Phase 1B Dose Range Study of (-)-Phenserine Tartrate vs. Donepezil Hydrochloride in Early or Mild Alzheimer's Disease and Mild Cognitive Impairment
- Trial ID
- 2023-510282-10-00
- Sponsor
- Helse Stavanger HF
Trial statistics
Diseases & Conditions
Objectives
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 Alzheimer's disease. This is clinically relevant as it may provide insights into the potential neuroprotective effects of phenserine, which could influence treatment strategies for Alzheimer's disease.
Secondary objectives include:
- Evaluating the safety and tolerability profile of phenserine at ascending doses up to 15 mg qds compared to donepezil at doses up to 10 mg od in participants with early or mild Alzheimer's disease.
- Assessing steady state blood levels of phenserine and donepezil to characterize and compare dose-response relationships for pharmacodynamic outcomes and key safety assessments.
- Evaluating the proportion of participants in the phenserine arm who achieve the target cholinesterase inhibition of approximately 45% across different dosing regimens, as well as the time required to reach the target and the duration of maintaining this inhibition.
- Measuring compliance by assessing the extent to which participants take the study medication according to the protocol, using the subject diary and the registration of returned capsules.
- Evaluating disease modification by assessing changes in specific biomarkers of Alzheimer's disease in cerebrospinal fluid (CSF): Aβ1-40, Aβ1-42, Tau, and p-tau, and in blood plasma: p-tau217 and Nfl.
- Assessing phenserine’s potential short-term effects on specific cognitive tasks using the FLAME Memory Composite and other cognitive sub-tests.
- Assessing the effect on global cognition.
Participants
The clinical trial involves participants diagnosed with **Mild Cognitive Impairment** or **Alzheimer's disease**, focusing on individuals aged 50 years and older. Both male and female subjects are included in the study, with no specific vulnerable populations being targeted. The trial population was selected based on their ability to participate in all scheduled evaluations and complete all required tests, as well as their capacity to provide informed consent. Participants must have a significant change on a validated Alzheimer's disease amyloid or tau biomarker and must be fluent in Norwegian with evidence of adequate premorbid intellectual functioning. Additionally, participants are required to have an MRI scan within the past two years showing no findings inconsistent with Alzheimer's disease. The sponsor has not provided information regarding the total number of participants in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the effects of **phenserine** compared to **donepezil** in participants with early or mild **Alzheimer's disease**. The primary objective is to assess changes in exosome biomarkers of cell death, synaptic integrity, and function. The trial will also evaluate the safety and tolerability of phenserine compared to donepezil, along with pharmacokinetic parameters and compliance with the treatment schedule. The trial is expected to commence on January 1, 2025, and conclude by December 31, 2025, with an estimated duration of 8 to 10 weeks for each participant, depending on the treatment arm.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Alzheimer's disease, age of 50 years or older, and fluency in Norwegian. The screening will also ensure participants have undergone a recent MRI scan and have not been treated with certain medications within four weeks prior to the study. Following the screening, participants will be randomized to receive either phenserine or donepezil, administered orally in capsule or film-coated tablet form, respectively.
Throughout the trial, participants will attend regular follow-up visits to monitor safety, tolerability, and efficacy. These visits will include assessments of vital signs, clinical laboratory evaluations, ECGs, and neuropsychological assessments using the FLAME computer-based domain composites and the Montreal Cognitive Assessment (MoCA). The primary endpoint will focus on changes in exosome biomarkers, while secondary endpoints will include safety profiles, pharmacokinetic assessments, and changes in Alzheimer's disease biomarkers in cerebrospinal fluid and blood plasma.
The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate overall cognitive function and treatment compliance. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the treatment regimen, or withdraw consent. The trial aims to provide valuable insights into the comparative effects of phenserine and donepezil, potentially informing future therapeutic strategies for Alzheimer's disease.
Treatment
The clinical trial involves the administration of **ARICEPT 10 mg film-coated tablets**, which contain the active substance **donepezil hydrochloride**. This pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 560 mg over a treatment period of up to 10 weeks. The product is manufactured by EISAI LTD and is authorized for use in the United Kingdom. The role of this medication in the trial is as a comparator treatment.
Another comparator treatment used in the study is **ARICEPT 5 mg film-coated tablets**, also containing **donepezil hydrochloride**. Similar to the 10 mg formulation, this medication is administered orally in the form of a film-coated tablet. The maximum daily dose is 10 mg, with a total maximum dose of 560 mg over a treatment period of up to 10 weeks. This product is also manufactured by EISAI LTD and authorized for use in the United Kingdom.
The experimental medication in this trial is **Phenserine tartrate**, which is provided in capsule form. The active substance is **(-)-phenserine tartrate**, and the medication is administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 1260 mg over a treatment period of up to 8 weeks. This product is manufactured by HELSE STAVANGER and is classified as an acetylcholinesterase inhibitor and neuroprotective agent. The role of phenserine tartrate in the trial is as the test treatment.
Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to assess the effects of phenserine compared to donepezil on exosome biomarkers of cell death in individuals with early or mild Alzheimer's disease.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating changes in exosome biomarkers related to pre-programmed cell death, synaptic integrity and function, neuroinflammation, and Alzheimer's Disease (AD)-related protein trafficking. These primary endpoints will be measured in participants treated with **phenserine** compared to those treated with donepezil. Secondary endpoints include the assessment of safety and tolerability based on the frequency of adverse events, pharmacokinetic parameters at steady state, and the proportion of participants achieving target cholinesterase inhibition. Additionally, changes in AD biomarkers in cerebrospinal fluid and blood plasma will be evaluated, alongside neuropsychological assessments using the FLAME computer-based domain composites and the Montreal Cognitive Assessment (MoCA) to evaluate cognitive function changes over the treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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]).
- MCI (FDA stage 3) or mild dementia (FDA stage 4) based on a CDR Global rating of 0.5 (MCI) or 1.0 (mild dementia)
- 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 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.
- Females of childbearing potential and males must commit to use highly effective methods of birth control from signing informed consent form until at least 30 days after last administration of phenserine or donepezil.
Exclusion Criteria
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Norway | Not Recruiting | 01 Jan 2025 | 16 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ARICEPT 10 mg film coated tablets | Comparator | FILM COATED TABLETS | ORAL | 10 | 10 | PRD684135 |
ARICEPT 5 mg film coated tablets | Comparator | FILM COATED TABLETS | ORAL | 10 | 10 | PRD684134 |
Phenserine tartrate | Test | CAPSULE | ORAL | 30 | 8 | PRD11543288 |
Phenserine tartrate | Test | CAPSULE | ORAL | 30 | 8 | PRD11543289 |