •Currently ongoing life-threatening disease, such as metastatic cancer, advanced cardiovascular disease, advanced respiratory disease, terminal kidney disease, or advanced stages of an infectious disease.
- •Any current or past neurological disease unrelated to AD and with cognitive sequelae.
研究组 & 干预措施
Phenserine
Phenserine will be formulated as a capsule, with dosages of 5mg and 10mg. Participants randomized to the phenserine arm will start at 5 mg twice daily (bd) with escalations every two weeks, as tolerated to 10 mg bd and to a maximum dose of 10 mg three times daily (tds).
干预措施: Phenserine (Drug)
Donepezil
Participants randomized to the donepezil arm will start at 5 mg tablet once daily (od) with escalation, to 10 mg od from Week 5, as tolerated.
干预措施: Donepezil (Aricept®) (Drug)
结局指标
主要结局
Panel 1: Concentration of Biomarkers Associated with Preprogrammed Cell Death (PNCDD)
时间窗: From enrollment to the end of treatment at 8 weeks.
Quantification of exosome-derived BAX and Bcl-2 markers. This outcome measure will assess changes in biomarkers related to preprogrammed cell death, specifically BAX and Bcl-2. These biomarkers provide insights into apoptotic processes and any alterations observed following treatment with phenserine or donepezil.
Panel 2: Concentration of Synaptic Integrity Biomarkers
时间窗: From enrollment to the end of treatment at 8 weeks.
Measurement of exosome-derived synaptic markers. This outcome measure will evaluate changes in synaptic markers, including synaptotagmin, to provide insights into synaptic integrity and function.
Panel 3: Concentration of TNF-α (Inflammatory Biomarker)
时间窗: From enrollment to the end of treatment at 8 weeks.
Quantification of exosome-derived TNF-α. This outcome measure will assess changes in TNF-α levels (ng/mL), a key inflammatory biomarker.
Panel 3: Concentration of interleukins, IL-1β, IL-6, and IL-10. (Inflammatory Biomarker)
时间窗: From enrollment to the end of treatment at 8 weeks.
Quantification of exosome-derived IL-1β, IL-6, and IL-10.IL-1β (pg/mL). This outcome measure will assess changes in interleukin levels, a key inflammatory biomarker.
Panel 4: Concentration of Exosome-Derived Alzheimer's Disease-Specific Biomarkers
时间窗: From enrollment to the end of treatment at 8 weeks.
Quantification of exosome-derived Aβ1-42. This outcome measure will assess changes in exosome-derived Alzheimer's Disease-specific biomarkers, including Aβ1-42, to elucidate molecular signatures associated with AD pathology.
次要结局
- Calcium (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Glucose (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Creatinine (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Total and Direct Bilirubin (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- C-Reactive Protein (CRP) (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Liver function (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Adverse Events (AEs) and Tolerability Profile(From enrollment to the end of treatment at 8 weeks.)
- Cholinesterase Inhibition Target Achievement(From enrollment to the end of treatment at 8 weeks.)
- Blood Pressure (Safety Assessment)(From enrollment to the end of treatment at 8 weeks)
- Pulse (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Urine Testing (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Blood Urea Nitrogen (BUN) (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Potassium (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Sodium (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Electrocardiogram (ECG) (Safety Assessment)(From enrollment to the end of treatment at 8 weeks.)
- Columbia Suicide Severity Rating Scale (C-SSRS) (Safety Assessment)(At enrollment, week 4 and of treatment at 8 weeks.)
- Maximum Plasma Concentration (Cmax) of Phenserine(Measured at week 2, week 4, week 6 and of treatment at 8 weeks.)
- Half-Life (t1/2) of Phenserine and Donepezil(Measured at week 2, week 4, week 6 and of treatment at 8 weeks.)
- Steady-State Concentration of Phenserine and Donepezil(Measured at week 2, week 4, week 6 and of treatment at 8 weeks.)