A Phase 1B Dose Range Finding Study of Phenserine Compared to Donepezil in Participants with Early or Mild Alzheimer’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Stavanger HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

11 Feb 2025 → 8 Dec 2025

Decision date (initial)

2024-12-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Efficacy, Pharmacokinetic, Safety

To assess the effects of phenserine compared to donepezil on exosome biomarkers of cell death in people with early or mild Alzheimer`s Disease

Secondary objectives 7

1. To evaluate the safety and tolerability profile of phenserine at ascending doses up to 15 mg qds as compared to donepezil at doses up to 10 mg od in participants with early or mild AD.
2. To evaluate steady state blood levels of phenserine and donepezil for the purpose of characterizing and comparing dose-response relationships for pharmacodynamic outcomes and key safety assessments.
3. To evaluate 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.
4. To evaluate compliance, the study will measure the extent to which participants take the study medication according to the protocol. Compliance will be assessed using the subject diary and the registration of returned capsules.
5. To evaluate disease modification by assessing changes in specific biomarkers of Alzheimer's Disease (AD) in cerebrospinal fluid (CSF): Aβ1-40, Aβ1-42, Tau, and p-tau, and in blood plasma: p-tau217 and Nfl.
6. To assess phenserine’s potential short-term effects on specific cognitive tasks using the FLAME Memory Composite and other cognitive sub-tests
7. To assess effect on global cognition

Conditions and MedDRA coding

Mild Cognitive Impairment

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. A diagnosis of AD based on the most recent NIA-AA diagnostic criteria for AD
2. 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]).
3. 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)
4. An MRI scan within the past two years that has no findings inconsistent with AD.
5. 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.
6. Capacity to give informed consent based on the clinical judgement of an experienced clinician.
7. 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.
8. Age ≥50 years.
9. Fluency in Norwegian and evidence of adequate premorbid intellectual functioning
10. Capable of participating in all scheduled evaluations and complete all required tests.
11. 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 13

1. 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.
2. Current treatment with a cholinesterase inhibitor or memantine.
3. Hypersensitivity to AChE inhibitors or related compounds: Known hypersensitivity to donepezil, piperidine derivatives, or any formulation components
4. 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.
5. Active peptic ulcer disease or gastrointestinal bleeding, or a history of gastrointestinal ulcers or bleeding.
6. Severe cardiac conditions: Significant arrhythmias, sick sinus syndrome, supraventricular conduction abnormalities, or other cardiac rhythm disorders that could pose a risk with cholinesterase inhibitors.
7. Severe respiratory disease: Chronic obstructive pulmonary disease (COPD) or poorly controlled asthma.
8. History of urinary obstruction or bladder issues, particularly those requiring catheterization.
9. Current clinically significant depression or other mental disorders likely to affect cognition or interfere with study participation.
10. 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.
11. Current participation in any other drug trial(s).
12. 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
13. Any current or past neurological disease unrelated to AD and with cognitive sequelae.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Changes in exosome biomarkers of pre-programmed cell death, synaptic integrity and function, neuroinflammation, and AD-related protein trafficking in participants treated with phenserine versus those treated with donepezil.

Secondary endpoints 7

1. Safety and tolerability of phenserine compared to donepezil in participants with early or mild AD based on the frequencies of reported or observed adverse events (AEs) and serious adverse events (SAE), vital signs, clinical laboratory evaluations, ECGs, modified CSSRS scores.
2. Pharmacokinetic parameters will be assessed at steady state for determination of dose-response relationships for phenserine and donepezil
3. Proportion of participants in the phenserine arm achieving the target cholinesterase inhibition of ~45%, stratified by dosing regimen and the time to reach the target inhibition and the duration of maintaining this target will be assessed and recorded
4. Compliance will be recorded, including the proportion of participants complying with the treatment schedule. Compliance is defined as drug intake within 80-120% of the scheduled dosing.
5. Assess changes in Alzheimer's Disease (AD) biomarkers in cerebrospinal fluid (CSF): Aβ1-40, Aβ1-42, Tau, and p-tau, and in blood plasma: p-tau217 and Nfl.
6. Neuropsychology assessments will be conducted using the FLAME computer-based domain composites for memory, executive function, attention and sustained attention to evaluate changes over the 8-week treatment period in the phenserine treated participants compared to those who received donepezil.
7. The Montreal Cognitive Assessment (MoCA) will be administered at baseline and at the end of the study to evaluate changes in overall cognitive function across multiple domains, including visuospatial abilities, language, attention, memory, and executive function.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Stavanger HF

Sponsor organisation

Helse Stavanger HF

Address

Gerd-Ragna Bloch Thorsens Gate 8

City

Stavanger

Postcode

4011

Country

Norway

Scientific contact point

Organisation

Helse Stavanger HF

Contact name

Dag Aarsland

Public contact point

Organisation

Helse Stavanger HF

Contact name

Dag Aarsland

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications